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Special Issue "Immuno- and Neuropathogenesis of HIV Disease: Mechanisms, Prevention, Treatment, and Cure"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 October 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Brian Wigdahl

Professor and Chair, Department of Microbiology and Immunology; Director, Institute for Molecular and Medicine and Infectious Disease; Director, Center for Molecular Virology and Translational Neuroscience, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
Website | E-Mail
Phone: +1-215-991-8352
Fax: +1-215-848-2271
Interests: immuno- and neuropathogenesis of HIV-1, HTLV-1, and HSV infection; Transcriptional regulation of retroviral gene expression; Viral genetic variation, viral reservoirs, latency, activation; Prevention, treatment, and cure of retrovirus and herpesvirus disease

Special Issue Information

Dear Colleagues,

The fourth decade in the fight against the human immunodeficiency virus (HIV) is now in progress and the acquired immunodeficiency syndrome (AIDS) pandemic, with its many associated comorbidities, continues to present a major health crisis worldwide. Encouraging, is that, in the industrialized world, ever increasing efficacious therapeutic combination regimens have converted a hopeless and devastating clinical picture to one that is getting closer to a long-term but clinically manageable chronic human disease with still an all-to-often lethal endpoint. In contrast, in economically challenged regions of the world, HIV infection and the associated clinical problems remain an acute life threatening pandemic in the absence of the most effective combination therapies, state-of-the-art clinical care, and an effective vaccine. Despite the significant progress with regard to understanding the pathogenesis of HIV/AIDS and the development of more than 30 FDA approved therapeutic agents that have been used in numerous and very effective combination therapies to dramatically extend the average lifespan of the HIV-infected patient population, there are many avenues of research that are very needed to optimally prevent, diagnose, and treat HIV disease, and cure the HIV-infected patient population across the many subtypes of HIV infection around the world. This Special Issue will center on reviews and primary data manuscripts that focus on defining (1) new cellular and viral targets to prevent and further control HIV replication and minimize long-term toxicity; (2) viral reservoirs in the periphery including cells involved in harboring latent viral genomes, molecular mechanisms of latency, and activating and non-activating viral genotypes; (3) mechanisms to cure latently infected or activated cells; (4) events involved in transmigration of HIV-infected cells across the blood-brain barrier; (5) mechanisms that result in disruption of the blood-brain barrier; (6) interactions between the astrocytes, pericytes, brain endothelial cells and neurons that lead to central nervous system (CNS) dysfunction; (7) the impact of HIV-infected microglial cells and other cells of the monocyte-macrophage lineage and their viral and cellular products on astrocyte-neuronal function that lead to impairment; (8) links between metabolic and vascular disease and HIV neuropathogenesis; and (9) the differential phenotypic and genotypic properties of HIV with respect to the spectrum of HIV CNS disease.

Prof. Dr. Brian Wigdahl
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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

  • Human immunodeficiency virus
  • Acquired immunodeficiency syndrome
  • HIV treatment and prevention
  • Therapeutics
  • Vaccines
  • Viral reservoirs
  • Cell trafficking
  • Transmigration
  • Genetic variation
  • Genetic diversity
  • Viral latency
  • HIV cure
  • HIV quasispecies
  • Blood–brain barrier
  • Neuropathogenesis
  • Immunopathogenesis

Published Papers (9 papers)

