CNS reservoirs for HIV: implications for eradication.
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ABSTRACT:
SUBMITTER: Hellmuth J
PROVIDER: S-EPMC4586130 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesInterest in targeting HIV reservoirs is fueling trials that may decrease reservoir size and/or induce viral replication. Therefore, we aimed to develop strategies to sensitively measure changes in these parameters in patients on and off antiretroviral therapy (ART). Achieving these goals may help evaluate the effects of future clinical trials.DesignTo determine the relationship between measurements of total and integrated HIV DNA and their role as markers of reservoir size and ongoing replication, these parameters were measured during the first year of ART, during long-term effective ART, and during a clinical trial aimed at targeting reservoirs.MethodsTotal and integrated HIV DNA were measured in patient samples using quantitative PCR techniques. CD4(+)T cell counts and plasma viremia were also monitored.ResultsUnintegrated HIV DNA became undetectable during the first year of ART. Total and integrated HIV DNA levels were generally equal in well controlled patients on ART, and low-level plasma viremia correlated best with integration measures. Finally, patients who controlled plasma viremia (<400 copies/ml) during interferon-α monotherapy exhibited a decrease in the level of integrated but not total HIV DNA and a rise in the ratio of total to integrated HIV DNA over time.ConclusionOur findings suggest that appearance of unintegrated HIV DNA reflects residual HIV expression and de-novo reverse transcription, providing insight into the mechanism by which interferon-α reduces the HIV reservoir. We conclude that concurrent measurements of total and integrated HIV DNA provide information regarding reservoir size and ongoing replication in trials targeting HIV.
| S-EPMC4692807 | biostudies-literature
Project description:Subtype-A HIV was introduced into Israel in the mid-1990s, predominantly by immigrants from the former Soviet Union (FSU) infected via intravenous drug use (IVDU). HIV subsequently spread beyond the FSU-IVDU community. In 2012, a mini-HIV outbreak, associated with injection of amphetamine cathinone derivatives, started in Tel Aviv, prompting public health response. To assess current trends and the impact of the outbreak and control measures, we conducted a phyloepidemiologic analysis. Demographic and clinical records and HIV sequences were compiled from 312 subtype-A HIV-infected individuals attending the Tel-Aviv Sourasky Medical Center between 2005-2016, where >40% of all subtype-A HIV-infected individuals in Israel are undergoing care. Molecular evolutionary genetics analysis (MEGA) and ayesian evolutionary analysis sampling trees (BEAST) programs were implemented in a phylogenetic analysis of pol sequences. Reconstructed phylogenies were assessed in the context of demographic information and drug-resistance profiles. Clusters were identified as sequence populations with posterior probability ≥0.95 of having a recent common ancestor. After 2010, the subtype-A epidemic acquired substantial phylogenetic structure, having been unrecognized in studies covering the earlier period. Nearly 50% of all sequences were present in 11 distinct clusters consisting of 4-43 individuals. Cluster composition reflected transmission across ethnic groups, with men who have sex with men (MSM) playing an increasing role. The cathinone-associated cluster was larger than previously documented, containing variants that continued to spread within and beyond the IVDU community. Phyloepidemiologic analysis revealed diverse clusters of HIV infection with MSM having a central role in transmission across ethic groups. A mini outbreak was reduced by public health measures, but molecular evidence of ongoing transmission suggests additional measures are necessary.
