HIV Latency Reversal Research Articles

NSC95397 Is a Novel HIV-1 Latency-Reversing Agent.

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the "kick and kill" (also called "shock and kill") approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair-highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.

MALAT1 is important for facilitating HIV-1 latency reversal in latently infected monocytes

Long non-coding RNAs (lncRNAs) are long RNA transcripts with length >200 nucleotides that do not encode proteins. They play a crucial role in regulating HIV-1 infection, yet their involvement in myeloid cells remains underexplored. Myeloid cells are susceptible to HIV infection and contribute substantially to the latent HIV reservoir. Therefore, disruption of latency within these reservoirs is crucial for achieving a definite cure. In this study, we aimed to ascertain the role of MALAT1 lncRNA in reversal of HIV-1 latency. Latently HIV-infected cell line, U1 was treated with SAHA, followed by qRT-PCR assays to confirm HIV-1 reactivation, and MALAT1 expression was assessed. The in vitro experiments revealed a significant increase in MALAT1 expression following latency reactivation and HIV-1 infection, while its knockdown using siRNA resulted in suppression of HIV transcription, which implies that MALAT1 play a significant role in facilitating the reversal of HIV-1 latency by promoting HIV transcription. Clinical samples were analysed to measure MALAT1 and pro-inflammatory cytokines expression. The elevated MALAT1 expression in treatment-naïve subjects compared to those on ART and HIV-negative controls suggests its association with HIV replication. Moreover, correlation analysis revealed a positive association between MALAT1 expression and pro-inflammatory cytokines, TNF-α and IP-10. To conclude, MALAT1 lncRNA emerged as a crucial facilitator of HIV-1 latency reversal in latently infected monocytes by inducing the expression of pro-inflammatory factors. These findings highlight that MALAT1 could potentially be explored as the therapeutic intervention to reactivate latent cells in monocytes.

Transcriptomic study reveals alteration in the expression of long non-coding RNAs (lncRNAs) during reversal of HIV-1 latency in monocytic cell line.

The presence of latent HIV reservoirs continues to be the biggest obstacle to achieving an HIV cure. Thus, long non-coding RNAs (lncRNAs) may serve as the preferred targets for HIV latency reversal. The goal of the study was to identify prospective lncRNAs for subsequent in vitro molecular and functional characterization. RNA-sequencing was performed in latently HIV-infected monocytic cell line (U1) under stimulated and unstimulated condition using Illumina-HiSeqX platform, followed by its validation using qRT-PCR assay. Gene ontology (GO), KEGG pathway, and co-expression analyses were performed to identify the enriched biological processes and pathways in U1 cells post-stimulation with the latency reversal agent SAHA. A total of 3,576 and 1,467 significantly altered lncRNAs and protein-coding genes respectively, were identified in SAHA-stimulated U1 cells compared to unstimulated ones. The GO and KEGG pathway analyses of the differentially expressed protein-coding genes showed the enrichment of diverse biological processes and pathways respectively, in SAHA-stimulated U1 cells. Co-expression analysis between lncRNAs and protein-coding gene pairs, helped predict potential pathways with which these lncRNAs are associated. Further in vitro validation in HIV-infected monocytes showed that the expression of the top two candidate lncRNAs, LINC01231 and LINC00560, are specific to HIV infection. Transcriptome analysis revealed changes in the expression of numerous lncRNAs and protein-coding genes following stimulation with SAHA. Co-expression analysis identified candidate lncRNAs and their associated biological pathways. However, additional in vitro experimental exploration using gene knockdown strategies is needed to ascertain the specific role of LINC01231 and LINC00560 lncRNAs in latently infected monocytes.

HIV-1 latency reversal agent boosting is not limited by opioid use.

Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.

Epitranscriptomic m6A modifications during reactivation of HIV-1 latency in CD4+ T cells.

RNA m6A modification is important for regulating gene expression and innate immune responses to HIV-1 infection. However, the functional significance of m6A modification during HIV-1 latency reactivation is unknown. To address this important question, in this study, we used established cellular models of HIV-1 latency, m6A-specific sequencing at single-base resolution, and functional assays. We demonstrate that HIV-1 latency reversal leads to increased levels of cellular m6A modification, correlates with cellular m6A levels, and is dependent on the catalytic activity of the m6A methyltransferase enzyme. We also identified cellular genes that are differentially m6A-modified during HIV-1 reactivation, as well as the sites of m6A within HIV-1 RNA. Our novel findings point toward a significant role for m6A modification in HIV-1 latency reversal.

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.

The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 & I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo. We also detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 prevents full-length HIV RNA production in primary T cells.

A high-throughput, microplate reader-based method to monitor in vitro HIV latency reversal in the absence of flow cytometry.

J-Lat T-cell lines are important to HIV cure research but require flow cytometryWe describe a method to work with J-Lat cells using a standard microplate readerThis assay can detect control LRAs similar to flow cytometry and discover new LRAsThis assay allows low-resourced laboratories to contribute to HIV cure research.

Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.

The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.

Immune checkpoint inhibitors in infectious disease.

Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection. We highlight several key studies and future directions of research in relation to anti-PD-1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV-specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti-PD-1 and anti-CTLA-4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti-PD-1 in vivo in people with HIV on ART without cancer and potential combinations of anti-PD-1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers.

Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a “shock and kill” strategy for ART-free virological control: a phase II single-arm study

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

SARS-CoV-2 Modulation of HIV Latency Reversal in a Myeloid Cell Line: Direct and Bystander Effects.

Coronavirus disease 2019 (COVID-19) might impact disease progression in people living with HIV (PLWH), including those on effective combination antiretroviral therapy (cART). These individuals often experience chronic conditions characterized by proviral latency or low-level viral replication in CD4+ memory T cells and tissue macrophages. Pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, can reactivate provirus expression in both primary cells and cell lines. These cytokines are often elevated in individuals infected with SARS-CoV-2, the virus causing COVID-19. However, it is still unknown whether SARS-CoV-2 can modulate HIV reactivation in infected cells. Here, we report that exposure of the chronically HIV-1-infected myeloid cell line U1 to two different SARS-CoV-2 viral isolates (ancestral and BA.5) reversed its latent state after 24 h. We also observed that SARS-CoV-2 exposure of human primary monocyte-derived macrophages (MDM) initially drove their polarization towards an M1 phenotype, which shifted towards M2 over time. This effect was associated with soluble factors released during the initial M1 polarization phase that reactivated HIV production in U1 cells, like MDM stimulated with the TLR agonist resiquimod. Our study suggests that SARS-CoV-2-induced systemic inflammation and interaction with macrophages could influence proviral HIV-1 latency in myeloid cells in PLWH.

HIV-1 latency reversal and immune enhancing activity of IL-15 is not influenced by sex hormones.

The role of different biological variables including biological sex, age, and sex hormones in Human immunodeficiency virus (HIV) cure approaches is not well understood. The γc-cytokine IL-15 is a clinically relevant cytokine that promotes immune activation and mediates HIV reactivation from latency. In this work, we examined the interplay that biological sex, age, and sex hormones 17β-estradiol, progesterone, and testosterone may have on the biological activity of IL-15. We found that IL-15-mediated CD4+ T cell activation was higher in female donors than in male donors. This difference was abrogated at high 17β-estradiol concentration. Additionally, there was a positive correlation between age and both IL-15-mediated CD8+ T cell activation and IFN-γ production. In a primary cell model of latency, biological sex, age, or sex hormones did not influence the ability of IL-15 to reactivate latent HIV. Finally, 17β-estradiol did not consistently affect reactivation of translation-competent reservoirs in CD4+ T cells from people living with HIV who are antiretroviral therapy (ART) suppressed. Our study has found that biological sex and age, but not sex hormones, may influence some of the biological activities of IL-15. Understanding how different biological variables may affect HIV cure therapies will help us evaluate current and future clinical trials aimed toward HIV cure in diverse populations.

HIV-1 latency reversal agent boosting is not limited by opioid use.

The opioid epidemic may impact the HIV-1 reservoir and its reversal from latency in virally suppressed people with HIV (PWH). We studied forty-seven PWH and observed that lowering the concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that do not reverse latency, synergistically increases the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combines a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, can generate significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation in CD4+ T cells and modulated T cell activation-induced markers and intracellular cytokine production; Smac mimetic-based boosting was less likely to induce immune activation. We found that HIV-1 reservoirs in PWH contain unspliced and polyadenylated (polyA) virus mRNA, the ratios of which are greater in resting than total CD4+ T cells and can correct to 1:1 with PMAi exposure. Latency reversal results in greater fold-change increases to HIV-1 poly(A) mRNA than unspliced message. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe the mechanisms of an effective cellular HIV-1 latency reversal program.

Immune checkpoint inhibition as a therapeutic strategy for HIV eradication: current insights and future directions.

HIV-1 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective prophylactic vaccine. Combination antiretroviral therapy (ART) suppresses HIV replication, but latent viral reservoirs allow the virus to persist and reignite active replication if ART is discontinued. Moreover, inflammation and immune disfunction persist despite ART-mediated suppression of HIV. Immune checkpoint molecules facilitate immune dysregulation and viral persistence. However, their therapeutic modulation may offer an avenue to enhance viral immune control for patients living with HIV-1 (PLWH). The success of immune checkpoint inhibitor (ICI) therapy in oncology suggests that targeting these same immune pathways might be an effective therapeutic approach for treating PLWH. Several ICIs have been evaluated for their ability to reinvigorate exhausted T cells, and possibly reverse HIV latency, in both preclinical and clinical HIV-1 studies. Although there are very encouraging findings showing enhanced CD8 + T-cell function with ICI therapy in HIV infection, it remains uncertain whether ICIs alone could demonstrably impact the HIV reservoir. Moreover, safety concerns and significant clinical adverse events present a hurdle to the development of ICI approaches. This review provides an update on the current knowledge regarding the development of ICIs for the remission of HIV-1 in PWH. We detail recent findings from simian immunodeficiency virus (SIV)-infected rhesus macaque models, clinical trials in PLWH, and the role of soluble immune checkpoint molecules in HIV pathogenesis.

Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells.

Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Although PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.

Effective and targeted latency reversal in CD4+ T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection

ABSTRACT To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most “latency reversal” agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5–20 years on stable cART, HLP could target CD4+ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

CRISPR-Cas9 screen of E3 ubiquitin ligases identifies TRAF2 and UHRF1 as regulators of HIV latency in primary human T cells.

HIV, the virus that causes AIDS, heavily relies on the machinery of human cells to infect and replicate. Our study focuses on the host cell's ubiquitination system which is crucial for numerous cellular processes. Many pathogens, including HIV, exploit this system to enhance their own replication and survival. E3 proteins are part of the ubiquitination pathway that are useful drug targets for host-directed therapies. We interrogated the 116 E3s found in human immune cells known as CD4+ T cells, since these are the target cells infected by HIV. Using CRISPR, a gene-editing tool, we individually removed each of these enzymes and observed the impact on HIV infection in human CD4+ T cells isolated from healthy donors. We discovered that 10 of the E3 enzymes had a significant effect on HIV infection. Two of them, TRAF2 and UHRF1, modulated HIV activity within the cells and triggered an increased release of HIV from previously dormant or "latent" cells in a new primary T cell assay. This finding could guide strategies to perturb hidden HIV reservoirs, a major hurdle to curing HIV. Our study offers insights into HIV-host interactions, identifies new factors that influence HIV infection in immune cells, and introduces a novel methodology for studying HIV infection and latency in human immune cells.

The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy.

The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy. Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400 mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy. VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention. These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit. Clinical Trials Registration. NCT03212989.

Experimental models for HIV latency and molecular tools for reservoir quantification-an update.

A major impediment for HIV cure is the ability of the virus to integrate its genome in the form of replication-competent proviral DNA into the cellular genome of the host and remain transcriptionally silent and hidden from the host's immune defense mechanisms in latent reservoir cells. These latent reservoirs are highly heterogeneous, long-lived cells that are capable of reactivating to restore the viremic stage in virally suppressed individuals upon treatment interruption, thus necessitating life-long antiretroviral treatment. Latency reversal has become one of the most explored therapeutic approaches for eliminating HIV reservoirs and effecting HIV cure. Various aspects governing the establishment, maintenance, and reversal of HIV latency continue to be an enigma and warrant further research. Quantifying the size of the latent reservoir pool is also a challenge as these cells are very few in number and cannot be easily differentiated from uninfected cells. This article provides a comprehensive review of the in vitro and in vivo models currently available for studying HIV latency as well as the recently developed molecular tools for detection and quantification of latent viral reservoirs.

IMMU-32. CAN PEMBROLIZUMAB TREAT RECURRENT GLIOBLASTOMA AND REVERSE HIV LATENCY?

Abstract Immunotherapy revolutionized treatment for many solid tumors. Early studies show that immunotherapy may be effective for recurrent glioblastoma. The ongoing Phase 2 LEEP-005 clinical trial (pembrolizumab+lenvima) is currently enrolling glioblastoma patients, but excludes patients with HIV. However, there is a strong need to treat this special patient population. One of the barriers to achieving cure in HIV patients is HIV latency within infect CD4+ T cells. Recently published data suggests that pembrolizumab can reverse HIV latency by forcing the HIV out of intracellular hiding into the plasma where anti-retroviral therapy can be effective. We present a case of a 39 year-old male with HIV and a Left Parietal Glioblastoma who had progressive disease following a subtotal resection and radiation alone due persistent neutropenia. Post-radiation MR brain wwo showed progressive disease in the left parietal lobe and new dural-based lesions in the left frontal and temporal lobes. HIV viral load was < 20 and CD4 count was 406 on HAART. The patient declined lenvima, but was amenable to bevacizumab. At 1 month follow-up, after 1 infusion of pembrolizumab 200mg and 2 infusions of bevacizumab, he achieved CR in the original site of disease and stable disease in the left frontal and temporal lobes. HIV viral load was 52. CD4 count was 660. Though it is too early to draw any firm conclusions, in our patient, pembrolizumab appears to induce HIV reversal, which is supported by an increase in the increase in his HIV viral load. The combination of pembrolizumab and bevacizumab appears to be effective at short-term follow-up. Our study is significant because there is limited evidence on the use of PD-L1 inhibitors in active HIV patients with cancer. To our knowledge, our case is the first reported case of the use of pembrolizumab in a patient with HIV and glioblastoma.