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Open AccessReview

Gene Therapy Applications of Non-Human Lentiviral Vectors

Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
Viruses 2020, 12(10), 1106; https://doi.org/10.3390/v12101106
Received: 21 August 2020 / Revised: 23 September 2020 / Accepted: 25 September 2020 / Published: 29 September 2020
(This article belongs to the Special Issue Lentiviral Vectors)

Abstract

Recent commercialization of lentiviral vector (LV)-based cell therapies and successful reports of clinical studies have demonstrated the untapped potential of LVs to treat diseases and benefit patients. LVs hold notable and inherent advantages over other gene transfer agents based on their ability to transduce non-dividing cells, permanently transform target cell genome, and allow stable, long-term transgene expression. LV systems based on non-human lentiviruses are attractive alternatives to conventional HIV-1-based LVs due to their lack of pathogenicity in humans. This article reviews non-human lentiviruses and highlights their unique characteristics regarding virology and molecular biology. The LV systems developed based on these lentiviruses, as well as their successes and shortcomings, are also discussed. As the field of gene therapy is advancing rapidly, the use of LVs uncovers further challenges and possibilities. Advances in virology and an improved understanding of lentiviral biology will aid in the creation of recombinant viral vector variants suitable for translational applications from a variety of lentiviruses.
Keywords: gene therapy; lentivirus; lentiviral vector; HIV-1; SIV; FIV; EIAV; non-primate lentivirus gene therapy; lentivirus; lentiviral vector; HIV-1; SIV; FIV; EIAV; non-primate lentivirus

1. Introduction to Lentiviral Vectors

The field of gene and cell therapy is advancing rapidly with lentiviral-based vectors being the preferred vector of choice due to their ability to infect both dividing and non-dividing cells and integrate transgenes into the host cell genome [1]. Lentiviruses belong to the Orthoretroviridae subfamily of the genus retroviruses and are characterized by their long latent incubation periods with low levels of viral pathogenicity [2].
They are divided into two major classes: primate and non-primate lentiviruses [3]. The primate lentiviruses include human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2) and simian immunodeficiency virus (SIV). The HIV-1 pandemic in the twentieth century and the resulting acquired immune deficiency syndrome (AIDS) instigated extensive research into the virus and uncovered crucial information regarding viral genome organization, replication, and life cycle, paving the way for the generation of HIV-1-based lentiviral vectors (LVs). The prototype virus for the non-primate lentiviruses is the ovine visna-maedi virus (VMV) [4]. Other members include feline immunodeficiency virus (FIV) [5,6], equine infectious anemia virus (EIAV) [7], caprine arthritis encephalitis virus (CAEV) [8], bovine immunodeficiency virus (BIV) [9], and jembrana disease virus (JDV) [10].

1.1. Retroviral Biology

Retroviruses are enveloped RNA viruses containing two copies of a positive-sense single-stranded RNA genome [11]. The hallmark of this family of viruses is the reverse transcription and integration steps [12]. Reverse transcriptase encoded by viral genome transcribes viral RNA to synthesize double-stranded DNA, which is then integrated into the host cell genome by the viral integrase (defined as provirus) [13].
Most retroviruses share similar virion morphology: A nucleocapsid core containing the RNA genome, the capsid surrounding the core containing the three essential enzymes; protease, reverse transcriptase, and integrase, and lastly, the viral envelope that forms spikes protruding from the virion surface [14]. All retroviruses encode three fundamental genes—gag, pol, and env—which are necessary for the formation of the structural proteins mentioned above [15] (Figure 1A). However, complex retroviruses, including lentiviruses, encode other regulatory and accessory genes. HIV-1, the most studied lentivirus, encodes nine genes: gag, pol, env, rev, tat, vpr, vpu, vif, and nef [16] (Figure 1B).

1.2. HIV-1-Based Lentiviral Vectors

Characterization of HIV-1 not only improved our understanding of the virus but also enabled its adaptation for research and various medical applications, including gene therapy. Gene therapy, first intended for the treatment of inherited diseases, currently has the potential to bring curative interventions to many medical fields. In contrast to traditional protein or chemical-based therapies, gene therapy, in principle, allows for ‘one-shot’ curative benefits following the introduction of correct genetic material into the patients. Therefore, optimal vectors are required for the efficient delivery of genomic materials to targets cells. Owing to reverse genetics techniques, researchers have exploited the ability of viruses to modify mammalian cells and converted them into viral vectors. Lentiviruses are especially popular due to their ability to infect both dividing and slow or non-dividing cells (e.g., stem cells, neurons, muscle cells), their capacity to permanently integrate transgenes into the host cell genome, allowing for long-term stable gene expression, and their low-immunogenic characteristics (compared to that of other vectors, such as the ones derived from adenoviruses) [17].
First, replication-competent retroviral vectors were established based on HIV-1, Rous sarcoma virus, and murine leukemia virus through modifications to the viral long terminal repeats (LTRs) or accessory genes to introduce transgenes of interest [18,19,20]. Further improvements resulted in the development of first-generation replication-incompetent LVs through the splitting of viral components into multiple plasmid constructs [21]. The packaging plasmid contained the structural, enzymatic, regulatory, and accessory viral genes, while the heterologous envelope (usually the glycoprotein of vesicular stomatitis virus, VSV.G) was delivered in a separate pseudotyping plasmid. Several cis-acting viral sequences were included in the vector construct to ensure high genome expression during vector production and efficient transduction and integration of vectors (Figure 1C). Long terminal repeats contain identical regions (i.e., U3, R, and U5), which flank the proviral genome, and contain a promoter, enhancer, and polyadenylation motifs, which drive transcription and are vital for reverse transcription [22]. The viral packaging signal, psi (Ψ), is required for packaging of the viral RNA into the virion [23]. In addition, the primer binding site (PBS) and the polypurine tract (PPT) are involved in DNA synthesis during reverse transcription [24].
As researchers started using these initial, or first-generation, LVs for gene therapy applications, the creation of safer vectors became a necessity. Initially, all non-essential accessory genes were removed from the packaging plasmid that was provided in trans during viral vector production (Figure 1D). Currently, in third-generation LVs, only genes encoding structural and enzymatic components (i.e., gag-pol) and the regulatory rev are included (Figure 1E). The LTRs of the viral genome encoding the transgene are substantially modified. While the 5′ U3 element is replaced by a heterologous promoter to drive RNA expression in a Tat-independent manner, most of the transcription factor binding sites are deleted from the 3′ U3 region (i.e., ∆U3), referred to as self- inactivating (SIN) vector design. These SIN vectors, following reverse transcription and integration, minimize the potential of full-length viral RNA production in target cells and, therefore, ensure one round of infection [25]. Several other cis-acting modifications to the viral genome have also been made, increasing both the titers and transgene expression levels. The main three elements are the inclusion of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) [26], polyadenylation (polyA) motifs [27], and the central polypurine tract [28].
Since their development, LVs have been in the mainstream of gene and cell therapy applications with notable successes in the clinic (reviewed in [29] and [30]). Recently, Kymriah and Yescarta, two chimeric antigen receptor T (CAR-T) cell therapies, which consist of T cells modified ex vivo via LV interventions, have been approved for use in B cell malignancies in the US [31,32]. Furthermore, currently, there are almost 200 active gene therapy clinical trials using LVs worldwide [33].

2. Non-Human Lentiviruses

As mentioned earlier, lentiviruses are a diverse group of viruses isolated from various host species broadly divided into two major groups: primate and non-primate lentiviruses. While there are only two known human lentiviruses—HIV-1 and HIV-2—due to years of major viral cross-species and host-switching transmission [34], there are more than 45 known non-human primate lentivirus (i.e., SIV) subtypes [35]. Notably, HIV-1 and HIV-2 arose as a result of cross-species transmissions to humans from chimpanzees [36] and sooty mangabeys [37], respectively. Known SIV strains demonstrate high species-specific divergence and have been divided into six distinct major subtypes: chimpanzees (SIVcpz), sooty mangabeys (SIVsmm), African green monkeys (SIVagm), L’Hoest monkeys (SIVlho), Sykes’ monkeys (SIVsyk), and Colobus guerezas (SIVcol) [38,39]. Amongst these strains, SIVsmm has been dominantly used in LV-based research and, therefore, referred to as the prototype SIV lineage hereafter unless otherwise specified. Although SIV has been demonstrated to be less pathogenic than HIV-1, it displays similar characteristics during infection phases. Interestingly, while SIV infections seem to be benign (i.e., non-pathogenic) in their natural hosts, infection of other simian species results in AIDS-like diseases [40,41]. On the other hand, the non-primate lentiviruses group comprises viruses from several different species, including cats, horses, sheep, cattle, and goats [10,42].
All lentiviruses share similar morphology and genome organization. They have the following cis-acting genomic elements: two LTRs, the polypurine tract necessary for reverse transcription, and the packaging signal psi [43,44,45]. In addition, they share functional characteristics, such as the ability to infect terminally differentiated non-dividing cells. Overall, all lentiviruses demonstrate tropism towards cells from the monocyte/macrophage lineages [46,47,48] (an exception to this among non-primate LVs is FIV, which is also able to infect T cells via CD134 (also known as OX40) receptor [49]). However, there are notable differences in the accessory and regulatory proteins encoded as well as their genomic organization amongst different lentiviruses (Figure 2).
Amongst all accessory and regulatory genes, rev is the most functionally conserved one, followed by vif and tat. Typically, rev and tat genes are encoded by multiple exons towards the 3′ end of the genome. For rev, FIV and JDV are notable exceptions. Not only the 3′ rev exon in FIV overlaps with the 3′ LTR, but also it contains a unique nuclear export signal compared to other lentiviruses [50]. On the other hand, for JDV rev, exons are found farther apart in the genome overlapping vif and 3′ LTR, respectively [51]. CAEV and VMV are the only lentiviruses to encode tat in a single exon (also referred to as orfS [52]), which lacks the transactivator function observed in other lentiviruses [53], while the first exon of EIAV tat is located 5′ of the gag gene [54]. OrfS is thought to function as a Vpr-like accessory protein, involved in cell cycle arrest during viral infection and replication [55]. In FIV, the transactivator function is conducted by the orf2 gene [56]. Furthermore, all lentiviral genomes contain vif between their pol and env genes, except for EIAV [57]. Vif encodes a protein essential for viral replication and propagation, notably counteracting the effects of host restriction factor APOBEC3G in HIV-1 infections [58]. While EIAV lacks vif, it encodes a unique accessory gene: s2. While the exact function of the protein encoded by s2 is still unclear, mutagenesis studies have demonstrated that disrupting its function severely affects viral replication and infectivity of EIAV in inoculated horses [59,60]. It has also been implicated to have an antagonistic function, similar to HIV-1 nef, against serine incorporator (SERINC) protein 3 and 5-mediated retroviral restriction in cells [61].
Moreover, vpr, an essential accessory gene for HIV-1 bearing crucial roles in the integration of the virus into non-dividing cells and inducing cell-cycle arrest, is conserved only in the primate lentivirus SIV [62]. Yet, its two functions are divided between the SIV vpr and a new accessory gene vpx in SIVsmm (Table 1). In addition, researchers have demonstrated that vpx defective SIVsmm fails to efficiently infect and replicate in macrophages. Contrarily, vpr defective virus could infect macrophages but failed to induce cell cycle arrest [63]. Lastly, there are three other accessory proteins identified only in bovine lentiviruses BIV and JDV (Table 2). Vpy and vpw, unique to BIV, contain vif-like motifs and are thought to have similar functionality [64]. Yet, the function of the tmx gene located at the 3′ end of the env in both BIV and JDV is currently unknown [65].
Another trademark feature of non-primate lentiviruses is the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) enzyme, which is not encoded by HIV or SIV. While BIV and JDV lack dUTPase, in other non-primate lentiviruses, it is encoded by the pol gene [66]. Other retroviruses, amongst other viruses (e.g., herpesviruses [67] and poxviruses [68]), such as murine mammary tumor virus and Mason-Pfizer monkey virus, also have similar functional copies of dUTPase [69,70]. In prokaryotic and eukaryotic organisms, dUTPase plays a crucial role in mitotic cells by driving dUTP hydrolysis. This helps to minimize uracil incorporation into DNA during cell division and hence mutagenesis [71]. It is postulated that the viral dUTPase carries a similar role, preventing the incorporation of uracil into the proviral DNA [72]. As mentioned, while both BIV and JDV lack functional dUTPases, the protein encoded by the corresponding region is still critical for viral replication [73]. Mutagenesis studies have demonstrated that defective dUTPase leads to the incorporation of uracil into the proviral DNA [74] as well as to a delayed replication in non-dividing cells [75,76,77]. Furthermore, infection of animals with defective viruses, in general, leads to reduced viral loads and attenuated disease phenotypes [78,79,80,81].

