Special Issue "Antiretroviral Drug Development and HIV Cure Research"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (30 June 2020).

Special Issue Editors

Prof. Dr. Enzo Tramontano
E-Mail Website
Guest Editor
Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy
Interests: virology; microbiology; antiviral drugs; drug development; endogenous retroviruses; innate immunity
Special Issues and Collections in MDPI journals
Prof. Dr. Ben Berkhout
E-Mail Website
Guest Editor
Laboratory of Experimental Virology, Department of Medical Microbiology, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
Interests: HIV-1 gene expression and latency; viral RNA structure and function; virus evolution; antiviral therapy; patient-related virus studies
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection that results in acquired immunodeficiency syndrome (AIDS) if left untreated. Around 37 million people in the world live with HIV-1, with around 2 million new infections each year. While combined antiretroviral therapy (ART) has been shown to be very effective, inhibiting HIV-1 replication and preventing the development of AIDS, it has to be administered life-long, exposing the patients to possible side-effects. In addition, increasing emergence of resistance to ARV drugs could challenge ART efficacy, especially considering the international effort to reach 40% of HIV-infected people that live in developing countries and are yet to receive treatment. Therefore, despite ART effectiveness, the generation of new drugs against novel targets or with more favorable pharmacokinetics profiles and the development of novel delivery systems has to continue.

Furthermore, ART can limit HIV replication, but treatment interruption triggers a rapid viral rebound, indicating that HIV-1 forms long-lived reservoirs in infected individuals that persist despite decades of suppressive ART. An HIV cure remains a challenge and is not yet within reach. Depletion or silencing of the viral reservoirs has been considered the principal goal of HIV-1 curative strategies. However, very limited successes have been achieved so far, indicating the need for gathering more basic knowledge on HIV-1 latency in order to be able to design more effective therapeutic interventions.

In this Special Issue, we seek reviews and original research articles that discuss the latest developments in HIV drug development and drug delivery and approaches to understand HIV latency. The latter includes the interaction of HIV with human endogenous retroviruses. We hope to accelerate the design of novel strategies to eradicate this viral infection.

Prof. Enzo Tramontano
Prof. Dr. Ben Berkhout
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HIV latency
  • HIV reservoir
  • HIV drug development
  • HIV drug delivery
  • HERV
  • HIV eradication

Published Papers (13 papers)