| S-EPMC6657966 | biostudies-literature
Project description:HIV reservoirs persist despite antiretroviral therapy (ART) and are established within a few days after infection. Infected myeloid cells in the central nervous system (CNS) may contribute to the establishment of a CNS viral reservoir. The mature CD14+ CD16+ monocyte subset enters the CNS in response to chemokines, including CCL2. Entry of infected CD14+ CD16+ monocytes may lead to infection of other CNS cells, including macrophages or microglia and astrocytes, and to release of neurotoxic early viral proteins and additional cytokines. This contributes to neuroinflammation and neuronal damage leading to HIV-associated neurocognitive disorders (HAND) in ~50% of HIV-infected individuals despite ART. We examined the mechanisms of monocyte entry in the context of HIV infection and report for the first time that HIV+ CD14+ CD16+ monocytes preferentially transmigrate across the blood-brain barrier (BBB). The junctional proteins JAM-A and ALCAM and the chemokine receptor CCR2 are essential to their preferential transmigration across the BBB to CCL2. We show here that JAM-A and ALCAM are increased on HIV+ CD14+ CD16+ monocytes compared to their expression on HIVexp CD14+ CD16+ monocytes-cells that are uninfected but exposed to HIV, viral proteins, and inflammatory mediators. Antibodies against JAM-A and ALCAM and the novel CCR2/CCR5 dual inhibitor cenicriviroc prevented or significantly reduced preferential transmigration of HIV+ CD14+ CD16+ monocytes. This indicates that JAM-A, ALCAM, and CCR2 may be potential therapeutic targets to block entry of these infected cells into the brain and prevent or reduce the establishment and replenishment of viral reservoirs within the CNS.IMPORTANCE HIV infects different tissue compartments of the body, including the central nervous system (CNS). This leads to establishment of viral reservoirs within the CNS that mediate neuroinflammation and neuronal damage, contributing to cognitive impairment. Our goal was to examine the mechanisms of transmigration of cells that contribute to HIV infection of the CNS and to continued replenishment of CNS viral reservoirs, to establish potential therapeutic targets. We found that an HIV-infected subset of monocytes, mature HIV+ CD14+ CD16+ monocytes, preferentially transmigrates across the blood-brain barrier. This was mediated, in part, by increased junctional proteins JAM-A and ALCAM and chemokine receptor CCR2. We show that the CCR2/CCR5 dual inhibitor cenicriviroc and blocking antibodies against the junctional proteins significantly reduce, and often completely block, the transmigration of HIV+ CD14+ CD16+ monocytes. This suggests new opportunities to eliminate infection and seeding or reseeding of viral reservoirs within the CNS, thus reducing neuroinflammation, neuronal damage, and cognitive impairment.
| S-EPMC5654927 | biostudies-literature
Project description:Macrophages, one of the most abundant populations of leukocytes in the body, function as the first line of defense against pathogen invaders. Human Immunodeficiency virus 1 (HIV-1) remains to date one of the most extensively studied viral infections. Naturally occurring lentiviruses in domestic and primate species serve as valuable models to investigate lentiviral pathogenesis and novel therapeutics. Better understanding of the role macrophages play in HIV pathogenesis will aid in the advancement towards a cure. Even with current efficacy of first- and second-line Antiretroviral Therapy (ART) guidelines and future efficacy of Long Acting Slow Effective Release-ART (LASER-ART); ART alone does not lead to a cure. The major challenge of HIV eradication is viral latency. Latency Reversal Agents (LRAs) show promise as a possible means to eradicate HIV-1 from the body. It has become evident that complete eradication will need to include combinations of various effective therapeutic strategies such as LASER-ART, LRAs, and gene editing. Review of the current literature indicates the most promising HIV eradication strategy appears to be LASER-ART in conjunction with viral and receptor gene modifications via the CRISPR/Cas9 system. Graphical abstract A multimodal approach to HIV treatment including gene editing, LASER-ART, and latency reversal agents may provide a means to achieve HIV eradication.
| S-EPMC6391209 | biostudies-literature
Project description:IntroductionThe currently available anti-HIV-1 drugs can control the infection but do not eradicate the virus. Their long-term use can lead to side effects and resistance to therapy. Therefore, eradication of the virus has been a major goal of research. Biological therapeutics including broadly neutralizing monoclonal antibodies (bnAbs) are promising tools to reach this goal. They could also help design novel vaccine immunogens potentially capable of eliciting bnAbs targeting the HIV-1 envelope glycoproteins (Envs).Areas coveredWe review HIV-1 bnAbs and their potential as candidate prophylactics and therapeutics used individually, in combination, or as bispecific fusion proteins. We also discuss their potential use in the 'activation-elimination' approach for HIV-1 eradication in infected patients receiving antiretroviral treatment as well as current vaccine design efforts based on understanding of interactions of candidate vaccine immunogens with matured bnAbs and their putative germline predecessors, and related antibody maturation pathways.Expert opinionExploration of HIV-1 bnAbs has provided and will continue to provide useful knowledge that helps develop novel types of biotherapeutics and vaccines. It is possible that bnAb-based candidate therapeutics could help eradicate HIV-1. Development of vaccine immunogens capable of eliciting potent bnAbs in humans remains a fundamental challenge.
| S-EPMC6953398 | biostudies-literature
Project description:HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.