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Research

Jump to: Review

Open AccessArticle Probiotics Differently Affect Gut-Associated Lymphoid Tissue Indolamine-2,3-Dioxygenase mRNA and Cerebrospinal Fluid Neopterin Levels in Antiretroviral-Treated HIV-1 Infected Patients: A Pilot Study
Int. J. Mol. Sci. 2016, 17(10), 1639; doi:10.3390/ijms17101639
Received: 27 July 2016 / Revised: 7 September 2016 / Accepted: 20 September 2016 / Published: 27 September 2016
Cited by 2 | PDF Full-text (1248 KB) | HTML Full-text | XML Full-text
Abstract
Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients’ quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the
[...] Read more.
Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients’ quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the microbial translocation, the chronic immune activation, and the altered utilization of tryptophan observed in these individuals, we speculated a correlation between high levels of immune activation markers in the cerebrospinal fluid (CSF) of HIV-1 infected patients and the over-expression of indolamine-2,3-dioxygenase (IDO) at the gut mucosal surface. In order to evaluate this issue, we measured the levels of neopterin in CSF, and the expression of IDO mRNA in gut-associated lymphoid tissue (GALT), in HIV-1-infected patients on effective combined antiretroviral therapy (cART), at baseline and after six months of probiotic dietary management. We found a significant reduction of neopterin and IDO mRNA levels after the supplementation with probiotic. Since the results for the use of adjunctive therapies to reduce the levels of immune activation markers in CSF have been disappointing so far, our pilot study showing the efficacy of this specific probiotic product should be followed by a larger confirmatory trial. Full article
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Open AccessArticle Impact of HIV Infection and Anti-Retroviral Therapy on the Immune Profile of and Microbial Translocation in HIV-Infected Children in Vietnam
Int. J. Mol. Sci. 2016, 17(8), 1245; doi:10.3390/ijms17081245
Received: 3 July 2016 / Revised: 26 July 2016 / Accepted: 28 July 2016 / Published: 2 August 2016
PDF Full-text (1010 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
CD4+ T-lymphocyte destruction, microbial translocation, and systemic immune activation are the main mechanisms of the pathogenesis of human immunodeficiency virus type 1 (HIV) infection. To investigate the impact of HIV infection and antiretroviral therapy (ART) on the immune profile of and microbial
[...] Read more.
CD4+ T-lymphocyte destruction, microbial translocation, and systemic immune activation are the main mechanisms of the pathogenesis of human immunodeficiency virus type 1 (HIV) infection. To investigate the impact of HIV infection and antiretroviral therapy (ART) on the immune profile of and microbial translocation in HIV-infected children, 60 HIV vertically infected children (31 without ART: HIV(+) and 29 with ART: ART(+)) and 20 HIV-uninfected children (HIV(−)) aged 2–12 years were recruited in Vietnam, and their blood samples were immunologically and bacteriologically analyzed. Among the HIV(+) children, the total CD4+-cell and their subset (type 1 helper T-cell (Th1)/Th2/Th17) counts were inversely correlated with age (all p < 0.05), whereas regulatory T-cell (Treg) counts and CD4/CD8 ratios had become lower, and the CD38+HLA (human leukocyte antigen)-DR+CD8+- (activated CD8+) cell percentage and plasma soluble CD14 (sCD14, a monocyte activation marker) levels had become higher than those of HIV(−) children by the age of 2 years; the CD4/CD8 ratio was inversely correlated with the plasma HIV RNA load and CD8+-cell activation status. Among the ART(+) children, the total CD4+-cell and Th2/Th17/Treg-subset counts and the CD4/CD8 ratio gradually increased, with estimated ART periods of normalization being 4.8–8.3 years, whereas Th1 counts and the CD8+-cell activation status normalized within 1 year of ART initiation. sCD14 levels remained high even after ART initiation. The detection frequency of bacterial 16S/23S ribosomal DNA/RNA in blood did not differ between HIV-infected and -uninfected children. Thus, in children, HIV infection caused a rapid decrease in Treg counts and the early activation of CD8+ cells and monocytes, and ART induced rapid Th1 recovery and early CD8+-cell activation normalization but had little effect on monocyte activation. The CD4/CD8 ratio could therefore be an additional marker for ART monitoring. Full article
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Open AccessArticle Prolonged Morphine Exposure Induces Increased Firm Adhesion in an in Vitro Model of the Blood–Brain Barrier
Int. J. Mol. Sci. 2016, 17(6), 916; doi:10.3390/ijms17060916
Received: 30 March 2016 / Revised: 25 May 2016 / Accepted: 31 May 2016 / Published: 9 June 2016
Cited by 1 | PDF Full-text (2274 KB) | HTML Full-text | XML Full-text
Abstract
The blood–brain barrier (BBB) has been defined as a critically important protective barrier that is involved in providing essential biologic, physiologic, and immunologic separation between the central nervous system (CNS) and the periphery. Insults to the BBB can cause overall barrier damage or
[...] Read more.
