Search

OBJECTIVES: Elite controllers (EC) are a rare group of individuals living with HIV-1 who naturally control HIV-1 replication to levels below the limit of detection without antiretroviral therapy (ART) and rarely progress to AIDS. The mechanisms contributing to this control remain incompletely elucidated. In the present study, we have assessed whether cellular host factors could modulate HIV-1 replication post-entry in a controller-discordant couple living with HIV-1. METHODS: CD4 T cells from a controller-discordant couple, one partner being an EC and the other an HIV-1 progressor (PR), and healthy controls (HC) were isolated, activated and infected with VSV-G pseudotyped yellow fluorescent protein-encoding single-round HIV-1 virus (HIV-YFP). Viral reverse transcripts, 2-LTR circles and integrated proviral HIV-1 DNA were monitored by quantitative PCR (qPCR) and integration sites were analysed. We further measured LEDGF/p75 and p21 mRNA expression levels by qPCR. RESULTS: Infection of activated CD4 T cells with HIV-YFP was reduced in EC compared with the PR partner, and HC. Evaluation of viral DNA forms suggested a block after entry and during the early steps of HIV-1 reverse transcription in EC. The integration site distribution pattern in EC, PR and HC was similar. The p21 expression in CD4 T cells of EC was elevated compared with the PR or HC, in line with previous work. CONCLUSIONS: Our study suggests a reduced permissiveness to HIV-1 infection of CD4 T cells from EC due to a block of HIV-1 replication after entry and before integration that might contribute to the EC phenotype in our patient. ispartof: JOURNAL OF VIRUS ERADICATION vol:4 issue:3 pages:170-173 ispartof: location:England status: published

International audience; Over 4 days, more than 270 scientists involved in HIV persistence research convened to share their data and discuss future avenues to control HIV without continuous antiretroviral therapy. This 7(th) International Workshop on HIV Persistence followed the format of the preceding conferences but more time was given for discussing abstracts submitted by the participants and selected by the Steering and Scientific Committees. The topic of the workshop is HIV persistence: consequently, issues of HIV reservoirs and HIV cure are also addressed. In this article we report as closely as possible what was discussed. However, owing to length constraints, not everything is reported here but all the Workshop abstracts can be found online (www.viruseradication.com).

Objective We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Results The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ≈belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.

Author(s): Yek, Christina; Gianella, Sara; Plana, Montserrat; Castro, Pedro; Scheffler, Konrad; Garcia, Felipe; Massanella, Marta; Smith, Davey M | Abstract: ObjectivesCurative strategies using agents to perturb the HIV reservoir have demonstrated only modest activity, whereas increases in viremia after standard vaccination have been described. We investigated whether vaccination against non-HIV pathogens can induce HIV transcription and thereby play a role in future eradication strategies.DesignA randomized controlled trial (NCT00329251) was performed to compare the effects of clinical vaccines with placebo on HIV transcription and immune activation.MethodsTwenty-six HIV-infected individuals on suppressive antiretroviral therapy were randomized to receive a vaccination schedule (n = 13) or placebo (n = 13). Cell-associated RNA and DNA were extracted from peripheral blood mononuclear cells, and HIV was quantified by droplet digital PCR using primers for gag and 2-LTR (for HIV DNA), unspliced gag RNA (gag usRNA), multispliced tat-rev RNA (tat-rev msRNA) and polyA mRNA.ResultsSignificant increases in gag usRNA after influenza/hepatitis B vaccination (P = 0.02) and in gag usRNA (P = 0.04) and polyA mRNA (P = 0.04) after pneumococcus/hepatitis B vaccination were seen in vaccinees but not controls. HIV DNA and plasma HIV RNA did not change in either group. Increases in CD4 and CD8 T-cell activation markers (P = 0.08 and P l 0.001, respectively) and HIV-specific CD8 responses (P = 0.04 for p24 gag, P = 0.01 for p17 gag and P = 0.04 for total gag) were seen in vaccinees but not controls.ConclusionIn this study, vaccination was associated with increases in HIV cell-associated RNA and HIV-specific responses during antiretroviral therapy. Using standard vaccines to stimulate HIV transcription may therefore be a useful component of future eradication strategies.

The examination of antibody responses in human immunodeficiency virus (HIV)-1-infected individuals in the setting of antiretroviral treatment (ART) interruption can provide insight into the evolution of antibody responses during viral rebound. In this study, we assessed antibody responses in 20 subjects in AIDS Clinical Trials Group A5187, wherein subjects were treated with antiretroviral therapy during acute/early HIV-1 infection, underwent analytic treatment interruption, and subsequently demonstrated viral rebound. Our data suggest that early initiation of ART arrests the maturation of HIV-1-specific antibody responses, preventing epitope diversification of antibody binding and the development of functional neutralizing capacity. Antibody responses do not appear permanently blunted, however, because viral rebound triggered the resumption of antibody maturation in our study. We also found that antibody responses measured by these assays did not predict imminent viral rebound. These data have important implications for the HIV-1 vaccine and eradication fields.