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Research

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Open AccessArticle
Multiplexed tat-Targeting CRISPR-Cas9 Protects T Cells from Acute HIV-1 Infection with Inhibition of Viral Escape
Viruses 2020, 12(11), 1223; https://doi.org/10.3390/v12111223 - 28 Oct 2020
Viewed by 995
Abstract
HIV-1 cure strategy by means of proviral knock-out using CRISPR-Cas9 has been hampered by the emergence of viral resistance against the targeting guide RNA (gRNA). Here, we proposed multiple, concentrated gRNA attacks against HIV-1 regulatory genes to block viral escape. The T cell [...] Read more.
HIV-1 cure strategy by means of proviral knock-out using CRISPR-Cas9 has been hampered by the emergence of viral resistance against the targeting guide RNA (gRNA). Here, we proposed multiple, concentrated gRNA attacks against HIV-1 regulatory genes to block viral escape. The T cell line were transduced with single and multiple gRNAs targeting HIV-1 tat and rev using lentiviral-based CRISPR-Cas9, followed by replicative HIV-1NL4-3 challenge in vitro. Viral p24 rebound was observed for almost all gRNAs, but multiplexing three tat-targeting gRNAs maintained p24 suppression and cell viability, indicating the inhibition of viral escape. Multiplexed tat gRNAs inhibited acute viral replication in the 2nd round of infection, abolished cell-associated transmission to unprotected T cells, and maintained protection through 45 days, post-infection (dpi) after a higher dose of HIV-1 infection. Finally, we describe here for the first time the assembly of all-in-one lentiviral vectors containing three and six gRNAs targeting tat and rev. A single-vector tat-targeting construct shows non-inferiority to the tat-targeting multi-vector in low-dose HIV-1 infection. We conclude that Cas9-induced, DNA repair-mediated mutations in tat are sufficiently deleterious and deplete HIV-1 fitness, and multiplexed disruption of tat further limits the possibility of an escape mutant arising, thus elevating the potential of CRISPR-Cas9 to achieve a long-term HIV-1 cure. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
Targeting HIV-1 RNase H: N’-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants
Viruses 2020, 12(7), 729; https://doi.org/10.3390/v12070729 - 06 Jul 2020
Cited by 2 | Viewed by 719
Abstract
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase [...] Read more.
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action of N’-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 µM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound 13 targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound 13 binds within the RNase H domain in a position different from other selective RNase H inhibitors; site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound 13 can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
A High-Throughput HIV-1 Drug Screening Platform, Based on Lentiviral Vectors and Compatible with Biosafety Level-1
Viruses 2020, 12(5), 580; https://doi.org/10.3390/v12050580 - 25 May 2020
Cited by 1 | Viewed by 982
Abstract
HIV-1 infection is a complex, multi-step process involving not only viral, but also multiple cellular factors. To date, drug discovery methods have primarily focused on the inhibition of single viral proteins. We present an efficient and unbiased approach, compatible with biosafety level 1 [...] Read more.
HIV-1 infection is a complex, multi-step process involving not only viral, but also multiple cellular factors. To date, drug discovery methods have primarily focused on the inhibition of single viral proteins. We present an efficient and unbiased approach, compatible with biosafety level 1 (BSL-1) conditions, to identify inhibitors of HIV-1 reverse transcription, intracellular trafficking, nuclear entry and genome integration. Starting with a fluorescent assay setup, we systematically improved the screening methodology in terms of stability, efficiency and pharmacological relevance. Stability and throughput were optimized by switching to a luciferase-based readout. BSL-1 compliance was achieved without sacrificing pharmacological relevance by using lentiviral particles pseudo-typed with the mouse ecotropic envelope protein to transduce human PM1 T cells gene-modified to express the corresponding murine receptor. The cellular assay was used to screen 26,048 compounds selected for maximum diversity from a 200,640-compound in-house library. This yielded z’ values greater than 0.8 with a hit rate of 3.3% and a confirmation rate of 50%. We selected 93 hits and enriched the collection with 279 similar compounds from the in-house library to identify promising structural features. The most active compounds were validated using orthogonal assay formats. The similarity of the compound profiles across the different platforms demonstrated that the reported lentiviral assay system is a robust and versatile tool for the identification of novel HIV-1 inhibitors. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