The blood–brain barrier (BBB) has been defined as a critically important protective barrier that is involved in providing essential biologic, physiologic, and immunologic separation between the central nervous system (CNS) and the periphery. Insults to the BBB can cause overall barrier damage or deregulation of the careful homeostasis maintained between the periphery and the CNS. These insults can, therefore, yield numerous phenotypes including increased overall permeability, interendothelial gap formation, alterations in cytokine and chemokine secretion, and accelerated cellular passage. The current studies expose the human brain microvascular endothelial cell line, hCMEC/D3, to prolonged morphine exposure and aim to uncover the mechanisms underlying alterations in barrier function in vitro. These studies show alterations in the mRNA and protein levels of the cellular adhesion molecules (CAMs) intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and activated leukocyte cell adhesion molecule that correlate with an increased firm adhesion of the CD3+ subpopulation of peripheral blood mononuclear cells (PBMCs). Overall, these studies suggest that prolonged morphine exposure may result in increased cell migration into the CNS, which may accelerate pathological processes in many diseases that involve the BBB. Full article
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Open AccessArticle Disrupted Homeostatic Cytokines Expression in Secondary Lymph Organs during HIV Infection
Int. J. Mol. Sci. 2016, 17(3), 413; doi:10.3390/ijms17030413
Received: 4 January 2016 / Revised: 5 February 2016 / Accepted: 14 March 2016 / Published: 22 March 2016
Cited by 2 | PDF Full-text (2740 KB) | HTML Full-text | XML Full-text
Abstract
Research has firmly established that infection by human immunodeficiency virus (HIV) leads to structural disruption in secondary lymph organs (SLOs) and that IL-7 expression by SLOs is downregulated in simian immunodeficiency virus (SIV)-infected rhesus macaques. However, the foregoing has not been demonstrated in
[...] Read more.
Research has firmly established that infection by human immunodeficiency virus (HIV) leads to structural disruption in secondary lymph organs (SLOs) and that IL-7 expression by SLOs is downregulated in simian immunodeficiency virus (SIV)-infected rhesus macaques. However, the foregoing has not been demonstrated in HIV-infected patients. As well, SLO-produced chemokines and cytokines, other than IL-7, have not been tested. In this study, SLOs in HIV-infected patients exhibit decreased levels of lymphoid cytokines, such as IL-7 and C–C motif chemokine ligand 21 (CCL21), due to lower expression of lymphotoxin (LT)-β. Previous research has shown that LT-β is produced mainly by CD4+T cells in rhesus macaques, while our study found the same level of LT-β expressed by CD4+T and CD8+T cells in humans. CD8+T cells substitute for depleted CD4+T cells LT-β production. Only the total number of CD3+T cells can account for the majority of LT-β in human SLOs. This study indicates a possible mechanism and a potential target for improvement of SLO function in HIV-infected patients, a novel adjuvant therapy for AIDS. Full article
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Open AccessArticle Evolving Diversity of Hepatitis C Viruses in Yunnan Honghe, China
Int. J. Mol. Sci. 2016, 17(3), 403; doi:10.3390/ijms17030403
Received: 16 January 2016 / Revised: 26 February 2016 / Accepted: 9 March 2016 / Published: 18 March 2016
Cited by 2 | PDF Full-text (2074 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Chinese Honghe Autonomous Prefecture (Honghe) in Yunnan Province is a unique ethnic area because it is inhabited by more than ten different minority ethnic groups. Geographically, Honghe directly shares a border with Vietnam. The objective of this study was to investigate genetic
[...] Read more.
The Chinese Honghe Autonomous Prefecture (Honghe) in Yunnan Province is a unique ethnic area because it is inhabited by more than ten different minority ethnic groups. Geographically, Honghe directly shares a border with Vietnam. The objective of this study was to investigate genetic diversity and distribution of the Hepatitis C virus (HCV) in Honghe. Ninety nine subjects who were infected with HCV or HCV/HIV (Human Immunodeficiency Virus Type 1) were recruited into this study. HCV genotypes and subtypes were determined based on the sequences of the core/envelope 1 (C/E1) and the nonstructural protein 5B (NS5B) genomic regions. The viral diversity and origins of dissemination were examined by phylogenetic analyses. Three HCV genotypes (1, 3 and 6) with six subtypes (1b, 3b, 3a, 6a, 6n and 6v) were identified. The most predominant form was genotype 3 (54.6%) followed by 6 (34.3%), and 1 (9.1%). The HCV subtype 3b appeared to be the most frequent form (38.4%) followed by 6n (20.2%) and 3a (16.2%). Statistical analyses suggested a possible rise of the genotype 6a in Honghe among intravenous drug users with HCV/HIV co-infections. Further phylogenetic analyses suggested that similar HCV-6a viruses might have been circulating in the Honghe area for more than a decade, which likely originated from Vietnam or vice versa. Two HCV samples with single HCV infection (SC34 and SC45) were isolated that could represent new recombinant variants. Although the genetic prevalence of HCV in Honghe is in general agreement with that of Southwest China and Yunnan Province, the diversity of HCV genotypes and subtypes in Honghe is somewhat unique and evolving. Information presented here should provide useful information for future health surveillance and prevention of HCV infection in this area. Full article
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Review

