scholarly journals Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Wen Peng ◽  
Zhongsi Hong ◽  
Xi Chen ◽  
Hongbo Gao ◽  
Zhuanglin Dai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Viral Reactivation ◽  
Immune Recognition ◽  
Bryostatin 1 ◽  
Functional Cure ◽  
Cellular Models ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. The “shock and kill” strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4+ T cells from ART-suppressed individuals ex vivo. TSR does not induce global T cell activation, severe cytotoxicity, or CD8+ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4+ T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-κB signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.

scholarly journals X4-Tropic Latent HIV-1 Is Enriched in Peripheral Follicular Helper T Cells and Is Correlated with Disease Progression

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Fei Yu ◽  
Qijuan Li ◽  
Xi Chen ◽  
Jun Liu ◽  
Linghua Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Clinical Relevance ◽  
Cell Recovery ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Counts ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Follicular helper T (TFH) cells have been shown to support productive human immunodeficiency virus type 1 (HIV-1) replication and to serve as a key component of the latent viral reservoir. However, the viral characteristics of this latent reservoir and the clinical relevance of this reservoir remain unclear. In this study, we assessed the tropic composition of latent viruses from peripheral TFH (pTFH), non-TFH memory, and naive CD4+ T cells from individuals with HIV-1 infections on suppressive combined antiretroviral therapy (cART). X4-tropic latent HIV-1 was preferentially enriched in pTFH cells compared to levels in the other two subsets. Interestingly, the ratio of X4-tropic latent HIV-1 in pTFH cells not only was robustly and inversely correlated with blood CD4+ T cell counts across patients but also was prognostic of CD4+ T cell recovery in individuals on long-term cART. Moreover, patients with higher X4-tropic latent HIV-1 ratios in pTFH cells showed greater risks of opportunistic coinfections. These findings reveal the characteristics of latent HIV-1 in TFH cells and suggest that the ratio of X4-tropic latent HIV-1 in pTFH cells is a valuable indicator for disease progression and cART efficacy. IMPORTANCE TFH cells have been shown to harbor a significant amount of latent HIV-1; however, the viral characteristics of this reservoir and its clinical relevance remain largely unknown. In this study, we demonstrate that X4-tropic latent HIV-1 is preferentially enriched in pTFH cells, which also accurately reflects the viral tropism shift. The ratio of X4-tropic proviruses in pTFH cells but not in other memory CD4+ T cell subsets is inversely and closely correlated with blood CD4+ T cell counts and CD4+ T cell recovery rates with cART. Our data suggest that the ratio of X4-tropic provirus in peripheral TFH cells can be easily measured and reflects disease progression and treatment outcomes during cART.

scholarly journals Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells

2021 ◽  
Vol 17 (1) ◽  
pp. e1008748
Author(s):  
Eric Carlin ◽  
Braxton Greer ◽  
Kelsey Lowman ◽  
Alexandra Duverger ◽  
Frederic Wagner ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Network Analysis ◽  
Cell Lines ◽  
Data Set ◽  
Latently Infected ◽  
Latent Hiv ◽  
T Cell Lines ◽  
Hiv 1

The biomolecular mechanisms controlling latent HIV-1 infection, despite their importance for the development of a cure for HIV-1 infection, are only partially understood. For example, ex vivo studies have recently shown that T cell activation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, but the molecular biology of this phenomenon is unclear. We demonstrate that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of T cell receptor (TCR)/CD3 activation-inert latently infected T cells. RNA-level analysis identified extensive transcriptomic differences between uninfected, TCR/CD3 activation-responsive and -inert T cells, but did not reveal a gene expression signature that could functionally explain TCR/CD3 signaling inertness. Network analysis suggested a largely stochastic nature of these gene expression changes (transcriptomic noise), raising the possibility that widespread gene dysregulation could provide a reactivation threshold by impairing overall signal transduction efficacy. Indeed, compounds that are known to induce genetic noise, such as HDAC inhibitors impeded the ability of TCR/CD3 activation to trigger HIV-1 reactivation. Unlike for transcriptomic data, pathway enrichment analysis based on phospho-proteomic data directly identified an altered TCR signaling motif. Network analysis of this data set identified drug targets that would promote TCR/CD3-mediated HIV-1 reactivation in the fraction of otherwise TCR/CD3-reactivation inert latently HIV-1 infected T cells, regardless of whether the latency models were based on T cell lines or primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell responsiveness prior to the use of any activating stimulus will likely have to be an element of future HIV-1 cure therapies.