An Elvitegravir Nanoformulation Crosses the Blood–Brain Barrier and Suppresses HIV-1 Replication in Microglia
Viruses 2020, 12(5), 564; https://doi.org/10.3390/v12050564 - 20 May 2020
Cited by 7 | Viewed by 1247
Abstract
Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication [...] Read more.
Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication in the brain and in subsequent HAND pathogenesis. However, due to the limited ability of ART drugs to cross the blood–brain barrier (BBB) after systemic administration, in addition to efflux transporter expression on microglia, the efficacy of ART drugs for viral suppression in microglia is suboptimal. Previously, we developed novel poly (lactic-co-glycolic acid) (PLGA)-based elvitegravir nanoparticles (PLGA-EVG NPs), which showed improved BBB penetration in vitro and improved viral suppression in HIV-1-infected primary macrophages, after crossing an in vitro BBB model. Our objective in the current study was to evaluate the efficacy of our PLGA-EVG NPs in an important central nervous system (CNS) HIV-1 reservoir, i.e., microglia. In this study, we evaluated the cyto-compatibility of the PLGA-EVG NPs in microglia, using an XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and cellular morphology observation. We also studied the endocytosis pathway and the subcellular localization of PLGA NPs in microglia, using various endocytosis inhibitors and subcellular localization markers. We determined the ability of PLGA-EVG NPs to suppress HIV-1 replication in microglia, after crossing an in vitro BBB model. We also studied the drug levels in mouse plasma and brain tissue, using immunodeficient NOD scid gamma (NSG) mice, and performed a pilot study, to evaluate the efficacy of PLGA-EVG NPs on viral suppression in the CNS, using an HIV-1 encephalitic (HIVE) mouse model. From our results, the PLGA-EVG NPs showed ~100% biocompatibility with microglia, as compared to control cells. The internalization of PLGA NPs in microglia occurred through caveolae-/clathrin-mediated endocytosis. PLGA NPs can also escape from endo-lysosomal compartments and deliver the therapeutics to cells efficiently. More importantly, the PLGA-EVG NPs were able to show ~25% more viral suppression in HIV-1-infected human-monocyte-derived microglia-like cells after crossing the in vitro BBB compared to the EVG native drug, without altering BBB integrity. PLGA-EVG NPs also showed a ~two-fold higher level in mouse brain and a trend of decreasing CNS HIV-1 viral load in HIV-1-infected mice. Overall, these results help us to create a safe and efficient drug delivery method to target HIV-1 reservoirs in the CNS, for potential clinical use. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
Comprehensive Analysis of HERV Transcriptome in HIV+ Cells: Absence of HML2 Activation and General Downregulation of Individual HERV Loci
Viruses 2020, 12(4), 481; https://doi.org/10.3390/v12040481 - 23 Apr 2020
Cited by 2 | Viewed by 1035
Abstract
Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 [...] Read more.
Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 replication, either complementing HIV or possibly influencing antiretroviral therapy. However, little information is available on the expression of other HERV groups in HIV infection. In the present study, we used a bioinformatics pipeline to investigate the transcriptional modulation of approximately 3250 well-characterized HERV loci, comparing their expression in a public RNA-seq profile, including a HIV-1-infected and a control T cell culture. In our pilot study, we found approximately 200 HERV loci belonging to 35 HERV groups that were expressed in one or both conditions, with transcripts per million (TPM) values from 1 to >500. Intriguingly, HML2 elements constituted only the 3% of expressed HERV loci, and in most cases (160) HERV expression was downregulated in the