3. Lentiviral Vector Systems Generated Based on Non-Human Lentiviruses

The success of gene therapy interventions ultimately depends on the efficacy and safety of the vectors. Replication-defective vectors, first based on retroviruses and later lentiviruses, have been traditionally preferred over other alternatives to treat several diseases, such as hemophilia. Since the establishment of HIV-1-based LV systems, considerable research has been undertaken to study alternatives from animal lentiviruses. With respect to increased biosafety considerations, the investigation of viruses non-pathogenic for the development of gene transfer vectors has been an attractive option.

3.1. Simian Lentiviral Vectors

Simian immunodeficiency virus-based LVs offer certain advantages compared to the other animal lentiviruses. Due to the homology, it shares with both HIV subtypes, SIV has been extensively studied. Initially, replication-competent SIV-based vectors were generated in which the nef gene was replaced with the transgene of interest, such as interferon-gamma or green fluorescent protein genes [82,83]. Owing to their attenuated pathogenicity, nef-deleted and later nef-vpr double-deleted SIV vectors were tested as anti-AIDS vaccines, however, with limited success [84,85]. This was rapidly followed by the generation of first and second-generation SIV-based LVs. Similar to the development of HIV-1 vectors, first SIV LVs harbored deletions in the env gene or completely lacked it [86,87], and vectors were almost exclusively pseudotyped with the commonly used VSV.G envelope. Several novel approaches involve the design of chimeric vectors using SIV packaging genes and the HIV-1 vector genome [88]. This hybrid system allowed for the generation of Rev-independent vectors as well as the omission of several accessory SIV genes, such as nef, vpx, vpr, and vif. Cross-packaging of these viruses enabled the production of LVs with comparable titers to that of SIV-only and HIV-1-only systems, while providing an added level of biosafety by decreasing the potential for homologous recombination between genomic sequences from the two lentiviruses [89,90].
Unlike HIV-1, several subtypes of SIV have been utilized and continued to be developed as LV systems. Comparative studies of the systems have revealed that similar to HIV-1, the elimination of accessory genes does not affect vector titers and efficacy [91]. This has led to the development of several third-generation LVs based on two SIV strains: SIVagm and SIVmac (macaques; part of sooty mangabeys clade) [92,93]. While earlier packaging constructs encoded vif, vpr, tat, and nef, these new minimal self-inactivation vectors only contain genomic sequences of gag, pol, and rev.
The capacity of SIV-derived LVs to transduce a variety of cell types has been assessed extensively using retroviral and non-retroviral envelopes. Transduction of hematopoietic stem cells [93,94], neurons [95], retinal [96], and lung tissue [97], as well as T cells [87,98] and dendritic cells [99], has been achieved using envelope glycoproteins derived from VSV [87,99], lymphocytic choriomeningitis mammarenavirus (LCMV) [98], murine leukemia virus (MLV), feline endogenous retrovirus RD114 [98], gibbon ape leukemia virus [100], Ebola virus [98], and Sendai virus [92,101]. The choice of envelopes has not only allowed for specific tissue targeting (e.g., lung in the case of Sendai virus) but also conferred advantageous characteristics, such as broad tropism and stability (e.g., VSV.G), and complement resistance (e.g., RD114).
Furthermore, although researchers have sought to remove accessory viral proteins from LV systems due to biosafety concerns, it has been demonstrated that LV tropism and efficacy can be altered by the inclusion of vpx. In in vivo studies in mice and rats, SIV-based LVs lacking accessory proteins have demonstrated robust tropism towards neurons [95,102]; however, Hlavaty and colleagues were able to modify the vector to preferentially target glial cells in mice via the introduction of the vpx gene in the packaging construct [102]. In addition, the accessory Vpx protein has been exploited to manipulate the early phases of lentiviral infection. Several studies have highlighted that Vpx, encoded by SIVsmm and HIV-2, is essential to counteracting innate antiviral restriction factors in myeloid cells, which makes it an absolute necessity when using SIV-based vectors to target myeloid lineages [103,104]. Negri et al. further highlighted that the Vpx-encoding integration-deficient SIV vector could transduce primary human and simian dendritic cells in vitro with greater efficiency [105]. This study, investigating the efficacy of the Vpx-encoding vectors to deliver the reporter green fluorescent protein gene, underlined the promise of integration-deficient LV-based vaccines and clustered regularly interspaced short palindromic repeats(CRISPR)-Cas9 based gene modification strategies. Furthermore, several studies have demonstrated that a similar enhancement of infection can be achieved for heterologous LVs (e.g., HIV-1 and FIV-based) when Vpx protein is provided in trans during LV challenge via non-infectious virus-like particles [106,107].
Simian immunodeficiency virus, similar to human lentiviruses, is subject to innate antiviral restriction. There are several classes of restriction factors identified that target HIV-1 infection in human and simian cells: apolipoprotein B editing complex (APOBEC) family proteins [108], tripartite motif-containing (TRIM) proteins [109], tetherin [110,111], sterile alpha motif- and histidine-aspartate domain-containing protein 1 (SAMHD1) [112], and SERINC [113,114]. As with all primate lentiviruses, SIV has evolved to antagonize these factors. Studies have demonstrated that SIV Vpx and Vpr could degrade SAMHD1 [115], while Nef could antagonize tetherin [116] and SERINC5 [117,118]. Furthermore, it has been demonstrated that only SIVcpz and SIVsmm Vif could effectively antagonize human APOBEC3G, highlighting one of the possible reasons why cross-species infection has been only observed with these two strains [119]. Ylinen and colleagues demonstrated that human TRIM5α has minimal activity against a variety of SIV strains [120]; however, recently, a study revealed that TRIM34 could restrict both SIVagm and SIVsmm capsids in human monocyte-like cells in a TRIM5α-dependent manner [121]. A similar capsid-specific viral restriction post-entry to the nucleus was observed by Pizzato et al., directed at SIVsmm in human blood cells (B and T lymphocytes) [122]. In contrast, human epithelial, primary lung, and CD34+ hematopoietic stem cells have been shown to be permissive for SIV-derived LVs, resulting in robust transduction efficiencies comparable to that of HIV-1 vectors [97,122,123]. In addition, SIV-based vectors have proven invaluable and superior to HIV-1 vectors in the evaluation of SIV and HIV-based hematopoietic stem cell gene therapy strategies in rhesus macaques, owing to their resistance to restriction via rhesus TRIM5α [93,124].

3.2. Feline Lentiviral Vectors

Feline immunodeficiency virus-based LVs are the first non-primate vectors to be described [125]. Due to its highly restrictive feline tropism, FIV-based vectors are still considered attractive alternatives to primate LVs (reviewed in [126]). The first-generation of FIV-LVs consisted of a three-plasmid system, where the packaging construct carried a functional vif and a non-functional truncated orf2.
The initial steps following the development of the vector system addressed questions around pseudotyping, LTR activity in human cells, and the need for wt accessory proteins and cis-acting genome elements. This led to the generation of minimal vector systems devoid of all accessory genes, except rev [127,128,129]. Partial gag sequences were retained in the vector genome, thought to contain the putative packaging signal [125]. Initially, the production of FIV LVs in human cells was, however, proven difficult due to the lack of promoter/enhancer activity of FIV LTRs. This transcriptional limitation was overcome via the hybrid LTR strategy used for HIV-1-based LVs, replacing the 5′ U3 region with a strong heterologous promoter [127,128].
The VSV.G envelope conferring broad tropism to the LVs has allowed for comparative assessments regarding transduction efficiencies of cells from various species [130,131]. It was established that FIV vectors could transduce many cell types from murine, human, porcine, and feline origins, including neurons [125,132], salivary glands [133], muscle cells [127,134], hepatocytes [134], and dendritic cells [127]. Pseudotyping LVs with less widely used envelopes from arenaviruses (e.g., LCMV) [132], alphaviruses (e.g., Ross river virus) [134], influenza virus (e.g., hemagglutinin from influenza A and GP75 from influenza D) [135], and baculoviruses (e.g., GP64) [136,137,138] has allowed for retargeting of vectors to liver (Ross river virus envelope) and lung cells (influenza, GP64 envelopes), as well as neurons (LCMV envelope) with greater efficacy compared to that of pantropic VSV.G envelope. In addition, FIV vectors have been extensively examined for their suitability for ocular gene therapies. Toxicity and biodistribution studies have been performed in many species, including humans [139,140], monkeys [141,142], mice [143,144], and rabbits [145,146]. Comparative studies have highlighted that FIV LVs could target both the cornea as well as the retina following subretinal and intravitreal injections at levels similar to that of HIV-1-based LVs.
Nonetheless, FIV-based LVs are subject to potent antiviral restriction in human and simian cells, substantially reducing viral vector efficacy and hindering their translational potential. This innate restriction is particularly caused by species-specific variants of tripartite motif-containing 5 α (TRIM5α) protein [147]. Saenz and colleagues demonstrated that rhesus and human TRIM5α, known for its post-entry blocking activity prior to reverse transcription against HIV-1 [109], blocked FIV replication as well [148]. However, for FIV vectors, this could be circumvented by saturating the antiviral activity [149]. Increasing the multiplicity of infection or co-infection with decoy genome-less virus-like particles enables efficient transduction of cells. Although effective in vitro, translation of such strategies to in vivo experiments or the clinic seems impractical and doubtful.