Introduction : HIV eradication and remission research has largely taken place in high-income countries. In low- and middle-income countries (LMIC), there may be factors that have a substantial impact on the size of the latent HIV reservoir and the immunological response to infection. If a curative strategy is to be available to all HIV-infected individuals, these factors must be understood. Methods : We use a scoping review to examine the literature on biological factors that may have an impact on HIV persistence in LMIC. Three databases were searched without date restrictions. Results : Uncontrolled viral replication and higher coinfection prevalence may alter the immunological milieu of individuals in LMIC and increase the size of the HIV reservoir. Differences in HIV subtype could also influence the measurement and size of the HIV reservoir. Immune activation may differ due to late presentation to care, presence of chronic infections, increased gut translocation of bacterial products and poor nutrition. Conclusions : Research on HIV remission is urgently needed in LMIC. Research into chronic immune activation in resource poor environments, the immune response to infection, the mechanisms of HIV persistence and latency in different viral clades and the effect of the microbiological milieu must be performed. Geographic differences, which may be substantial and may delay access to curative strategies, should be identified. Keywords HIV eradication; HIV cure; HIV remission; resource limited; low- and middle-income countries; immune system (Published: 5 June 2017) Rossouw T et al. Journal of the International AIDS Society 2017, 20 :21521 http://www.jiasociety.org/index.php/jias/article/view/21521 | http://dx.doi.org/10.7448/IAS.20.1.21521

International audience; In the global fight against HIV/AIDS, the persistence of viral reservoirs, established early during primary infection by the Human Immunodeficiency virus (HIV), is probably the biggest challenge to finding a cure for HIV, despite the major progress provided by antiviral treatments. This persistence reflects virus latency in the immune system and imposes the prospect of life-long treatment with risk of toxicities, and major costs for society. Innovative strategies aimed at purging these viral reservoirs are therefore required, but the complexity of the latency mechanisms has made a sterilization cure difficult to realize until now. However, recent cases of HIV remission have encouraged the research community, and a functional cure seems to be a more realistic goal to attempt. A better understanding of the mechanisms responsible for such latency has been provided by basic research, although recent attempts at purging the reservoirs by disrupting latency have been somewhat disappointing. In contrast, the early initiation of anti-retroviral treatment appears to be extremely beneficial for HIV remission, as recently suggested by the Mississippi baby case or by the series of post-treatment controllers, respectively. Early treatment initiation can indeed rapidly limit the size of viral reservoirs, or hamper their formation and preserve the host’s immune responses. Despite these encouraging results, it is nevertheless important to deploy more effort toward a better understanding of latency mechanisms and to the development of innovative approaches and molecules in the hope of achieving a cure for HIV.

(See the editorial commentary by Henrich and Gandhi on pages 1189–93 and the major article by Yukl et al 1212–20.) T-cell immune activation, defined by coexpression of CD38 and HLA-DR on CD4+ and CD8+ T cells, has been linked to morbidity and mortality in untreated human immunodeficiency virus (HIV) infection, both AIDS-related and non-AIDS-related [1, 2]. In patients receiving HIV antiretroviral therapy (ART), higher levels of T-cell activation has been linked to diminished CD4+ T-cell count recovery [3–5], surrogate markers of cardiovascular disease [6, 7], and increased mortality [8]. ART-mediated virologic suppression reduces both CD4+ and CD8+ T-cell activation levels [3, 9]. However, patients frequently continue to exhibit T-cell activation levels higher than those seen in HIV-negative controls, indicating that ART reduces but does not fully reverse HIV-related immune activation [3, 9, 10]. A key unanswered question, therefore, is whether ART initiated early (within the first months after HIV infection) can reduce on-therapy immune activation more than ART initiated during chronic HIV infection. A related question is whether early initiation of ART durably limits the size of persistent HIV reservoirs. Cellular reservoirs of latent genomically integrated HIV are established quickly after infection [11–14], but studies investigating whether ART initiated in the first few months after infection can limit the size of the established reservoir have reached inconsistent conclusions. One study found that ART initiated 2 years. We assessed T-cell activation levels and measured the HIV reservoir (based on both HIV DNA and cell-associated RNA levels) to study the impact of early ART on these outcomes.

Introduction: Distinct biological factors exist that affect the natural history of HIV and the host immune response between women and men. These differences must be addressed to permit the optimal design of effective HIV eradication strategies for much of the HIV-positive population. Methods and results: Here, we review the literature on sex-based differences in HIV pathogenesis and natural history in tissues and anatomic compartments, HIV latency and transcriptional activity, and host immunity including the role of sex hormones. We then outline the potential effects of these differences on HIV persistence, and on the safety and efficacy of HIV eradication and curative interventions. Finally, we discuss the next steps necessary to elucidate these factors to achieve a cure for HIV, taking in account the complex ethical issues and the regulatory landscape in the hopes of stimulating further research and awareness in these areas. Conclusions: Targeted enrolment of women in clinical trials and careful sex-based analysis will be crucial to gain further insights into sex-based differences in HIV persistence and to design sex-specific approaches to HIV eradication, if required.

The December 2011 5th International Workshop on HIV Persistence during Therapy addressed the issue of HIV persistence among 210 scientists from 10 countries involved in the study of HIV reservoirs and the search of an HIV cure. High quality abstracts were selected and discussed as oral or poster presentations. The aim of this review is to distribute the scientific highlights of this workshop outside the group as analyzed and represented by experts in retrovirology, immunology and clinical research.