| S-EPMC6760922 | biostudies-literature
Project description:HIV establishes a latent reservoir early in infection that is resistant to anti-retroviral therapy and has a slow rate of decay. It is thought that the majority of HIV DNA in treated patients is integrated since unintegrated HIV DNA appears to be unstable. Thus, to monitor the HIV latent reservoir, total HIV DNA is commonly measured in PBMC from infected individuals. We investigated how often total approaches integrated HIV DNA in treated patients. To do this, we first assessed how accurate our integration assay is and determined the error in our measurements of total and integrated HIV DNA. We demonstrated an excess of total over integrated HIV DNA was present in a subset of patients, suggesting that measurements of total HIV DNA do not always correlate to the level of integration. Determining the cause of this excess and its frequency may have important implications for understanding HIV latent reservoir maintenance.
| S-EPMC3253773 | biostudies-literature
Project description:Autologous transplantation and engraftment of HIV-resistant cells in sufficient numbers should recapitulate the functional cure of the Berlin Patient, with applicability to a greater number of infected individuals and with a superior safety profile. A robust preclinical model of suppressed HIV infection is critical in order to test such gene therapy-based cure strategies, both alone and in combination with other cure strategies. Here, we present a nonhuman primate (NHP) model of latent infection using simian/human immunodeficiency virus (SHIV) and combination antiretroviral therapy (cART) in pigtail macaques. We demonstrate that transplantation of CCR5 gene-edited hematopoietic stem/progenitor cells (HSPCs) persist in infected and suppressed animals, and that protected cells expand through virus-dependent positive selection. CCR5 gene-edited cells are readily detectable in tissues, namely those closely associated with viral reservoirs such as lymph nodes and gastrointestinal tract. Following autologous transplantation, tissue-associated SHIV DNA and RNA levels in suppressed animals are significantly reduced (p ? 0.05), relative to suppressed, untransplanted control animals. In contrast, the size of the peripheral reservoir, measured by QVOA, is variably impacted by transplantation. Our studies demonstrate that CCR5 gene editing is equally feasible in infected and uninfected animals, that edited cells persist, traffic to, and engraft in tissue reservoirs, and that this approach significantly reduces secondary lymphoid tissue viral reservoir size. Our robust NHP model of HIV gene therapy and viral persistence can be immediately applied to the investigation of combinatorial approaches that incorporate anti-HIV gene therapy, immune modulators, therapeutic vaccination, and latency reversing agents.
| S-EPMC5908070 | biostudies-literature
Project description:After the success of combination antiretroviral therapy (cART) to treat HIV infection, the next great frontier is to cure infected persons, a formidable challenge. HIV persists in a quiescent state in resting CD4+ T cells, where the replicative enzymes targeted by cART are not active. Although low levels of HIV transcripts are detectable in these resting cells, little to no viral protein is produced, rendering this reservoir difficult to detect by the host CD8+ T cell response. However, recent advances suggest that this state of latency might be pharmacologically reversed, resulting in viral protein expression without the adverse effects of massive cellular activation. Emerging data suggest that with this approach, infected cells will not die of viral cytopathic effects, but might be eliminated if HIV-specific CD8+ T cells can be effectively harnessed. Here, we address the antiviral properties of HIV-specific CD8+ T cells and how these cells might be harnessed to greater effect toward achieving viral eradication or a functional cure.
| S-EPMC4731167 | biostudies-literature
Project description:The advent of combination antiretroviral therapy (cART) has transformed HIV-1 infection into a controllable chronic disease, but these therapies are incapable of eradicating the virus to bring about an HIV cure. Multiple strategies have been proposed and investigated to eradicate latent viral reservoirs from various biological sanctuaries. However, due to the complexity of HIV infection and latency maintenance, a single drug is unlikely to eliminate all HIV reservoirs and novel strategies may be needed to achieve better efficacy while limiting systemic toxicity. In this review, we describe HIV latency in cellular and anatomical reservoirs, and present an overview of current strategies for HIV cure with a focus on their challenges for clinical translation. Then we provide a summary of nanotechnology solutions that have been used to address challenges in HIV cure by delivering physicochemically diverse agents for combination therapy or targeting HIV reservoir sites. We also review nanocarrier-based gene delivery and immunotherapy used in cancer treatment but may have potential applications in HIV cure.
| S-EPMC6279622 | biostudies-literature