3.3. Equine Lentiviral Vectors

Soon after the reporting of LV systems based on FIV, EIAV-based LVs were developed using the split-genome strategy [150]. This first system contained all the accessory proteins of EIAV. However, further improvements were later made to eliminate all accessory proteins, but Rev [151]. Mitrophanous and colleagues also demonstrated that dUTPase could be deleted from Pol without any effect on vector titers [152]. These EIAV vectors could transduce growth-arrested cells and have been successfully pseudotyped with several rhabdovirus [151,153], lyssavirus [152,153], and murine leukemia virus envelopes to varying degrees of efficiency [152].
Using EIAV vectors, Ikeda and colleagues successfully transduced cell lines from several different species [154]. Another study demonstrated that when administered in vivo, EIAV LV could target mouse glial cells and neurons [153]. In addition, in a proof-of-concept study, Yamada and colleagues successfully corrected defects in hematopoietic stem cells from a Fanconi anemia patient using EIAV vectors [155]. Further comparative studies concluded that while EIAV vectors’ transduction efficiencies in several cell lines were comparable to that of HIV-1-based vectors, the transgene expression was unstable and significantly decreased over time [156]. To overcome this, an inducible promoter system was tested [157]. Human and rabbit corneal epithelial cells in the study were targeted more efficiently by EIAV vectors compared to that of HIV-1, and sustained transgene expression was achieved with minimal inflammatory responses.
Extensive studies of the abilities of EIAV vectors led to more developments. Currently, the only non-primate LV packaging cell line is based on EIAV vectors [150,158]. This latest EIAV vector system resembles the third-generation HIV-1-based LVs, owing to the lack of accessory proteins as well as LTR modifications in order to increase transcriptional efficiency and generate self-inactivating vectors. In addition, gag and pol genes are codon-optimized to further minimize sequence overlap and decrease the chance of potential recombination events [158,159]. Using these constructs, a tetracycline (Tet)-regulated packaging cell line has been described where both gag-pol and envelope VSV.G constructs are under the Tet-controlled transcriptional activation (i.e., Tet-on) to reduce protein-specific cytotoxicity and increase viral vector yields. Overall the generated cell line has displayed tight transcriptional regulation and high titers.
The favorable characteristics of EAIV vectors and vector development have advanced EIAV-based LVs into clinical trials for gene therapies targeting the eye and nervous system (ClinicalTrials.gov identifiers NCT01856439, NCT00627588, NCT01505062, NCT01301443, NCT01678872). Of the several clinical trials to date, ProSavin and RetinoStat have been the most successful. RetinoStat is applied for the treatment of neovascular age-related macular degeneration by subretinal administration of dual-transgene encoding EIAV vectors expressing endostatin and angiostatin [160]. A total of 21 patients were enrolled and were administered escalating doses of the viral vector. No adverse effects were noted, and transgene expression was stable up to a year in all patients. Long-term transgene stability was achieved up to 2.5 years in eight patients, while over 4 years in two patients. Although the vector was well tolerated, and the results were encouraging, no meaningful therapeutic correction was achieved in advanced neovascular age-related macular degeneration. ProSavin was developed for patients with Parkinson’s disease [161]. Escalating doses of the vector encoding three dopamine biosynthetic enzymes were administered to 15 patients via bilateral injections into the putamen. Although some adverse effects were reported, no serious events related to ProSavin administration were observed. Long-term follow-up studies demonstrated that the vector was well tolerated in patients for up to 4 years, and statistically significant improvements in motor behavior could be observed in all patients, confirming the therapeutic rationale of the gene therapy application.

3.4. Caprine and Ovine Lentiviral Vectors

Gene transfer systems based on goat and sheep lentiviruses have also been described. In the initial attempt of generating CAEV-based vectors, constructs encoding selectable transgenes (e.g., neomycin resistance gene) were generated with intact wt LTRs and stably transfected into goat cells [162]. To rescue vector productions, these cells were then infected with replication-competent CAEV. The titers achieved from this system were significantly lower compared to that of other LV systems. The researchers speculated that this was due to the lack of a packaging signal and a rev-responsive element in the vector construct. Mselli-Lakhal et al. showed that the poor vector production was connected to the low expression and accumulation of full-length viral RNA in the cells, leading to defective packaging of the vectors. However, the generation of env-defective CAEV vectors pseudotyped with the heterologous VSV.G envelope not only allowed for efficient transduction of human THP-1 and TE671 cells but also led to correct integration and expression of the proviral genome in infected cells [163]. This allowed the production of new viral particles, indicating the suitability of human cells to establish CAEV packaging cell lines. Later, Mselli-Lakhal and colleagues also established replication-defective CAEV vector systems encoding the only gag and truncated versions of pol and env [164]. Although this system was able to produce functional vectors, viral titers were again unacceptably low (<104 transducing units (TU)/mL).
Meanwhile, Berkowitz et al. reported the derivation of VMV-based vector systems [165]. An initial two-plasmid approach aimed to determine the required genes to establish a human embryonic kidney (HEK) 293 based producer cell line. The incorporation of the hybrid LTR into the viral genome allowed for substantial increases in the viral protein expression. However, neither 293 nor lymphoid CEM cells could be infected using the VMV LVs. Further improvements were made in the vector system, switching to the three-plasmid split-genome strategy. Although RNA expression levels in producer cells were comparable, the transduction efficiency of VMV LVs was approximately 2-logs lower than that of HIV-1 LVs. An investigation into this phenomenon revealed that the low transduction efficiency was associated with viral restriction occurring early in the infection process, namely poor reverse transcription and integration of the viral genome.

3.5. Bovine Lentiviral Vectors

Lentiviral vector systems for both JDV and the parental BIV have been described. Metharom and colleagues developed a second-generation replication-defective split genome system based on JDV [166]. This vector had all accessory protein open-reading frames intact. When pseudotyped with heterologous VSV.G envelope, JDV vectors demonstrated approximately 106 TU/mL titers and good transduction profiles in both dividing and growth-arrested HEK 293 and HeLa cells. Alternatively, several groups have derived LV systems based on BIV. Berkowitz et al., the first to report, constructed an earlier generation LV system in which a heterologous promoter-driven transgene was inserted in the env gene [167]. When supplemented with VSV.G in trans, the system was able to produce functional vector particles. Several constructs were evaluated for a split genome strategy, allowing for the production of vectors, which could infect a variety of primary cells and cell lines in vitro. Using this vector system, Takahashi et al. could efficiently target murine retinal pigment epithelium cells following a single subretinal injection [168]. They reported robust and stable transgene expression for up to 20 weeks with minimal anti-viral immune responses observed. Improvements to this vector system were made, yielding a third-generation replication-defective LV system, which lacked all BIV accessory genes [169]. Further modifications to the vector genome construct minimized sequence homology with the packaging plasmid, which existed previously [167].

4. Conclusions and Future Directions

Lentiviral vectors, with untapped potential, are widely used for gene and cell therapy applications in the laboratories and the clinic. A substantial amount of research has been performed to understand the molecular biology of the lentiviral life cycle due to its advantageous characteristics: relatively large packaging capacity (e.g., compared to that of adeno-associated virus vectors), ability to infect non-dividing cells, allowing for stable transgene expression, and low immunogenicity (e.g., compared to adenoviral vectors). The newer generations of replication-defective LV platforms, lacking accessory genes of wt lentiviruses as well as codon-optimized gag-pol, allow for increased safety measures and further minimization of the possibility to generate replication-competent viruses. Although permanent integration of a transgene into the host cell genome is considered a favorable trait, genotoxicity related to viral integration was a significant cause for concern following the adverse outcomes in gammretroviral clinical trials [170,171]. However, owing to the aforementioned safety modifications, current LVs are considerably different than gammaretroviral vectors. In addition, lentiviruses display a distinct integration profile with no preference for enhancer or promoter regions [172,173,174]. Altogether, inherent characteristics of LVs and safety modifications considerably reduce the risk of genotoxicity with no reports of genotoxicity-related adverse effects to date in any of the LV-based gene and cell therapies.
Lack of pathogenicity demonstrated by non-human lentiviruses in humans has made them attractive alternatives for the generation of LV platforms. In addition, the inherent tissue-specific antiviral restriction might provide a biosafety advantage in preventing replication and systemic spread of any potential replication-competent lentiviruses. Shared characteristics amongst lentiviruses and the ability to pseudotype these recombinant vectors with heterologous envelope glycoproteins from other viruses have allowed for targeting of a variety of cell and tissue types. While SIV, FIV, and EIAV have been developed into promising LV systems, VMV/CAEV and BIV/JDV are at their infancy, awaiting several challenges to be overcome. In the case of SIV-, FIV-, and EIAV-derived LVs, based on previous knowledge of and experiences with HIV-1 vectors, packaging systems followed similar iterative modifications: separation of viral genes, removal of accessory and regulatory genes, SIN vector design, and introduction of cis-acting elements, such as WPRE, cPPT, and polyA signals to increase titers and transgene expression.
When utilizing non-human LVs, innate antiviral host restriction responses in human cells is a significant obstacle to be conquered. As previously discussed, factors, such as TRIM5α, APOBEC3G, and SERINC proteins, can substantially curtail the efficacy of LV therapy. SAMHD1 has been implicated in such antiviral activity against HIV-1 and other primate lentiviruses, kinetically restricting lentiviral reverse transcription [175,176,177]. While SIVsmm can counteract this activity via its accessory proteins Vpx [178], recently, in a study, Mereby and colleagues demonstrated that non-primate lentiviruses lacked such uniquely gained abilities [177]. Furthermore, in the case of third-generation LVs devoid of all accessory genes, combatting host restriction becomes a crucial concern.
Lentiviral vector’s unprecedented ability to modify the host cell genome has ushered in the era of gene and cell therapies. A deeper understanding of lentiviral biology, as well as the exploitation of reverse genetics, will allow for the generation of a broader portfolio of LV systems to overcome roadblocks and ensure successful translation of advanced therapy medicinal products for clinical applications into the clinic.

Funding

This article received no external funding.