HIV-infected culture, showing from a 1- to 14-fold decrease as compared to uninfected cells. HERV transcriptome has been inferred de novo and employed to predict a total of about 950 HERV open reading frames (ORFs). These have been validated according to the coding potential and estimated abundance of the corresponding transcripts, leading to a set of 57 putative proteins potentially encoded by 23 HERV loci. Analysis showed that some individual loci have a coding potential that deserves further investigation. Among them, a HML6 provirus at locus 19q13.43 was predicted to produce a transcript showing the highest TPM among HERV-derived transcripts, being upregulated in HIV+ cells and inferred to produce Gag and Env puteins with possible biological activity. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules
Viruses 2020, 12(4), 452; https://doi.org/10.3390/v12040452 - 16 Apr 2020
Cited by 6 | Viewed by 1012
Abstract
HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral [...] Read more.
HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking PF74. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
CRISPR-Cas9 Dual-gRNA Attack Causes Mutation, Excision and Inversion of the HIV-1 Proviral DNA
Viruses 2020, 12(3), 330; https://doi.org/10.3390/v12030330 - 18 Mar 2020
Cited by 4 | Viewed by 1541
Abstract
Although several studies demonstrated that the HIV proviral DNA can be effectively targeted and inactivated by the CRISPR-Cas9 system, the precise inactivation mechanism has not yet been analyzed. Whereas some studies suggested efficient proviral DNA excision upon dual-gRNA/Cas9 treatment, we previously demonstrated that [...] Read more.
Although several studies demonstrated that the HIV proviral DNA can be effectively targeted and inactivated by the CRISPR-Cas9 system, the precise inactivation mechanism has not yet been analyzed. Whereas some studies suggested efficient proviral DNA excision upon dual-gRNA/Cas9 treatment, we previously demonstrated that hypermutation of the target sites correlated with permanent virus inactivation. To better understand the mechanism underlying HIV inactivation, we analyzed the proviral DNA upon Cas9 attack with gRNA pairs. We observed that dual-gRNA targeting resulted more frequently in target site mutation than fragment excision, while fragment inversion was rarely observed. The frequencies varied for different gRNA combinations without an obvious relationship with the distance between the target sites, indicating that other gRNA and target DNA characteristics influence the DNA cleavage and repair processes. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessArticle
HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice
Viruses 2020, 12(2), 204; https://doi.org/10.3390/v12020204 - 12 Feb 2020
Cited by 2 | Viewed by 812
Abstract
Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide [...] Read more.
Human immunodeficiency virus (HIV)-infected individuals treated with anti-retroviral therapy often develop chronic non-infectious lung disease. To determine the mechanism of HIV-1-associated lung disease we evaluated the dynamics of lung leukocytes in HIV-1 transgenic (Tg) mice with integrated HIV-1 provirus. In HIV-Tg mice, lipopolysacharide (LPS) induced significantly higher levels of neutrophil infiltration in the lungs compared to wild-type (WT) mice. In WT mice, the initial neutrophil infiltration was followed by macrophage infiltration and fast resolution of leukocytes infiltration. In HIV-Tg mice, resolution of lung infiltration by both neutrophils and macrophages was significantly delayed, with macrophages accumulating in the lumen of lung capillaries resulting in a 45% higher rate of mortality. Trans-endothelial migration of HIV-Tg macrophages was significantly reduced in vitro and this reduction correlated with lower HIV-1 gene expression. HIV-1 transcription inhibitor, 1E7-03, enhanced trans-endothelial migration of HIV-Tg macrophages in vitro, decreased lung neutrophil infiltration in vivo, and increased lung macrophage levels in HIV-Tg mice. Moreover, 1E7-03 reduced levels of inflammatory IL-6 cytokine, improved bleeding score and decreased lung injury. Together this indicates that inhibitors of HIV-1 transcription can correct abnormal dynamics of leukocyte infiltration in HIV-Tg, pointing to the utility of transcription inhibition in the treatment of HIV-1 associated chronic lung disease. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Review