scholarly journals A two-color haploid genetic screen identifies novel host factors involved in HIV latency

2021 ◽  
Author(s):  
Michael D Röling ◽  
Mahsa Mollapour Sisakht ◽  
Enrico Ne ◽  
Panagiotis Moulos ◽  
Mateusz Stoszko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd4 T Cells ◽  
Genetic Screen ◽  
Host Factors ◽  
Hiv Latency ◽  
Novel Host ◽  
Latent Hiv ◽  
Hiv 1

AbstractTo identify novel host factors as putative targets to reverse HIV latency, we performed an insertional mutagenesis genetic screen in a latently HIV-1-infected pseudo-haploid KBM7 cell line (Hap-Lat). Following mutagenesis, insertions were mapped to the genome and bioinformatic analysis resulted in the identification of 69 candidate host genes involved in maintaining HIV-1 latency. A select set of candidate genes was functionally validated using shRNA mediated depletion in latent HIV-1 infected J-Lat A2 and 11.1 T cell lines. We confirmed ADK, CHD9, CMSS1, EVI2B, EXOSC8, FAM19A, GRIK5, IRF2BP2, NF1, and USP15 as novel host factors involved in the maintenance of HIV latency. Chromatin immunoprecipitation assays indicated that CHD9, a Chromodomain Helicase DNA-binding protein, maintains HIV latency via direct association with the HIV 5’LTR, and its depletion results in increased histone acetylation at the HIV-1 promoter, concomitant with HIV-1 latency reversal. FDA-approved inhibitors 5-Iodotubercidin, Trametinib, and Topiramate, targeting ADK, NF1, and GRIK5, respectively were characterized for their latency reversal potential. While 5-Iodotubercidin exhibited significant cytotoxicity in both J-Lat and primary CD4+ T cells, Trametinib reversed latency in J-Lat cells but not in latently HIV-1-infected primary CD4+ T cells. Crucially, Topiramate reversed latency in cell-line models and latently infected primary CD4+ T cells, without inducing T cell activation or significant toxicity. Thus, using an adaptation of a haploid forward genetic screen, we identified novel and druggable host factors contributing to HIV-1 latency.ImportanceA reservoir of latent HIV-1-infected cells persists in the presence of combination antiretroviral therapy (cART), representing a major obstacle for viral eradication. Reactivation of the latent HIV-1 provirus is part of curative strategies which aim to promote clearance of the infected cells. Using a two-color haploid screen, we identified 69 candidate genes as latency maintaining host factors and functionally validated a subset of 10 of those in additional T-cell based cell line models of HIV-1 latency. We further demonstrated that CHD9 is associated with HIV-1’s promoter, the 5’LTR while this association is lost upon reactivation. Additionally, we characterized the latency reversal potential of FDA compounds targeting ADK, NF1, and GRIK5 and identify the GRIK5 inhibitor Topiramate as a viable latency reversal agent with clinical potential.

scholarly journals Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

2020 ◽  
Author(s):  
Iart Luca Shytaj ◽  
Francesco Andrea Procopio ◽  
Mohammad Tarek ◽  
Irene Carlon-Andres ◽  
Hsin-Yao Tang ◽  
...  
Keyword(s):  
Pentose Phosphate ◽  
Viral Reactivation ◽  
People Living With Hiv ◽  
Cellular Models ◽  
Downstream Effectors ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Living With Hiv ◽  
Hiv 1

AbstractHIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

scholarly journals Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8+T Cells

2016 ◽  
Vol 90 (19) ◽  
pp. 8552-8562 ◽  
Author(s):  
Esther Jimenez-Moyano ◽  
Alba Ruiz ◽  
Henrik N. Kløverpris ◽  
Maria T. Rodriguez-Plata ◽  
Ruth Peña ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Immunity ◽  
Acute Infection ◽  
Cyclophilin A ◽  
T Cell Responses ◽  
Immune Recognition ◽  
Cell Responses ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTTripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type 1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two nonhuman TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+T cells. We illustrate how TRIM5 restriction improves CD8+T-cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the nonimmunosuppressive analog of cyclosporine (CsA), sarcosine-3(4-methylbenzoate)–CsA (SmBz-CsA), we found a significant reduction in CD107a/MIP-1β expression in HIV-1-specific CD8+T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for nonhuman TRIM5 variants in cellular immunity. We hypothesize that TRIM5 can couple innate viral sensing and CD8+T-cell activation to increase species barriers against retrovirus infection.IMPORTANCENew therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The nonhuman TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+T-cell-mediated inhibition through the direct activation of HIV-1-specific CD8+T-cell responses. We found that the potency in CD8+activation was stronger for RhT5 variants and capsid-specific CD8+T cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection.