Acknowledgments

The author thanks Yasuhiro Takeuchi for the critical reading of the manuscript.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Weinberg, J.B.; Matthews, T.J.; Cullen, B.R.; Malim, M.H. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J. Exp. Med. 1991, 174, 1477–1482. [Google Scholar] [CrossRef]
  2. Clements, J.E.; Zink, M.C. Molecular biology and pathogenesis of animal lentivirus infections. Clin. Microbiol. Rev. 1996, 9, 100–117. [Google Scholar] [CrossRef] [PubMed]
  3. Gifford, R.J. Viral evolution in deep time: Lentiviruses and mammals. Trends Genet. 2012, 28, 89–100. [Google Scholar] [CrossRef] [PubMed]
  4. Narayan, O.; Silverstein, A.M.; Price, D.; Johnson, R.T. Visna Virus Infection of American Lambs. Science 1974, 183, 1202–1203. [Google Scholar] [CrossRef] [PubMed]
  5. Olmsted, R.A.; Barnes, A.K.; Yamamoto, J.K.; Hirsch, V.M.; Purcell, R.H.; Johnson, P.R. Molecular cloning of feline immunodeficiency virus. Proc. Natl. Acad. Sci. USA 1989, 86, 2448–2452. [Google Scholar] [CrossRef] [PubMed]
  6. Overbaugh, J.; Donahue, P.; Quackenbush, S.; Hoover, E.; Mullins, J. Molecular cloning of a feline leukemia virus that induces fatal immunodeficiency disease in cats. Science 1988, 239, 906–910. [Google Scholar] [CrossRef] [PubMed]
  7. Charman, H.P.; Bladen, S.; Gilden, R.V.; Coggins, L. Equine infectious anemia virus: Evidence favoring classification as a retravirus. J. Virol. 1976, 19, 1073–1079. [Google Scholar] [CrossRef]
  8. Crawford, T.; Adams, D.; Cheevers, W.; Cork, L. Chronic arthritis in goats caused by a retrovirus. Science 1980, 207, 997–999. [Google Scholar] [CrossRef]
  9. Gonda, M.A.; Braun, M.J.; Carter, S.G.; Kost, T.A.; Bess, J.W.; Arthur, L.O.; Van Der Maaten, M.J. Characterization and molecular cloning of a bovine lentivirus related to human immunodeficiency virus. Nature 1987, 330, 388–391. [Google Scholar] [CrossRef]
  10. Chadwick, B.J.; Coelen, R.J.; Sammels, L.M.; Kertayadnya, G.; Wilcox, G.E. Genomic sequence analysis identifies Jembrana disease virus as a new bovine lentivirus. J. Gen. Virol. 1995, 76, 189–192. [Google Scholar] [CrossRef]
  11. Chowdhury, S.; Ikeda, Y. Retroviruses. In Viral Therapy of Cancer; Wiley: Hoboken, NJ, USA, 2008; pp. 69–81. [Google Scholar]
  12. Baltimore, D. Viral RNA-dependent DNA Polymerase: RNA-dependent DNA Polymerase in Virions of RNA Tumour Viruses. Nature 1970, 226, 1209–1211. [Google Scholar] [CrossRef] [PubMed]
  13. Telesnitsky, A.; Goff, S.P. Reverse Transcriptase and the Generation of Retroviral DNA. In Retroviruses; Coffin, J.M., Hughes, S.H., Varmus, H.E., Eds.; Cold Spring Harbor Laboratory Press: New York, NY, USA, 1997; pp. 121–160. [Google Scholar]
  14. Coffin, J.M.; Hughes, S.H.; Varmus, H.E. (Eds.) The Interactions of Retroviruses and their Hosts. In Retroviruses; Cold Spring Harbor: New York, NY, USA, 1997. [Google Scholar]
  15. Vogt, V.M. Retroviral virions and genomes. In Retroviruses; Coffin, J.M., Varmus, H.E., Eds.; Cold Spring Harbor Laboratory Press: New York, NY, USA, 1997; pp. 27–71. [Google Scholar]
  16. Balvay, L.; López-Lastra, M.; Sargueil, B.; Darlix, J.-L.; Ohlmann, T. Translational control of retroviruses. Nat. Rev. Genet. 2007, 5, 128–140. [Google Scholar] [CrossRef]
  17. Abordo-Adesida, E.; Follenzi, A.; Barcia, C.; Sciascia, S.; Castro, M.G.; Naldini, L.; Lowenstein, P.R. Stability of Lentiviral Vector-Mediated Transgene Expression in the Brain in the Presence of Systemic Antivector Immune Responses. Hum. Gene Ther. 2005, 16, 741–751. [Google Scholar] [CrossRef] [PubMed]
  18. Reik, W.; Weiher, H.; Jaenisch, R. Replication-competent Moloney murine leukemia virus carrying a bacterial suppressor tRNA gene: Selective cloning of proviral and flanking host sequences. Proc. Natl. Acad. Sci. USA 1985, 82, 1141–1145. [Google Scholar] [CrossRef] [PubMed]
  19. Hughes, S.; Kosik, E. Mutagenesis of the region between env and src of the SR-A strain of rous sarcoma virus for the purpose of constructing helper-independent vectors. Virology 1984, 136, 89–99. [Google Scholar] [CrossRef]
  20. Page, K.A.; Liegler, T.; Feinberg, M.B. Use of a Green Fluorescent Protein as a Marker for Human Immunodeficiency Virus Type 1 Infection. AIDS Res. Hum. Retrovir. 1997, 13, 1077–1081. [Google Scholar] [CrossRef]
  21. Naldini, L.; Blömer, U.; Gallay, P.; Ory, D.; Mulligan, R.; Gage, F.H.; Verma, I.M.; Trono, D. In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector. Science 1996, 272, 263–267. [Google Scholar] [CrossRef]
  22. Shimotohno, K.; Temin, H.M. Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus. Cell 1981, 26, 67–77. [Google Scholar] [CrossRef]
  23. Delenda, C. Lentiviral vectors: Optimization of packaging, transduction and gene expression. J. Gene Med. 2004, 6, S125–S138. [Google Scholar] [CrossRef]
  24. Miller, A.D. Development and Applications of Retroviral Vectors. In Retroviruses; Coffin, J.M., Hughes, S.H., Varmus, H.E., Eds.; Cold Spring Harbor Laboratory Press: New York, NY, USA, 1997; pp. 437–474. [Google Scholar]
  25. Miyoshi, H.; Blömer, U.; Takahashi, M.; Gage, F.H.; Verma, I.M. Development of a Self-Inactivating Lentivirus Vector. J. Virol. 1998, 72, 8150–8157. [Google Scholar] [CrossRef]
  26. Donello, J.E.; Loeb, J.E.; Hope, T.J. Woodchuck Hepatitis Virus Contains a Tripartite Posttranscriptional Regulatory Element. J. Virol. 1998, 72, 5085–5092. [Google Scholar] [CrossRef] [PubMed]
  27. Schambach, A.; Galla, M.; Maetzig, T.; Loew, R.; Baum, C. Improving Transcriptional Termination of Self-inactivating Gamma-retroviral and Lentiviral Vectors. Mol. Ther. 2007, 15, 1167–1173. [Google Scholar] [CrossRef] [PubMed]
  28. Logan, A.C.; Nightingale, S.J.; Haas, D.L.; Cho, G.J.; Pepper, K.A.; Kohn, D.B. Factors Influencing the Titer and Infectivity of Lentiviral Vectors. Hum. Gene Ther. 2004, 15, 976–988. [Google Scholar] [CrossRef] [PubMed]
  29. Milone, M.C.; O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 2018, 32, 1529–1541. [Google Scholar] [CrossRef]
  30. Loza, L.I.M.; Yuen, E.C.; McCray, J.P.B. Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease. Genes 2019, 10, 218. [Google Scholar] [CrossRef]
  31. Tisagenlecleucel. Available online: https://www.cancer.gov/about-cancer/treatment/drugs/tisagenlecleucel (accessed on 12 June 2020).
  32. Axicabtagene Ciloleucel. Available online: https://www.cancer.gov/about-cancer/treatment/drugs/axicabtageneciloleucel (accessed on 12 June 2020).
  33. Lentiviral Vector. Available online: https://clinicaltrials.gov/ct2/results?cond=&term=lentiviral+vector&cntry=&state=&city=&dist= (accessed on 12 June 2020).
  34. Locatelli, S.; Peeters, M. Cross-species transmission of simian retroviruses. AIDS 2012, 26, 659–673. [Google Scholar] [CrossRef]
  35. Aghokeng, A.F.; Ayouba, A.; Mpoudi-Ngolé, E.; Loul, S.; Liegeois, F.; Delaporte, E.; Peeters, M. Extensive survey on the prevalence and genetic diversity of SIVs in primate bushmeat provides insights into risks for potential new cross-species transmissions. Infect. Genet. Evol. 2010, 10, 386–396. [Google Scholar] [CrossRef]
  36. Gao, F.; Bailes, E.; Robertson, D.L.; Chen, Y.; Rodenburg, C.M.; Michael, S.F.; Cummins, L.B.; Arthur, L.O.; Peeters, M.; Shaw, G.M.; et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999, 397, 436–441. [Google Scholar] [CrossRef]
  37. Hirsch, V.M.; Olmsted, R.A.; Murphey-Corb, M.; Purcell, R.H.; Johnson, P.R. An African primate lentivirus (SIVsmclosely related to HIV-2. Nature 1989, 339, 389–392. [Google Scholar] [CrossRef]
  38. Lauck, M.; Switzer, W.M.; Sibley, S.D.; Hyeroba, D.; Tumukunde, A.; Weny, G.; Taylor, B.; Shankar, A.; Ting, N.; Chapman, C.A.; et al. Discovery and full genome characterization of two highly divergent simian immunodeficiency viruses infecting black-and-white colobus monkeys (Colobus guereza) in Kibale National Park, Uganda. Retrovirology 2013, 10, 107. [Google Scholar] [CrossRef]
  39. Sauter, D.; Kirchhoff, F. Chapter 4-Properties of Human and Simian Immunodeficiency Viruses. In Natural Hosts of SIV; Ansari, A.A., Silvestri, G., Eds.; Elsevier: Amsterdam, The Netherlands, 2014; Chapter 4; pp. 69–84. Available online: https://doi.org/10.1016/B978-0-12-404734-1.00004-8 (accessed on 20 August 2020).
  40. Pandrea, I.; Apetrei, C. Where the Wild Things Are: Pathogenesis of SIV Infection in African Nonhuman Primate Hosts. Curr. HIV/AIDS Rep. 2010, 7, 28–36. [Google Scholar] [CrossRef] [PubMed]
  41. Martin, M.A. SIV pathogenicity. Fast-acting slow viruses. Nature 1990, 345, 572–573. [Google Scholar] [CrossRef] [PubMed]
  42. Pisoni, G.; Bertoni, G.; Boettcher, P.; Ponti, W.; Moroni, P. Phylogenetic analysis of the gag region encoding the matrix protein of small ruminant lentiviruses: Comparative analysis and molecular epidemiological applications. Virus Res. 2006, 116, 159–167. [Google Scholar] [CrossRef] [PubMed]
  43. VandenDriessche, T.; Thorrez, L.; Naldini, L.; Follenzi, A.; Moons, L.; Berneman, Z.; Collen, D.; Chuah, M.K. Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. Blood 2002, 100, 813–822. [Google Scholar] [CrossRef]
  44. Frech, K.; Brack-Werner, R.; Werner, T. Common Modular Structure of Lentivirus LTRs. Virology 1996, 224, 256–267. [Google Scholar] [CrossRef]
  45. Kim, S.H.; Jun, H.J.; Jang, S.I.; You, J.C. The Determination of Importance of Sequences Neighboring the Psi Sequence in Lentiviral Vector Transduction and Packaging Efficiency. PLoS ONE 2012, 7, e50148. [Google Scholar] [CrossRef]
  46. Naldini, L.; Trono, D.; Verma, I.M. Lentiviral vectors, two decades later. Science 2016, 353, 1101–1102. [Google Scholar] [CrossRef]
  47. Naldini, L.; Verma, I.M. Lentiviral Vectors; Elsevier: Amsterdam, The Netherlands, 2000; Volume 55, pp. 599–609. [Google Scholar]