Jump to: Research

Open AccessReview Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children
Int. J. Mol. Sci. 2017, 18(2), 423; doi:10.3390/ijms18020423
Received: 19 November 2016 / Revised: 9 February 2017 / Accepted: 10 February 2017 / Published: 15 February 2017
PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the
[...] Read more.
Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-“boosted” lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero. Full article
Open AccessReview The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention
Int. J. Mol. Sci. 2017, 18(1), 126; doi:10.3390/ijms18010126
Received: 28 October 2016 / Revised: 22 December 2016 / Accepted: 3 January 2017 / Published: 10 January 2017
Cited by 1 | PDF Full-text (1300 KB) | HTML Full-text | XML Full-text
Abstract
The human immunodeficiency virus type 1 (HIV-1) Vpr protein is an attractive target for antiretroviral drug development. The conservation both of the structure along virus evolution and the amino acid sequence in viral isolates from patients underlines the importance of Vpr for the
[...] Read more.
The human immunodeficiency virus type 1 (HIV-1) Vpr protein is an attractive target for antiretroviral drug development. The conservation both of the structure along virus evolution and the amino acid sequence in viral isolates from patients underlines the importance of Vpr for the establishment and progression of HIV-1 disease. While its contribution to virus replication in dividing and non-dividing cells and to the pathogenesis of HIV-1 in many different cell types, both extracellular and intracellular forms, have been extensively studied, its precise mechanism of action nevertheless remains enigmatic. The present review discusses how the apparently multifaceted interplay between Vpr and host cells may be due to the impairment of basic metabolic pathways. Vpr protein modifies host cell energy metabolism, oxidative status, and proteasome function, all of which are likely conditioned by the concentration and multimerization of the protein. The characterization of Vpr domains along with new laboratory tools for the assessment of their function has become increasingly relevant in recent years. With these advances, it is conceivable that drug discovery efforts involving Vpr-targeted antiretrovirals will experience substantial growth in the coming years. Full article
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Open AccessReview Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis
Int. J. Mol. Sci. 2016, 17(12), 1985; doi:10.3390/ijms17121985
Received: 23 September 2016 / Revised: 18 November 2016 / Accepted: 22 November 2016 / Published: 26 November 2016
PDF Full-text (1056 KB) | HTML Full-text | XML Full-text
Abstract
The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed
[...] Read more.
The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed to review DCs-based therapeutic vaccines reports and critically assess evidence to gain insights for the improvement of these strategies. We performed a systematic review, followed by meta-analysis and meta-regression, of clinical trial reports. Twelve studies were selected for meta-analysis. The experimental vaccines had low efficiency, with an overall success rate around 38% (95% confidence interval = 26.7%–51.3%). Protocols differed according to antigen choice, DC culture method, and doses, although multivariate analysis did not show an influence of any of them on overall success rate. The DC-based vaccines elicited at least some immunogenicity, that was sometimes associated with plasmatic viral load transient control. The protocols included both naïve and antiretroviral therapy (ART)-experienced individuals, and used different criteria for assessing vaccine efficacy. Although the vaccines did not work as expected, they are proof of concept that immune responses can be boosted against HIV-1. Protocol standardization and use of auxiliary approaches, such as latent HIV-1 reservoir activation and patient genomics are paramount for fine-tuning future HIV-1 cure strategies. Full article
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Open AccessReview Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies
Int. J. Mol. Sci. 2016, 17(11), 1901; doi:10.3390/ijms17111901
Received: 31 August 2016 / Revised: 10 November 2016 / Accepted: 10 November 2016 / Published: 18 November 2016
Cited by 2 | PDF Full-text (709 KB) | HTML Full-text | XML Full-text
Abstract
Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral
[...] Read more.
Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs) with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Antiretroviral Treatment in HIV Positive Mothers: Neurological Implications in Virus Free Children
Author: Sergio Crovella
Abstract: Many studies have already analyzed the direct effects of HIV on the central nervous system (CNS), however CNS neuropathology after HIV infection, remains partially unknown. In early childhood, the effect of HIV on the central nervous system is even more important, being the CNS a structure in development. Although principal mechanisms for neurological impairment remain elusive, they can be attributed either to persistence of HIV in brain or antiretroviral therapy (ART) side-effects. This review aims at discussing the possible neurological impairment following ART treatment in patients with high neuronal plasticity, as children born to ART-treated mother; focusing the attention on neuro-inflammation, autophagy and epigenetic mechanisms connected to antiretroviral therapy.
Keywords: antiretroviral therapy; HIV; neurological impairment; neuro-inflammation; autophagy; epigenetic mechanisms