scholarly journals HLA Class II Defects in Burkitt Lymphoma: Bryostatin-1-Induced 17 kDa Protein Restores CD4+ T-Cell Recognition

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Azim Hossain ◽  
Jason M. God ◽  
Faisal F. Y. Radwan ◽  
Shereen Amria ◽  
Dan Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Burkitt Lymphoma ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cd4 T Cell ◽  
Immune Recognition ◽  
Antigenic Peptides ◽  
Bryostatin 1

While the defects in HLA class I-mediated Ag presentation by Burkitt lymphoma (BL) have been well documented, CD4+ T-cells are also poorly stimulated by HLA class II Ag presentation, and the reasons underlying this defect(s) have not yet been fully resolved. Here, we show that BL cells are deficient in their ability to optimally stimulate CD4+ T cells via the HLA class II pathway. The observed defect was not associated with low levels of BL-expressed costimulatory molecules, as addition of external co-stimulation failed to result in BL-mediated CD4+ T-cell activation. We further demonstrate that BL cells express the components of the class II pathway, and the defect was not caused by faulty Ag/class II interaction, because antigenic peptides bound with measurable affinity to BL-associated class II molecules. Treatment of BL with broystatin-1, a potent modulator of protein kinase C, led to significant improvement of functional class II Ag presentation in BL. The restoration of immune recognition appeared to be linked with an increased expression of a 17 kDa peptidylprolyl-like protein. These results demonstrate the presence of a specific defect in HLA class II-mediated Ag presentation in BL and reveal that treatment with bryostatin-1 could lead to enhanced immunogenicity.

scholarly journals Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+T CellsIn Vitro

2016 ◽  
Vol 90 (18) ◽  
pp. 8059-8073 ◽  
Author(s):  
Jennifer M. Zerbato ◽  
Erik Serrao ◽  
Gina Lenzi ◽  
Baek Kim ◽  
Zandrea Ambrose ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Central Memory ◽  
T Cell Subsets ◽  
Latent Reservoir ◽  
Memory Cells ◽  
Consistent Finding ◽  
Latent Hiv ◽  
Hiv 1 ◽  
Reversing Agents

ABSTRACTThe latent HIV-1 reservoir primarily resides in resting CD4+T cells which are a heterogeneous population composed of both naive (TN) and memory cells. In HIV-1-infected individuals, viral DNA has been detected in both naive and memory CD4+T cell subsets although the frequency of HIV-1 DNA is typically higher in memory cells, particularly in the central memory (TCM) cell subset. TNand TCMcells are distinct cell populations distinguished by many phenotypic and physiological differences. In this study, we used a primary cell model of HIV-1 latency that utilizes direct infection of highly purified TNand TCMcells to address differences in the establishment and reversal of HIV-1 latency. Consistent with what is seenin vivo, we found that HIV-1 infected TNcells less efficiently than TCMcells. However, when the infected TNcells were treated with latency-reversing agents, including anti-CD3/CD28 antibodies, phorbol myristate acetate/phytohemagglutinin, and prostratin, as much (if not more) extracellular virion-associated HIV-1 RNA was produced per infected TNcell as per infected TCMcell. There were no major differences in the genomic distribution of HIV-1 integration sites between TNand TCMcells that accounted for these observed differences. We observed decay of the latent HIV-1 cells in both T cell subsets after exposure to each of the latency-reversing agents. Collectively, these data highlight significant differences in the establishment and reversal of HIV-1 latency in TNand TCMCD4+T cells and suggest that each subset should be independently studied in preclinical and clinical studies.IMPORTANCEThe latent HIV-1 reservoir is frequently described as residing within resting memory CD4+T cells. This is largely due to the consistent finding that memory CD4+T cells, specifically the central (TCM) and transitional memory compartments, harbor the highest levels of HIV-1 DNA in individuals on suppressive therapy. This has yielded little research into the contribution of CD4+naive T (TN) cells to the latent reservoir. In this study, we show that although TNcells harbor significantly lower levels of HIV-1 DNA, following latency reversal, they produced as many virions as did the TCMcells (if not more virions). This suggests that latently infected TNcells may be a major source of virus following treatment interruption or failure. These findings highlight the need for a better understanding of the establishment and reversal of HIV-1 latency in TNcells in evaluating therapeutic approaches to eliminate the latent reservoir.