  48. Clements, J.E.; Zink, M.C.; Narayan, O.; Gabuzda, D.H. Lentivirus infection of macrophages. Immunol. Ser. 1994, 60, 589–600. [Google Scholar]
  49. Shimojima, M.; Miyazawa, T.; Ikeda, Y.; McMonagle, E.; Haining, H.; Akashi, H.; Takeuchi, Y.; Hosie, M.J.; Willett, B.J. Use of CD134 As a Primary Receptor by the Feline Immunodeficiency Virus. Science 2004, 303, 1192–1195. [Google Scholar] [CrossRef]
  50. Phillips, T.R.; Lamont, C.; A Konings, D.; Shacklett, B.L.; A Hamson, C.; A Luciw, P.; Elder, J.H. Identification of the Rev transactivation and Rev-responsive elements of feline immunodeficiency virus. J. Virol. 1992, 66, 5464–5471. [Google Scholar] [CrossRef]
  51. Chadwick, B.J.; Coelen, R.J.; Wilcox, G.E.; Sammels, L.M.; Kertayadnya, G. Nucleotide sequence analysis of Jembrana disease virus: A bovine lentivirus associated with an acute disease syndrome. J. Gen. Virol. 1995, 76, 1637–1650. [Google Scholar] [CrossRef] [PubMed]
  52. Curran, M.A.; Nolan, G.P. Nonprimate Lentiviral Vectors; Springer Science and Business Media LLC: Berlin/Heidelberg, Germany, 2002; Volume 261, pp. 75–105. [Google Scholar]
  53. Villet, S.; Faure, C.; Bouzar, B.A.; Morin, T.; Verdier, G.; Chebloune, Y.; Legras, C. Lack of trans-activation function for Maedi Visna virus and Caprine arthritis encephalitis virus Tat proteins. Virology 2003, 307, 317–327. [Google Scholar] [CrossRef]
  54. Schiltz, R.L.; Shih, D.S.; Rasty, S.; Montelaro, R.C.; E Rushlow, K. Equine infectious anemia virus gene expression: Characterization of the RNA splicing pattern and the protein products encoded by open reading frames S1 and S2. J. Virol. 1992, 66, 3455–3465. [Google Scholar] [CrossRef] [PubMed]
  55. Villet, S.; Bouzar, B.A.; Morin, T.; Verdier, G.; Legras, C.; Chebloune, Y. Maedi-Visna Virus and Caprine Arthritis Encephalitis Virus Genomes Encode a Vpr-Like but No Tat Protein. J. Virol. 2003, 77, 9632–9638. [Google Scholar] [CrossRef]
  56. De Parseval, A.; Elder, J.H. Demonstration that orf2 Encodes the Feline Immunodeficiency Virus Transactivating (Tat) Protein and Characterization of a Unique Gene Product with Partial Rev Activity. J. Virol. 1999, 73, 608–617. [Google Scholar] [CrossRef]
  57. Leroux, C.; Montelaro, R.C. Equine Infectious Anemia Virus (EIAV): What has HIV?s country cousin got to tell us? Vet. Res. 2004, 35, 485–512. [Google Scholar] [CrossRef]
  58. Stopak, K.; De Noronha, C.; Yonemoto, W.; Greene, W.C. HIV-1 Vif Blocks the Antiviral Activity of APOBEC3G by Impairing Both Its Translation and Intracellular Stability. Mol. Cell 2003, 12, 591–601. [Google Scholar] [CrossRef]
  59. Li, F.; Leroux, C.; Craigo, J.K.; Cook, S.J.; Issel, C.J.; Montelaro, R.C. The S2 Gene of Equine Infectious Anemia Virus Is a Highly Conserved Determinant of Viral Replication and Virulence Properties in Experimentally Infected Ponies. J. Virol. 2000, 74, 573–579. [Google Scholar] [CrossRef]
  60. Fagerness, A.J.; Flaherty, M.T.; Perry, S.T.; Jia, B.; Payne, S.L.; Fuller, F. The S2 accessory gene of equine infectious anemia virus is essential for expression of disease in ponies. Virology 2006, 349, 22–30. [Google Scholar] [CrossRef]
  61. Chande, A.; Cuccurullo, E.C.; Rosa, A.; Ziglio, S.; Carpenter, S.; Pizzato, M. S2 from equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3. Proc. Natl. Acad. Sci. USA 2016, 113, 13197–13202. [Google Scholar] [CrossRef]
  62. Stivahtis, G.L.; A Soares, M.; A Vodicka, M.; Hahn, B.H.; Emerman, M. Conservation and host specificity of Vpr-mediated cell cycle arrest suggest a fundamental role in primate lentivirus evolution and biology. J. Virol. 1997, 71, 4331–4338. [Google Scholar] [CrossRef] [PubMed]
  63. Fletcher, T.M.; Brichacek, B.; Sharova, N.; Newman, M.A.; Stivahtis, G.; Sharp, P.M.; Emerman, M.; Hahn, B.H.; Stevenson, M. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J. 1996, 15, 6155–6165. [Google Scholar] [CrossRef] [PubMed]
  64. Gonda, M.A.; Luther, D.G.; Fong, S.E.; Tobin, G.J. Bovine immunodeficiency virus: Molecular biology and virus-host interactions. Virus Res. 1994, 32, 155–181. [Google Scholar] [CrossRef] [PubMed]
  65. St-Louis, M.-C.; Cojocariu, M.; Archambault, D. The molecular biology of bovine immunodeficiency virus: A comparison with other lentiviruses. Anim. Health Res. Rev. 2004, 5, 125–143. [Google Scholar] [CrossRef] [PubMed]
  66. Elder, J.H.; Lerner, D.L.; Hasselkus-Light, C.S.; Fontenot, D.J.; Hunter, E.; A Luciw, P.; Montelaro, R.C.; Phillips, T.R. Distinct subsets of retroviruses encode dUTPase. J. Virol. 1992, 66, 1791–1794. [Google Scholar] [CrossRef]
  67. CaraDonna, S.J.; Cheng, Y.C. Induction of uracil-DNA glycosylase and dUTP nucleotidohydrolase activity in herpes simplex virus-infected human cells. J. Boil. Chem. 1981, 256, 9834–9837. [Google Scholar]
  68. Broyles, S.S. Vaccinia Virus Encodes a Functional dUTPase. Virology 1993, 195, 863–865. [Google Scholar] [CrossRef]
  69. Bergman, A.-C.; Bjornberg, O.; Nord, J.; Nyman, P.; Rosengren, A. The Protein p30, Encoded at the gag-pro Junction of Mouse Mammary Tumor Virus, is a dUTPase Fused with a Nucleocapsid Protein. Virology 1994, 204, 420–421. [Google Scholar] [CrossRef]
  70. Köppe, B.; Menéndez-Arias, L.; Oroszlan, S. Expression and purification of the mouse mammary tumor virus gag-pro transframe protein p30 and characterization of its dUTPase activity. J. Virol. 1994, 68, 2313–2319. [Google Scholar] [CrossRef]
  71. Vassylyev, D.G.; Morikawa, K. Precluding uracil from DNA. Structure 1996, 4, 1381–1385. [Google Scholar] [CrossRef]
  72. Hizi, A.; Herzig, E. dUTPase: The frequently overlooked enzyme encoded by many retroviruses. Retrovirology 2015, 12, 70. [Google Scholar] [CrossRef] [PubMed]
  73. Podolny, Y.; Herzig, E.; Hizi, A. Insights into the molecular and biological features of the dUTPase-related gene of bovine immunodeficiency virus. Virology 2017, 506, 55–63. [Google Scholar] [CrossRef] [PubMed]
  74. Steagall, W.K.; Robek, M.D.; Perry, S.T.; Fuller, F.J.; Payne, S.L. Incorporation of Uracil into Viral DNA Correlates with Reduced Replication of EIAV in Macrophages. Virology 1995, 210, 302–313. [Google Scholar] [CrossRef]
  75. Wagaman, P.C.; Hasselkus-Light, C.S.; Henson, M.; Lerner, D.L.; Phillips, T.R.; Elder, J.H. Molecular Cloning and Characterization of Deoxyuridine Triphosphatase from Feline Immunodeficiency Virus (FIV). Virology 1993, 196, 451–457. [Google Scholar] [CrossRef] [PubMed]
  76. Threadgill, D.S.; Steagall, W.K.; Flaherty, M.T.; Fuller, F.J.; Perry, S.T.; E Rushlow, K.; Le Grice, S.F.; Payne, S.L. Characterization of equine infectious anemia virus dUTPase: Growth properties of a dUTPase-deficient mutant. J. Virol. 1993, 67, 2592–2600. [Google Scholar] [CrossRef]
  77. Turelli, P.; Pétursson, G.; Guiguen, F.; Mornex, J.F.; Vigne, R.; Quérat, G. Replication properties of dUTPase-deficient mutants of caprine and ovine lentiviruses. J. Virol. 1996, 70, 1213–1217. [Google Scholar] [CrossRef]
  78. Lichtenstein, D.L.; E Rushlow, K.; Cook, R.F.; Raabe, M.L.; Swardson, C.J.; Kociba, G.J.; Issel, C.J.; Montelaro, R.C. Replication in vitro and in vivo of an equine infectious anemia virus mutant deficient in dUTPase activity. J. Virol. 1995, 69, 2881–2888. [Google Scholar] [CrossRef]
  79. Pétursson, G.; Turelli, P.; Matthíasdóttir, S.; Georgsson, G.; Andrésson, O.S.; Torsteinsdóttir, S.; Vigne, R.; Andrésdóttir, V.; Gunnarsson, E.; Agnarsdóttir, G.; et al. Visna Virus dUTPase Is Dispensable for Neuropathogenicity. J. Virol. 1998, 72, 1657–1661. [Google Scholar] [CrossRef]
  80. Turelli, P.; Guiguen, F.; Mornex, J.F.; Vigne, R.; Quérat, G. dUTPase-minus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions. J. Virol. 1997, 71, 4522–4530. [Google Scholar] [CrossRef]
  81. Lerner, D.L.; Wagaman, P.C.; Phillips, T.R.; Prospéro-García, O.; Henriksen, S.J.; Fox, H.S.; Bloom, F.E.; Elder, J.H. Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase. Proc. Natl. Acad. Sci. USA 1995, 92, 7480–7484. [Google Scholar] [CrossRef]
  82. Giavedoni, L.D.; Yilma, T. Construction and characterization of replication-competent simian immunodeficiency virus vectors that express gamma interferon. J. Virol. 1996, 70, 2247–2251. [Google Scholar] [CrossRef] [PubMed]
  83. Alexander, L.; Veazey, R.S.; Czajak, S.; DeMaria, M.; Rosenzweig, M.; Lackner, A.A.; Desrosiers, R.C.; Sasseville, V.G. Recombinant Simian Immunodeficiency Virus Expressing Green Fluorescent Protein Identifies Infected Cells in Rhesus Monkeys. AIDS Res. Hum. Retrovir. 1999, 15, 11–21. [Google Scholar] [CrossRef]
  84. Ruprecht, R.M. Live attenuated AIDS viruses as vaccines: Promise or peril? Immunol. Rev. 1999, 170, 135–149. [Google Scholar] [CrossRef] [PubMed]
  85. Koff, W.C.; Johnson, P.R.; Watkins, D.I.; Burton, D.R.; Lifson, J.D.; Hasenkrug, K.J.; McDermott, A.B.; Schultz, A.; Zamb, T.J.; Boyle, R.; et al. HIV vaccine design: Insights from live attenuated SIV vaccines. Nat. Immunol. 2005, 7, 19–23. [Google Scholar] [CrossRef] [PubMed]
  86. Nakajima, T.; Nakamaru, K.; Ido, E.; Terao, K.; Hayami, M.; Hasegawa, M. Development of Novel Simian Immunodeficiency Virus Vectors Carrying a Dual Gene Expression System. Hum. Gene Ther. 2000, 11, 1863–1874. [Google Scholar] [CrossRef]
  87. Stitz, J.; Mühlebach, M.; Blömer, U.; Scherr, M.; Selbert, M.; Wehner, P.; Steidl, S.; Schmitt, I.; König, R.; Schweizer, M.; et al. A Novel Lentivirus Vector Derived from Apathogenic Simian Immunodeficiency Virus. Virology 2001, 291, 191–197. [Google Scholar] [CrossRef]
  88. Pandya, S.; Boris-Lawrie, K.; Leung, N.J.; Akkina, R.; Planelles, V. Development of an Rev-Independent, Minimal Simian Immunodeficiency Virus-Derived Vector System. Hum. Gene Ther. 2001, 12, 847–857. [Google Scholar] [CrossRef]