Type of Paper: Review
Title: Dendritic Cell-Based Immunotherapies to Fight HIV: How Far from a Success Story? A Systematic Review and Meta-Analysis
Author: Sergio Crovella
Abstract: Antiretroviral therapy continues to save lives from AIDS-related deaths, which permitted the scientific community to search for the effective cure of HIV-1. One of the pursued strategies for this endeavor is the development of immunotherapeutic vaccines based on dendritic cells (DC) against HIV-1. These vaccines aim to boost immune response against HIV-1, for which some clinical trials have been developed. We summarized the pros and cons of DC-based therapeutic vaccines and critically review the evidence to gain insights for the improvement of immunotherapy strategies against HIV-1. A systematic review was performed using data from clinical trial reports (indexed on PubMed and ClinicalTrials.gov database) that recruited HIV-infected patients for DC-based therapeutic immunovaccines when compared with (1) placebo, (2) a reference vaccine or (3) no vaccination.

Title: In-Vitro Blood Brain Barrier Modeling to Characterize HIV-Infected Monocyte Transmigration for Clinical Research
Authors: Bruce Shiramizu, Valerie Wojna

Title: Differential Functional Significance of the Sub-Elements within the −1 Frameshifting Motifs of HIV-1 and Human Paternally Expressed Gene 10
Authors: Jack Rolfe, Yosuke Shimaki, Caillan Crowe-McAuliffe and Warren Tate
Affiliation: Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin 9016, New Zealand
Abstract: Programmed ribosomal frameshifting is essential for replication of retroviruses like HIV-1, and occurs when the translating ribosome encounters an RNA sequence motif made up of a ‘slippery sequence’, an ‘intercodon’, and a ‘downstream structured element’. Frameshifting (−1) was considered very rare in cellular genes, but human genes such as Paternally Expressed Gene 10 (PEG10) have been documented to use the mechanism for their expression. Fine details of the mechanism remain unclear, but a generic mechanism for all motifs is unlikely. We have created HIV-1/PEG10 hybrid frameshift motifs to elucidate the functional roles of each of the sub-elements. The pseudoknot of the PEG10 motif determines its relatively high frameshifting efficiency (~22%), and increased efficiency in the HIV-1 element when substituted for the stem loop (5% to 8%). Conversely, PEG10 frameshift efficiency fell dramatically to 1% with the HIV-1 stem loop. The HIV-1 slippery sequence is the dominant sub-element within its motif. The intercodon has smaller but observable effects. A detailed mass spectrometry analysis has confirmed frameshifting occurs within the PEG10 element at several positions but mostly before the intercodon in contrast to that of HIV-1. Thus, despite a similar outcome, the frameshifting signals of HIV-1 and PEG10 are significantly divergent.

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