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Open AccessReview
Block-And-Lock: New Horizons for a Cure for HIV-1
Viruses 2020, 12(12), 1443; https://doi.org/10.3390/v12121443 - 15 Dec 2020
Cited by 4 | Viewed by 1012
Abstract
HIV-1/AIDS remains a global public health problem. The world health organization (WHO) reported at the end of 2019 that 38 million people were living with HIV-1 worldwide, of which only 67% were accessing antiretroviral therapy (ART). Despite great success in the clinical management [...] Read more.
HIV-1/AIDS remains a global public health problem. The world health organization (WHO) reported at the end of 2019 that 38 million people were living with HIV-1 worldwide, of which only 67% were accessing antiretroviral therapy (ART). Despite great success in the clinical management of HIV-1 infection, ART does not eliminate the virus from the host genome. Instead, HIV-1 remains latent as a viral reservoir in any tissue containing resting memory CD4+ T cells. The elimination of these residual proviruses that can reseed full-blown infection upon treatment interruption remains the major barrier towards curing HIV-1. Novel approaches have recently been developed to excise or disrupt the virus from the host cells (e.g., gene editing with the CRISPR-Cas system) to permanently shut off transcription of the virus (block-and-lock and RNA interference strategies), or to reactivate the virus from cell reservoirs so that it can be eliminated by the immune system or cytopathic effects (shock-and-kill strategy). Here, we will review each of these approaches, with the major focus placed on the block-and-lock strategy. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessReview
Contribution of Human Retroviruses to Disease Development—A Focus on the HIV– and HERV–Cancer Relationships and Treatment Strategies
Viruses 2020, 12(8), 852; https://doi.org/10.3390/v12080852 - 04 Aug 2020
Viewed by 1096
Abstract
Animal retroviruses are known for their transforming potential, and this is also true for the ones hosted by humans, which have gathered expanding attention as one of the potent causative agents in various disease, including specific cancer types. For instance, Human T Lymphotropic [...] Read more.
Animal retroviruses are known for their transforming potential, and this is also true for the ones hosted by humans, which have gathered expanding attention as one of the potent causative agents in various disease, including specific cancer types. For instance, Human T Lymphotropic virus (HTLV) is a well-studied class of oncoviruses causing T cell leukemia, while human immunodeficiency virus (HIV) leads to acquired immunodeficiency syndrome (AIDS), which is linked to a series of defining cancers including Kaposi sarcoma, certain types of non-Hodgkin lymphoma, and cervical cancer. Of note, in addition to these “modern” exogenous retroviruses, our genome harbors a staggering number of human endogenous retroviruses (HERVs). HERVs are the genetic remnants of ancient retroviral germline infection of human ancestors and are typically silenced in normal tissues due to inactivating mutations and sequence loss. While some HERV elements have been appropriated and contribute to human physiological functions, others can be reactivated through epigenetic dysregulations to express retroviral elements and promote carcinogenesis. Conversely, HERV replication intermediates or protein products can also serve as intrinsic pathogen-associated molecular patterns that cause the immune system to interpret it as an exogenous infection, thereby stimulating immune responses against tumors. As such, HERVs have also been targeted as a potential internal strategy to sensitize tumor cells for promising immunotherapies. In this review, we discuss the dynamic role of human retroviruses in cancer development, focusing on HIV and HERVs contribution. We also describe potential treatment strategies, including immunotherapeutic targeting of HERVs, inhibiting DNA methylation to expose HERV signatures, and the use of antiretroviral drugs against HIV and HERVs, which can be employed as prospective anti-cancer modalities. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessReview
Differences in HIV Markers between Infected Individuals Treated with Different ART Regimens: Implications for the Persistence of Viral Reservoirs
Viruses 2020, 12(5), 489; https://doi.org/10.3390/v12050489 - 27 Apr 2020
Viewed by 890
Abstract
In adherent individuals, antiretroviral therapy (ART) suppresses HIV replication, restores immune function, and prevents the development of AIDS. However, ART is not curative and has to be followed lifelong. Persistence of viral reservoirs forms the major obstacle to an HIV cure. HIV latent [...] Read more.
In adherent individuals, antiretroviral therapy (ART) suppresses HIV replication, restores immune function, and prevents the development of AIDS. However, ART is not curative and has to be followed lifelong. Persistence of viral reservoirs forms the major obstacle to an HIV cure. HIV latent reservoirs persist primarily by cell longevity and proliferation, but replenishment by residual virus replication despite ART has been proposed as another potential mechanism of HIV persistence. It is a matter of debate whether different ART regimens are equally potent in suppressing HIV replication. Here, we summarized the current knowledge on the role of ART regimens in HIV persistence, focusing on differences in residual plasma viremia and other virological markers of the HIV reservoir between infected individuals treated with combination ART composed of different antiretroviral drug classes. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessReview
The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection
Viruses 2020, 12(4), 412; https://doi.org/10.3390/v12040412 - 07 Apr 2020
Cited by 3 | Viewed by 1319
Abstract
Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily [...] Read more.
Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily pill intake, the treatment is unable to clear the infection from the body. Furthermore, as cART drugs exhibit a much lower concentration in key HIV residual tissues, such as the brain and lymph nodes, there is a rationale for the development of drugs with enhanced tissue penetration. In addition, the treatment, with combinations of multiple different antiviral drugs that display different pharmacokinetic profiles, requires a strict dosing regimen to avoid the emergence of drug-resistant viral strains. An intriguing opportunity lies within the development of long-acting, synthetic scaffolds for delivering cART. These scaffolds can be designed with the goal to reduce the frequency of dosing and furthermore, hold the possibility of potential targeting to key HIV residual sites. Moreover, the synthesis of combinations of therapy as one molecule could unify the pharmacokinetic profiles of different antiviral drugs, thereby eliminating the consequences of sub-therapeutic concentrations. This review discusses the recent progress in the development of long-acting and tissue-targeted therapies against HIV for the delivery of direct antivirals, and examines how such developments fit in the context of exploring HIV cure strategies. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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Open AccessReview
Block-And-Lock Strategies to Cure HIV Infection
Viruses 2020, 12(1), 84; https://doi.org/10.3390/v12010084 - 10 Jan 2020
Cited by 20 | Viewed by 2182
Abstract
Today HIV infection cannot be cured due to the presence of a reservoir of latently infected cells inducing a viral rebound upon treatment interruption. Hence, the latent reservoir is considered as the major barrier for an HIV cure. So far, efforts to completely [...] Read more.
Today HIV infection cannot be cured due to the presence of a reservoir of latently infected cells inducing a viral rebound upon treatment interruption. Hence, the latent reservoir is considered as the major barrier for an HIV cure. So far, efforts to completely eradicate the reservoir via a shock-and-kill approach have proven difficult and unsuccessful. Therefore, more research has been done recently on an alternative block-and-lock functional cure strategy. In contrast to the shock-and-kill strategy that aims to eradicate the entire reservoir, block-and-lock aims to permanently silence all proviruses, even after treatment interruption. HIV silencing can be achieved by targeting different factors of the transcription machinery. In this review, we first describe the underlying mechanisms of HIV transcription and silencing. Next, we give an overview of the different block-and-lock strategies under investigation. Full article
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
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