  89. White, S.M.; Renda, M.; Nam, N.-Y.; Klimatcheva, E.; Zhu, Y.; Fisk, J.; Halterman, M.; Rimel, B.J.; Federoff, H.; Pandya, S.; et al. Lentivirus Vectors Using Human and Simian Immunodeficiency Virus Elements. J. Virol. 1999, 73, 2832–2840. [Google Scholar] [CrossRef]
  90. A Rizvi, T.; Panganiban, A.T. Simian immunodeficiency virus RNA is efficiently encapsidated by human immunodeficiency virus type 1 particles. J. Virol. 1993, 67, 2681–2688. [Google Scholar] [CrossRef]
  91. Schnell, T.; Foley, P.; Wirth, M.; Münch, J.; Überla, K. Development of a Self-Inactivating, Minimal Lentivirus Vector Based on Simian Immunodeficiency Virus. Hum. Gene Ther. 2000, 11, 439–447. [Google Scholar] [CrossRef]
  92. Hanawa, H.; Hematti, P.; Keyvanfar, K.; Metzger, M.E.; Krouse, A.; Donahue, R.E.; Kepes, S.; Gray, J.; Dunbar, C.E.; Persons, D.A.; et al. Efficient gene transfer into rhesus repopulating hematopoietic stem cells using a simian immunodeficiency virus–based lentiviral vector system. Blood 2004, 103, 4062–4069. [Google Scholar] [CrossRef] [PubMed]
  93. Kobayashi, M.; Iida, A.; Ueda, Y.; Hasegawa, M. Pseudotyped Lentivirus Vectors Derived from Simian Immunodeficiency Virus SIVagm with Envelope Glycoproteins from Paramyxovirus. J. Virol. 2003, 77, 2607–2614. [Google Scholar] [CrossRef] [PubMed]
  94. Naumann, N.; De Ravin, S.S.; Choi, U.; Moayeri, M.; Whiting-Theobald, N.; Linton, G.F.; Ikeda, Y.; Malech, H.L. Simian immunodeficiency virus lentivector corrects human X-linked chronic granulomatous disease in the NOD/SCID mouse xenograft. Gene Ther. 2007, 14, 1513–1524. [Google Scholar] [CrossRef] [PubMed]
  95. Kitagawa, R.; Miyachi, S.; Hanawa, H.; Takada, M.; Shimada, T. Differential characteristics of HIV-based versus SIV-based lentiviral vector systems: Gene delivery to neurons and axonal transport of expressed gene. Neurosci. Res. 2007, 57, 550–558. [Google Scholar] [CrossRef]
  96. Ikeda, Y.; Yonemitsu, Y.; Miyazaki, M.; Kohno, R.-I.; Murakami, Y.; Murata, T.; Tabata, T.; Ueda, Y.; Ono, F.; Suzuki, T.; et al. Stable Retinal Gene Expression in Nonhuman Primates via Subretinal Injection of SIVagm-Based Lentiviral Vectors. Hum. Gene Ther. 2009, 20, 573–579. [Google Scholar] [CrossRef]
  97. Alton, E.W.F.W.; Beekman, J.M.; Boyd, A.C.; Brand, J.; Carlon, M.S.; Connolly, M.M.; Chan, M.; Conlon, S.; E Davidson, H.; Davies, J.C.; et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax 2016, 72, 137–147. [Google Scholar] [CrossRef]
  98. Sandrin, V.; Boson, B.; Salmon, P.; Gay, W.; Nègre, D.; Le Grand, R.; Trono, D.; Cosset, F.-L.; Kaudewitz, P.; Steinhoff, M.; et al. Lentiviral vectors pseudotyped with a modified RD114 envelope glycoprotein show increased stability in sera and augmented transduction of primary lymphocytes and CD34+ cells derived from human and nonhuman primates. Blood 2002, 100, 823–832. [Google Scholar] [CrossRef]
  99. Mangeot, P.E.; Nègre, D.; Dubois, B.; Winter, A.J.; Leissner, P.; Mehtali, M.; Kaiserlian, D.; Cosset, F.-L.; Darlix, J.-L. Development of Minimal Lentivirus Vectors Derived from Simian Immunodeficiency Virus (SIVmac251) and Their Use for Gene Transfer into Human Dendritic Cells. J. Virol. 2000, 74, 8307–8315. [Google Scholar] [CrossRef]
  100. Stitz, J.; Buchholz, C.; Engelstädter, M.; Uckert, W.; Bloemer, U.; Schmitt, I.; Cichutek, K. Lentiviral Vectors Pseudotyped with Envelope Glycoproteins Derived from Gibbon Ape Leukemia Virus and Murine Leukemia Virus 10A1. Virology 2000, 273, 16–20. [Google Scholar] [CrossRef]
  101. Mitomo, K.; Griesenbach, U.; Inoue, M.; Somerton, L.; Meng, C.; Akiba, E.; Tabata, T.; Ueda, Y.; Frankel, G.M.; Farley, R.; et al. Toward Gene Therapy for Cystic Fibrosis Using a Lentivirus Pseudotyped With Sendai Virus Envelopes. Mol. Ther. 2010, 18, 1173–1182. [Google Scholar] [CrossRef]
  102. Hlavatý, J.; Tonar, Z.; Renner, M.; Panitz, S.; Petznek, H.; Schweizer, M.; Schüle, S.; Kloke, B.-P.; Moldzio, R.; Witter, K. Tropism, intracerebral distribution, and transduction efficiency of HIV- and SIV-based lentiviral vectors after injection into the mouse brain: A qualitative and quantitative in vivo study. Histochem. Cell Boil. 2017, 148, 313–329. [Google Scholar] [CrossRef] [PubMed]
  103. Goujon, C.; Rivière, L.; Jarrosson-Wuilleme, L.; Bernaud, J.; Rigal, D.; Darlix, J.-L.; Cimarelli, A. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells. Retrovirology 2007, 4, 2. [Google Scholar] [CrossRef] [PubMed]
  104. Sharova, N.; Wu, Y.; Zhu, X.; Stránská, R.; Kaushik, R.; Sharkey, M.; Stevenson, M. Primate Lentiviral Vpx Commandeers DDB1 to Counteract a Macrophage Restriction. PLoS Pathog. 2008, 4, e1000057. [Google Scholar] [CrossRef] [PubMed]
  105. Negri, D.; Rossi, A.; Blasi, M.; Michelini, Z.; Leone, P.; Chiantore, M.V.; Baroncelli, S.; Perretta, G.; Cimarelli, A.; E Klotman, M.; et al. Simian immunodeficiency virus-Vpx for improving integrase defective lentiviral vector-based vaccines. Retrovirology 2012, 9, 69. [Google Scholar] [CrossRef]
  106. Goujon, C.; Jarrosson-Wuillème, L.; Bernaud, J.; Rigal, D.; Darlix, J.-L.; Cimarelli, A. With a little help from a friend: Increasing HIV transduction of monocyte-derived dendritic cells with virion-like particles of SIVMAC. Gene Ther. 2006, 13, 991–994. [Google Scholar] [CrossRef] [PubMed]
  107. Berger, G.; Goujon, C.; Darlix, J.-L.; Cimarelli, A. SIVMAC Vpx improves the transduction of dendritic cells with nonintegrative HIV-1-derived vectors. Gene Ther. 2008, 16, 159–163. [Google Scholar] [CrossRef] [PubMed]
  108. Sheehy, A.M.; Gaddis, N.; Choi, J.D.; Malim, M.H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002, 418, 646–650. [Google Scholar] [CrossRef]
  109. Stremlau, M.; Owens, C.M.; Perron, M.J.; Kiessling, M.; Autissier, P.; Sodroski, J. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 2004, 427, 848–853. [Google Scholar] [CrossRef]
  110. Neil, S.J.; Zang, T.; Bieniasz, P. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008, 451, 425–430. [Google Scholar] [CrossRef]
  111. Van Damme, N.; Goff, D.; Katsura, C.; Jorgenson, R.L.; Mitchell, R.; Johnson, M.C.; Stephens, E.B.; Guatelli, J. The Interferon-Induced Protein BST-2 Restricts HIV-1 Release and Is Downregulated from the Cell Surface by the Viral Vpu Protein. Cell Host Microbe 2008, 3, 245–252. [Google Scholar] [CrossRef]
  112. Lahouassa, H.; Daddacha, W.; Hofmann, H.; Ayinde, D.; Logue, E.C.; Dragin, L.; Bloch, N.; Maudet, C.; Bertrand, M.; Gramberg, T.; et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 2012, 13, 223–228. [Google Scholar] [CrossRef] [PubMed]
  113. Rosa, A.; Chande, A.; Ziglio, S.; De Sanctis, V.; Bertorelli, R.; Goh, S.L.; McCauley, S.M.; Nowosielska, A.; Antonarakis, S.E.; Luban, J.; et al. HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature 2015, 526, 212–217. [Google Scholar] [CrossRef]
  114. Usami, Y.; Wu, Y.; Göttlinger, H. SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature 2015, 526, 218–223. [Google Scholar] [CrossRef] [PubMed]
  115. Lim, E.S.; Fregoso, O.I.; McCoy, C.O.; Matsen, F.A.; Malik, H.S.; Emerman, M. The Ability of Primate Lentiviruses to Degrade the Monocyte Restriction Factor SAMHD1 Preceded the Birth of the Viral Accessory Protein Vpx. Cell Host Microbe 2012, 11, 194–204. [Google Scholar] [CrossRef] [PubMed]
  116. Jia, B.; Serra-Moreno, R.; Neidermyer, W.; Rahmberg, A.; Mackey, J.; Ben Fofana, I.; Johnson, W.E.; Westmoreland, S.; Evans, D.T. Species-Specific Activity of SIV Nef and HIV-1 Vpu in Overcoming Restriction by Tetherin/BST2. PLoS Pathog. 2009, 5, e1000429. [Google Scholar] [CrossRef] [PubMed]
  117. Heigele, A.; Kmiec, D.; Regensburger, K.; Langer, S.; Peiffer, L.; Stürzel, C.M.; Sauter, D.; Peeters, M.; Pizzato, M.; Learn, G.H.; et al. The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild. Cell Host Microbe 2016, 20, 381–391. [Google Scholar] [CrossRef] [PubMed]
  118. Kmiec, D.; Akbil, B.; Ananth, S.; Hotter, D.; Sparrer, K.M.J.; Stürzel, C.M.; Trautz, B.; Ayouba, A.; Peeters, M.; Yao, Z.; et al. SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue. PLoS Pathog. 2018, 14, e1007269. [Google Scholar] [CrossRef]
  119. Gaddis, N.; Sheehy, A.M.; Ahmad, K.M.; Swanson, C.M.; Bishop, K.N.; Beer, B.E.; Marx, P.A.; Gao, F.; Bibollet-Ruche, F.; Hahn, B.H.; et al. Further Investigation of Simian Immunodeficiency Virus Vif Function in Human Cells. J. Virol. 2004, 78, 12041–12046. [Google Scholar] [CrossRef]
  120. Ylinen, L.M.J.; Keckesova, Z.; Wilson, S.J.; Ranasinghe, S.; Towers, G.J. Differential Restriction of Human Immunodeficiency Virus Type 2 and Simian Immunodeficiency Virus SIVmac by TRIM5α Alleles. J. Virol. 2005, 79, 11580–11587. [Google Scholar] [CrossRef]
  121. OhAinle, M.; Kim, K.; Keceli, S.K.; Felton, A.; Campbell, E.; Luban, J.; Emerman, M. TRIM34 restricts HIV-1 and SIV capsids in a TRIM5α-dependent manner. PLoS Pathog. 2020, 16, e1008507. [Google Scholar] [CrossRef]
  122. Pizzato, M.; McCauley, S.M.; Neagu, M.R.; Pertel, T.; Firrito, C.; Ziglio, S.; Dauphin, A.; Zufferey, M.; Berthoux, L.; Luban, J. Lv4 Is a Capsid-Specific Antiviral Activity in Human Blood Cells That Restricts Viruses of the SIVMAC/SIVSM/HIV-2 Lineage Prior to Integration. PLoS Pathog. 2015, 11, e1005050. [Google Scholar] [CrossRef] [PubMed]
  123. Kahl, C.A.; Cannon, P.M.; Oldenburg, J.; Tarantal, A.F.; Kohn, D.B. Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors. Gene Ther. 2008, 15, 1079–1089. [Google Scholar] [CrossRef] [PubMed]
  124. Kim, Y.-J.; Kim, Y.-S.; LaRochelle, A.; Renaud, G.; Wolfsberg, T.G.; Adler, R.; Donahue, R.E.; Hematti, P.; Hong, B.; Roayaei, J.; et al. Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector–transduced CD34+ cells. Blood 2009, 113, 5434–5443. [Google Scholar] [CrossRef] [PubMed]