scholarly journals Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

2019 ◽  
Vol 8 (12) ◽  
pp. 2089 ◽  
Author(s):  
Oscar Blanch-Lombarte ◽  
Cristina Gálvez ◽  
Boris Revollo ◽  
Esther Jiménez-Moyano ◽  
Josep M. Llibre ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Viral Reactivation ◽  
Viral Reservoir ◽  
Cell Responses ◽  
Hiv 1

Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8+ T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir. Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8+ T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load. Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8+ T-cells expressing HLA-DR+/CD38+ transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8+ T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence. Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8+ T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8+ T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement.

scholarly journals Differentiation into an Effector Memory Phenotype Potentiates HIV-1 Latency Reversal in CD4+ T Cells

2019 ◽  
Vol 93 (24) ◽  
Author(s):  
Deanna A. Kulpa ◽  
Aarthi Talla ◽  
Jessica H. Brehm ◽  
Susan Pereira Ribeiro ◽  
Sally Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Surface Markers ◽  
Cell Cycle Entry ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT During antiretroviral therapy (ART), human immunodeficiency virus type 1 (HIV-1) persists as a latent reservoir in CD4+ T cell subsets in central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells. We have identified differences in mechanisms underlying latency and responses to latency-reversing agents (LRAs) in ex vivo CD4+ memory T cells from virally suppressed HIV-infected individuals and in an in vitro primary cell model of HIV-1 latency. Our ex vivo and in vitro results demonstrate the association of transcriptional pathways of T cell differentiation, acquisition of effector function, and cell cycle entry in response to LRAs. Analyses of memory cell subsets showed that effector memory pathways and cell surface markers of activation and proliferation in the TEM subset are predictive of higher frequencies of cells carrying an inducible reservoir. Transcriptional profiling also demonstrated that the epigenetic machinery (known to control latency and reactivation) in the TEM subset is associated with frequencies of cells with HIV-integrated DNA and inducible HIV multispliced RNA. TCM cells were triggered to differentiate into TEM cells when they were exposed to LRAs, and this increase of TEM subset frequencies upon LRA stimulation was positively associated with higher numbers of p24+ cells. Together, these data highlight differences in underlying biological latency control in different memory CD4+ T cell subsets which harbor latent HIV in vivo and support a role for differentiation into a TEM phenotype in facilitating latency reversal. IMPORTANCE By performing phenotypic analysis of latency reversal in CD4+ T cells from virally suppressed individuals, we identify the TEM subset as the largest contributor to the inducible HIV reservoir. Differential responses of memory CD4+ T cell subsets to latency-reversing agents (LRAs) demonstrate that HIV gene expression is associated with heightened expression of transcriptional pathways associated with differentiation, acquisition of effector function, and cell cycle entry. In vitro modeling of the latent HIV reservoir in memory CD4+ T cell subsets identify LRAs that reverse latency with ranges of efficiency and specificity. We found that therapeutic induction of latency reversal is associated with upregulation of identical sets of TEM-associated genes and cell surface markers shown to be associated with latency reversal in our ex vivo and in vitro models. Together, these data support the idea that the effector memory phenotype supports HIV latency reversal in CD4+ T cells.

HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

2009 ◽  
Vol 19 (5) ◽  
pp. 177-187 ◽  
Author(s):  
Jason D Graci ◽  
Joseph M Colacino ◽  
Stuart W Peltz ◽  
Joseph P Dougherty ◽  
Zhengxian Gu
Keyword(s):  
T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Current Knowledge ◽  
Therapeutic Agents ◽  
Viral Reactivation ◽  
Highly Active ◽  
Hiv Type 1 ◽  
Latent Hiv ◽  
Hiv 1

HIV type-1 (HIV-1) can establish a state of latency in infected patients, most notably in resting CD4+ T-cells. This long-lived reservoir allows for rapid re-emergence of viraemia upon cessation of highly active antiretroviral therapy, even after extensive and seemingly effective treatment. Successful depletion of such latent reservoirs is probably essential to ‘cure’ HIV-1 infection and will require therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. The mechanisms underlying HIV-1 latency are not well characterized, and it is becoming clear that numerous factors, both cell- and virus-derived, are involved in the maintenance of proviral latency. The interplay of these various factors in the context of viral reactivation is still poorly understood. In this article, we review the current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.

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