  125. Poeschla, E.M.; Wong-Staal, F.; Looney, D.J. Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat. Med. 1998, 4, 354–357. [Google Scholar] [CrossRef] [PubMed]
  126. Hartmann, K. Clinical Aspects of Feline Retroviruses: A Review. Viruses 2012, 4, 2684–2710. [Google Scholar] [CrossRef]
  127. Curran, M.A.; Kaiser, S.M.; Achacoso, P.L.; Nolan, G.P. Efficient Transduction of Nondividing Cells by Optimized Feline Immunodeficiency Virus Vectors. Mol. Ther. 2000, 1, 31–38. [Google Scholar] [CrossRef]
  128. Johnston, J.C.; Gasmi, M.; Lim, L.E.; Elder, J.H.; Yee, J.-K.; Jolly, D.J.; Campbell, K.P.; Davidson, B.L.; Sauter, S.L. Minimum Requirements for Efficient Transduction of Dividing and Nondividing Cells by Feline Immunodeficiency Virus Vectors. J. Virol. 1999, 73, 4991–5000. [Google Scholar] [CrossRef]
  129. Khare, P.D.; A Loewen, N.; Teo, W.; A Barraza, R.; Saenz, D.T.; Johnson, D.H.; Poeschla, E.M. Durable, Safe, Multi-gene Lentiviral Vector Expression in Feline Trabecular Meshwork. Mol. Ther. 2008, 16, 97–106. [Google Scholar] [CrossRef]
  130. Yee, J.-K.; Friedmann, T.; Burns, J.C. Chapter 5 Generation of High-Titer Pseudotyped Retroviral Vectors with Very Broad Host Range. Method. Cell Biol. 1994, 43, 99–112. [Google Scholar] [CrossRef]
  131. Song, J.J.; Lee, B.; Chang, J.W.; Kim, J.-H.; Kwon, Y.K.; Lee, H. Optimization of vesicular stomatitis virus-G pseudotyped feline immunodeficiency virus vector for minimized cytotoxicity with efficient gene transfer. Virus Res. 2003, 93, 25–30. [Google Scholar] [CrossRef]
  132. Stein, C.S.; Martins, I.; Davidson, B.L. In The Lymphocytic Choriomeningitis Virus Envelope Glycoprotein Targets Lentiviral Gene Transfer Vector to Neural Progenitors in the Murine Brain. Mol. Ther. 2005, 11, 382–389. [Google Scholar] [CrossRef]
  133. Shai, E.; Palmon, A.; Panet, A.; Marmary, Y.; Sherman, Y.; Curran, M.A.; Galun, E.; Condiotti, R. Prolonged transgene expression in murine salivary glands following non-primate lentiviral vector transduction. Mol. Ther. 2005, 12, 137–143. [Google Scholar] [CrossRef] [PubMed]
  134. Kang, Y.; Stein, C.S.; Heth, J.A.; Sinn, P.L.; Penisten, A.K.; Staber, P.D.; Ratliff, K.L.; Shen, H.; Barker, C.K.; Martins, I.; et al. In Vivo Gene Transfer Using a Nonprimate Lentiviral Vector Pseudotyped with Ross River Virus Glycoproteins. J. Virol. 2002, 76, 9378–9388. [Google Scholar] [CrossRef] [PubMed]
  135. Sinn, P.L.; Burnight, E.R.; Hickey, M.A.; Blissard, G.W.; McCray, P.B. Persistent Gene Expression in Mouse Nasal Epithelia following Feline Immunodeficiency Virus-Based Vector Gene Transfer. J. Virol. 2005, 79, 12818–12827. [Google Scholar] [CrossRef] [PubMed]
  136. Sinn, P.L.; Goreham-Voss, J.D.; Arias, A.C.; Hickey, M.A.; Maury, W.J.; Chikkanna-Gowda, C.; McCray, P.B. Enhanced Gene Expression Conferred by Stepwise Modification of a Nonprimate Lentiviral Vector. Hum. Gene Ther. 2007, 18, 1244–1252. [Google Scholar] [CrossRef]
  137. Sinn, P.L.; Cooney, A.L.; Oakland, M.; E Dylla, D.; Wallen, T.J.; A Pezzulo, A.; Chang, E.H.; McCray, P.B. Lentiviral Vector Gene Transfer to Porcine Airways. Mol. Ther. Nucleic Acids 2012, 1, e56. [Google Scholar] [CrossRef]
  138. Oakland, M.; Maury, W.J.; McCray, P.B.; Sinn, P.L. Intrapulmonary Versus Nasal Transduction of Murine Airways With GP64-pseudotyped Viral Vectors. Mol. Ther. Nucleic Acids 2013, 2, e69. [Google Scholar] [CrossRef]
  139. Loewen, N.A.; Fautsch, M.P.; Peretz, M.; Bahler, C.K.; Cameron, J.D.; Johnson, D.H.; Poeschla, E.M. Genetic Modification of Human Trabecular Meshwork with Lentiviral Vectors. Hum. Gene Ther. 2001, 12, 2109–2119. [Google Scholar] [CrossRef]
  140. Loewen, N.; Bahler, C.; Teo, W.-L.; Whitwam, T.; Peretz, M.; Xu, R.; Fautsch, M.P.; Johnson, D.H.; Poeschla, E.M. Preservation of aqueous outflow facility after second-generation FIV vector-mediated expression of marker genes in anterior segments of human eyes. Investig. Ophthalmol. Vis. Sci. 2002, 43, 3686–3690. [Google Scholar]
  141. Lotery, A.; Derksen, T.A.; Russell, S.; Mullins, R.F.; Sauter, S.; Affatigato, L.M.; Stone, E.M.; Davidson, B.L. Gene Transfer to the Nonhuman Primate Retina with Recombinant Feline Immunodeficiency Virus Vectors. Hum. Gene Ther. 2002, 13, 689–696. [Google Scholar] [CrossRef]
  142. Barraza, R.A.; Rasmussen, C.A.; A Loewen, N.; Cameron, J.D.; Gabelt, B.T.; Teo, W.-L.; Kaufman, P.L.; Poeschla, E.M.E.M. Prolonged Transgene Expression with Lentiviral Vectors in the Aqueous Humor Outflow Pathway of Nonhuman Primates. Hum. Gene Ther. 2009, 20, 191–200. [Google Scholar] [CrossRef] [PubMed]
  143. Derksen, T.A.; Sauter, S.L.; Davidson, B.L. Feline immunodeficiency virus vectors. Gene transfer to mouse retina following intravitreal injection. J. Gene Med. 2002, 4, 463–469. [Google Scholar] [CrossRef] [PubMed]
  144. Janic, B.; Zhang, X.; Li, W. Feline immunodeficiency virus-mediated long-term transgene expression in undifferentiated retinal progenitor cells and its downregulation in differentiated cells. Mol. Vis. 2008, 14, 2117–2125. [Google Scholar] [PubMed]
  145. Cheng, L.; Toyoguchi, M.; Looney, D.J.; Lee, J.; Davidson, M.C.; Freeman, W.R. Efficient gene transfer to retinal pigment epithelium cells with long-term expression. Retin. J. Retin. Vit. Dis. 2005, 25, 193–201. [Google Scholar] [CrossRef] [PubMed]
  146. Liu, C.; Cheng, Q.; Nguyen, T.; A Bonanno, J. Knockdown of NBCe1 in vivo compromises the corneal endothelial pump. Investig. Opthalmology Vis. Sci. 2010, 51, 5190–5197. [Google Scholar] [CrossRef]
  147. Hatziioannou, T.; Perez-Caballero, D.; Yang, A.; Cowan, S.; Bieniasz, P.D. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5. Proc. Natl. Acad. Sci. USA 2004, 101, 10774–10779. [Google Scholar] [CrossRef]
  148. Saenz, D.T.; Teo, W.; Olsen, J.C.; Poeschla, E.M. Restriction of Feline Immunodeficiency Virus by Ref1, Lv1, and Primate TRIM5α Proteins. J. Virol. 2005, 79, 15175–15188. [Google Scholar] [CrossRef]
  149. Towers, G.J.; Collins, M.; Takeuchi, Y. Abrogation of Ref1 Retrovirus Restriction in Human Cells. J. Virol. 2002, 76, 2548–2550. [Google Scholar] [CrossRef]
  150. Olsen, J.C. Gene transfer vectors derived from equine infectious anemia virus. Gene Ther. 1998, 5, 1481–1487. [Google Scholar] [CrossRef]
  151. O’Rourke, J.P.; Olsen, J.C.; A Bunnell, B. Optimization of equine infectious anemia derived vectors for hematopoietic cell lineage gene transfer. Gene Ther. 2004, 12, 22–29. [Google Scholar] [CrossRef]
  152. Mitrophanous, K.; Yoon, S.; Rohll, J.B.; Patil, D.; Wilkes, F.J.; Kim, V.N.; Kingsman, S.M.; Kingsman, A.J.; Mazarakis, N.D. Stable gene transfer to the nervous system using a non-primate lentiviral vector. Gene Ther. 1999, 6, 1808–1818. [Google Scholar] [CrossRef] [PubMed]
  153. Wong, L.-F.; Azzouz, M.; Walmsley, L.E.; Askham, Z.; Wilkes, F.J.; Mitrophanous, K.A.; Kingsman, S.M.; Mazarakis, N.D. Erratum to “Transduction patterns of pseudotyped lentiviral vectors in the nervous system”. Mol. Ther. 2004, 9, 765. [Google Scholar] [CrossRef]
  154. Ikeda, Y.; Collins, M.; Radcliffe, P.; Mitrophanous, K.; Takeuchi, Y. Gene transduction efficiency in cells of different species by HIV and EIAV vectors. Gene Ther. 2002, 9, 932–938. [Google Scholar] [CrossRef] [PubMed]
  155. Yamada, K.; Olsen, J.C.; Patel, M.; Rao, K.W.; Walsh, C.E. Functional Correction of Fanconi Anemia Group C Hematopoietic Cells by the Use of a Novel Lentiviral Vector. Mol. Ther. 2001, 3, 485–490. [Google Scholar] [CrossRef] [PubMed]
  156. O’Rourke, J.P.; Newbound, G.C.; Kohn, D.B.; Olsen, J.C.; Bunnell, B.A. Comparison of Gene Transfer Efficiencies and Gene Expression Levels Achieved with Equine Infectious Anemia Virus- and Human Immunodeficiency Virus Type 1-Derived Lentivirus Vectors. J. Virol. 2002, 76, 1510–1515. [Google Scholar] [CrossRef]
  157. Beutelspacher, S.C.; Ardjomand, N.; Tan, P.H.; Patton, G.S.; Larkin, D.F.P.; George, A.J.; O McClure, M. Comparison of HIV-1 and EIAV-based lentiviral vectors in corneal transduction. Exp. Eye Res. 2005, 80, 787–794. [Google Scholar] [CrossRef] [PubMed]
  158. Stewart, H.J.; A Leroux-Carlucci, M.; Sion, C.J.M.; A Mitrophanous, K.; A Radcliffe, P. Development of inducible EIAV-based lentiviral vector packaging and producer cell lines. Gene Ther. 2009, 16, 805–814. [Google Scholar] [CrossRef]
  159. Rohll, J.B.; Mitrophanous, K.A.; Martin-Rendon, E.; Ellard, F.M.; Radcliffe, P.A.; Mazarakis, N.D.; Kingsman, S.M. [27] Design, production, safety, evaluation, and clinical applications of nonprimate lentiviral vectors. Methods Enzymol. 2002, 346, 466–500. [Google Scholar] [CrossRef]
  160. Campochiaro, P.A.; Lauer, A.K.; Sohn, E.H.; Mir, T.A.; Naylor, S.; Anderton, M.C.; Kelleher, M.; Harrop, R.; Ellis, S.; Mitrophanous, K.A. Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Hum. Gene Ther. 2016, 28, 99–111. [Google Scholar] [CrossRef]
  161. Palfi, S.; Gurruchaga, J.M.; Ralph, G.S.; Lepetit, H.; Lavisse, S.; Buttery, P.C.; Watts, C.; Miskin, J.; Kelleher, M.; Deeley, S.; et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: A dose escalation, open-label, phase 1/2 trial. Lancet 2014, 383, 1138–1146. [Google Scholar] [CrossRef]
  162. Mselli-Lakhal, L.; Favier, C.; Teixeira, M.F.D.S.; Chettab, K.; Legras, C.; Ronfort, C.; Verdier, G.; Mornex, J.F.; Chebloune, Y. Defective RNA packaging is responsible for low transduction efficiency of CAEV-based vectors. Arch. Virol. 1998, 143, 681–695. [Google Scholar] [CrossRef] [PubMed]
  163. Mselli-Lakhal, L.; Favier, C.; Leung, K.; Guiguen, F.; Grézel, D.; Miossec, P.; Mornex, J.-F.; Narayan, O.; Quérat, G.; Chebloune, Y. Lack of Functional Receptors Is the Only Barrier That Prevents Caprine Arthritis-Encephalitis Virus from Infecting Human Cells. J. Virol. 2000, 74, 8343–8348. [Google Scholar] [CrossRef] [PubMed]
  164. Mselli-Lakhal, L.; Guiguen, F.; Greenland, T.; Mornex, J.-F.; Chebloune, Y. Gene transfer system derived from the caprine arthritis–encephalitis lentivirus. J. Virol. Methods 2006, 136, 177–184. [Google Scholar] [CrossRef] [PubMed]
  165. Berkowitz, R.D.; Ilves, H.; Plavec, I.; Veres, G. Gene Transfer Systems Derived from Visna Virus: Analysis of Virus Production and Infectivity. Virology 2001, 279, 116–129. [Google Scholar] [CrossRef] [PubMed]
  166. Metharom, P.; Takyar, S.; Xia, H.H.; Ellem, K.A.O.; Macmillan, J.; Shepherd, R.W.; Wilcox, G.E.; Wei, M.Q. Novel bovine lentiviral vectors based on Jembrana disease virus. J. Gene Med. 2000, 2, 176–185. [Google Scholar] [CrossRef]
  167. Berkowitz, R.; Ilves, H.; Lin, W.Y.; Eckert, K.; Coward, A.; Tamaki, S.; Veres, G.; Plavec, I. Construction and Molecular Analysis of Gene Transfer Systems Derived from Bovine Immunodeficiency Virus. J. Virol. 2001, 75, 3371–3382. [Google Scholar] [CrossRef]
  168. Takahashi, K.; Luo, T.; Saishin, Y.; Saishin, Y.; Sung, J.; Hackett, S.; Brazzell, R.; Kaleko, M.; Campochiaro, P.A. Sustained Transduction of Ocular Cells with a Bovine Immunodeficiency Viral Vector. Hum. Gene Ther. 2002, 13, 1305–1316. [Google Scholar] [CrossRef]
  169. Matukonis, M.; Li, M.; Molina, R.P.; Paszkiet, B.; Kaleko, M.; Luo, T. Development of Second- and Third-Generation Bovine Immunodeficiency Virus-Based Gene Transfer Systems. Hum. Gene Ther. 2002, 13, 1293–1303. [Google Scholar] [CrossRef]
  170. Hacein-Bey-Abina, S.; Von Kalle, C.; Schmidt, M.; McCormack, M.P.; Wulffraat, N.; Leboulch, P.; Lim, A.; Osborne, C.S.; Pawliuk, R.; Morillon, E.; et al. LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1. Science 2003, 302, 415–419. [Google Scholar] [CrossRef]
  171. Hacein-Bey-Abina, S.; Garrigue, A.; Wang, G.P.; Soulier, J.; Lim, A.; Morillon, E.; Clappier, E.; Caccavelli, L.; Delabesse, E.; Beldjord, K.; et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Investig. 2008, 118, 3132–3142. [Google Scholar] [CrossRef]
  172. Wang, G.P.; Ciuffi, A.; Leipzig, J.; Berry, C.C.; Bushman, F.D. HIV integration site selection: Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 2007, 17, 1186–1194. [Google Scholar] [CrossRef] [PubMed]
  173. Wu, X.; Li, Y.; Crise, B.; Burgess, S.M. Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration. Science 2003, 300, 1749–1751. [Google Scholar] [CrossRef] [PubMed]
  174. Biffi, A.; Bartolomae, C.C.; Cesana, D.; Cartier, N.; Aubourg, P.; Ranzani, M.; Cesani, M.; Benedicenti, F.; Plati, T.; Rubagotti, E.; et al. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood 2011, 117, 5332–5339. [Google Scholar] [CrossRef] [PubMed]
  175. Goldstone, D.C.; Ennis-Adeniran, V.; Hedden, J.J.; Groom, H.C.T.; Rice, G.I.; Christodoulou, E.; Walker, P.A.; Kelly, G.; Haire, L.F.; Yap, M.W.; et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 2011, 480, 379–382. [Google Scholar] [CrossRef]
  176. E Mangeot, P.; Duperrier, K.; Nègre, D.; Boson, B.; Rigal, D.; Cosset, F.-L.; Darlix, J.-L. High Levels of Transduction of Human Dendritic Cells with Optimized SIV Vectors. Mol. Ther. 2002, 5, 283–290. [Google Scholar] [CrossRef]
  177. Mereby, S.A.; Maehigashi, T.; Holler, J.M.; Kim, N.-H.; Schinazi, R.F.; Kim, B. Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts. J. Boil. Chem. 2018, 293, 16402–16412. [Google Scholar] [CrossRef]
  178. Laguette, N.; Sobhian, B.; Casartelli, N.; Ringeard, M.; Chable-Bessia, C.; Ségéral, E.; Yatim, A.; Emiliani, S.; Schwartz, O.; Benkirane, M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 2011, 474, 654–657. [Google Scholar] [CrossRef]
Figure 1. Engineering of HIV-1-based lentiviral vector (LV) systems. Wild-type (wt) genomes of (A) Moloney murine leukemia virus, a simple retrovirus, and (B) HIV-1. Essential genes—gag, pol, env—encoding structural and enzymatic proteins have been indicated in light grey. Accessory genes—vif, vpr, vpu, and nef—are indicated in dark grey. Regulatory genes—rev and tat—are indicated in black. (C) First-generation of HIV-1-based LVs. All HIV-1 proteins, except for Env and Vpu, are included in the packaging plasmid construct (top). The heterologous pseudotyping envelope is provided in trans in a separate plasmid (middle). The vector genome encoding the transgene contains intact wt long terminal repeats (LTRs) (bottom). Expression of the packaging and pseudotyping plasmids are achieved via strong constitutive promoters. (D) In the second-generation LVs, all accessory proteins are removed, but the system is still rev and tat dependent. (E) In the current third-generation system, tat is removed, and essential HIV-1 genes are split into two separate plasmids. Vector genome LTRs are modified to include a 5′ promoter and SIN 3′ U3 element (∆U3). Other cis-acting modifications have also been made, including the addition of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), polyA sites, and the central polypurine tract (cPPT). U3: LTR element derived from sequences unique to the 3′ end of the RNA genome; R: LTR element derived from sequences repeated in both LTRs; U5: LTR element derived from sequences unique to the 5′ end of the RNA genome; Ψ: packaging signal; RRE: rev response element. Arrows stand for constitutive promoters.
Figure 1. Engineering of HIV-1-based lentiviral vector (LV) systems. Wild-type (wt) genomes of (A) Moloney murine leukemia virus, a simple retrovirus, and (B) HIV-1. Essential genes—gag, pol, env—encoding structural and enzymatic proteins have been indicated in light grey. Accessory genes—vif, vpr, vpu, and nef—are indicated in dark grey. Regulatory genes—rev and tat—are indicated in black. (C) First-generation of HIV-1-based LVs. All HIV-1 proteins, except for Env and Vpu, are included in the packaging plasmid construct (top). The heterologous pseudotyping envelope is provided in trans in a separate plasmid (middle). The vector genome encoding the transgene contains intact wt long terminal repeats (LTRs) (bottom). Expression of the packaging and pseudotyping plasmids are achieved via strong constitutive promoters. (D) In the second-generation LVs, all accessory proteins are removed, but the system is still rev and tat dependent. (E) In the current third-generation system, tat is removed, and essential HIV-1 genes are split into two separate plasmids. Vector genome LTRs are modified to include a 5′ promoter and SIN 3′ U3 element (∆U3). Other cis-acting modifications have also been made, including the addition of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), polyA sites, and the central polypurine tract (cPPT). U3: LTR element derived from sequences unique to the 3′ end of the RNA genome; R: LTR element derived from sequences repeated in both LTRs; U5: LTR element derived from sequences unique to the 5′ end of the RNA genome; Ψ: packaging signal; RRE: rev response element. Arrows stand for constitutive promoters.
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Figure 2. Genomic organization of non-human lentiviruses. Long terminal repeats (LTRs) and essential genes (i.e., gag, pol, env) are colored white. Accessory and regulatory genes are colored grey. Notable differences in the genome organization of each lentivirus are indicated in red.
Figure 2. Genomic organization of non-human lentiviruses. Long terminal repeats (LTRs) and essential genes (i.e., gag, pol, env) are colored white. Accessory and regulatory genes are colored grey. Notable differences in the genome organization of each lentivirus are indicated in red.
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Table 1. Comparison of accessory and regulatory genes in primate lentiviruses. HIV-1: human immunodeficiency virus type 1; HIV-2: human immunodeficiency virus type 2; SIVcpz: simian immunodeficiency virus from chimpanzees; SIVsmm: simian immunodeficiency virus from sooty mangabeys; SIVagm: simian immunodeficiency virus from African green monkeys; SIVlho: simian immunodeficiency virus from L’Hoest monkeys; SIVsyk: simian immunodeficiency virus from Sykes’ monkeys; SIVcol: simian immunodeficiency virus from Colobus guerezas.
Table 1. Comparison of accessory and regulatory genes in primate lentiviruses. HIV-1: human immunodeficiency virus type 1; HIV-2: human immunodeficiency virus type 2; SIVcpz: simian immunodeficiency virus from chimpanzees; SIVsmm: simian immunodeficiency virus from sooty mangabeys; SIVagm: simian immunodeficiency virus from African green monkeys; SIVlho: simian immunodeficiency virus from L’Hoest monkeys; SIVsyk: simian immunodeficiency virus from Sykes’ monkeys; SIVcol: simian immunodeficiency virus from Colobus guerezas.
HIV-1HIV-2SIVcpzSIVsmmSIVagmSIVlhoSIVsykSIVcol
rev++++++++
vif++++++++
tat++++++++
vpr++++++++
vpx++
vpu++
nef++++++++
Table 2. Comparison of accessory and regulatory genes in non-human lentiviruses. FIV: feline immunodeficiency virus; EIAV: equine infectious anemia virus; CAEV: caprine arthritis encephalitis virus; VMV: visna-maedi virus; BIV: bovine immunodeficiency virus; JDV: jembrana disease virus.
Table 2. Comparison of accessory and regulatory genes in non-human lentiviruses. FIV: feline immunodeficiency virus; EIAV: equine infectious anemia virus; CAEV: caprine arthritis encephalitis virus; VMV: visna-maedi virus; BIV: bovine immunodeficiency virus; JDV: jembrana disease virus.
SIVsmmFIVEIAVCAEV/VMVBIVJDV
rev++++++
vif+++++
tat++++
vpr+
vpx+
nef+
orf2+
orfS+
s2+
vpw-+
vpy-+
tmx-++
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