Human Immunodeficiency Virus Reservoir Research Articles

Interventions during Early Infection: Opening a Window for an HIV Cure?

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection.

Human Immunodeficiency Virus - a Review of the clinical aspects and detection of the infection

Introduction: Currently, many people are infected with the human immunodeficiency virus (HIV). Transmission is primarily through sexual contact, with additional routes including mother-infant exposure to needles and needle sharing. Since the HIV/AIDS pandemic was first identified in 1981, more than 75 million people have been infected. Numerous new cases continue to be reported, and infection can become the starting point for the development of HIV. Clinical manifestations include acute retroviral syndrome, opportunistic infections, and dermatological, neuromuscular, and other complications. Despite advances in antiretroviral therapy (ART), challenges remain, including drug resistance, opportunistic infections, and persistent HIV reservoirs in some cell types. Early and accurate diagnosis is essential, and recommended testing protocols include fourth-generation serological tests and point-of-care (POC) testing. ART, which includes combinations of antiretroviral drugs, is the standard treatment, and ongoing research into gene therapy shows promise for the future. Purpose of the work: The aim of this study is to review and characterize the clinical aspects and detection of human immunodeficiency virus infection. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: HIV, human immunodeficiency virus, ART, HIV manifestation, HIV detection, HIV diagnosis, HIV treatment.

Intact HIV Reservoir in Monocytes Is Associated With Cognitive Function in Virally Suppressed Women With HIV

Abstract Background Monocytes are susceptible to human immunodeficiency virus (HIV) infection, form HIV reservoirs, and contribute to central nervous system complications (eg, cognitive impairment) in virally suppressed women with HIV (vsWWH). However, it remains unknown if the quality and/or quantity of the monocyte reservoir contributes to cognition in vsWWH. Methods Sixty-two vsWWH (mean age = 56.1 years, SD = 7.1; 93% Black, non-Hispanic; all HIV RNA <250 copies/mL) completed a cognitive test battery, blood draw, and whole-blood immunophenotyping. Monocytes and CD4 T cells were isolated from a subset of 53 participants and the HIV reservoir was assessed using cell-specific intact proviral DNA assays (IPDA). Demographically adjusted z-scores were calculated for each outcome using data from participants without HIV in the Women's Interagency HIV Study. Cognitive outcomes of interest included domain-specific and global z-scores. Results Thirty-Eight percent of vsWWH had detectable intact HIV genomes in monocytes (median = 21.5 copies/million). Higher levels of intact HIV genomes per million monocytes were associated with poorer verbal memory (delayed recall, r = 0.55, P = .01; recognition, r = 0.46, P = .04), fine motor skills (r = 0.50, P = .03), and global function (r = 0.47, P = .04). Higher levels of intact HIV genomes in monocytes were associated with percent intermediate monocytes (r = 0.60, P = .008), and the ratio of intact per intermediate monocyte was associated with worse memory (r = −0.59, P = .008). There were no associations between CD4 reservoir and cognition. Conclusions The number of intact HIV genomes per million monocytes was related to poorer cognition and the percentage of intermediate monocytes. These findings suggest that the presence of HIV genomes in general do not relate to cognitive complications, but intact, and therefore potentially replication-competent HIV, may contribute to cognitive complications in vsWWH.

New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs.

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease.

Potential role of alveolar macrophages in HIV persistence and lung disease

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T-cells, and particularly memory CD4+ T-cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory co-infections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.

Potential role of alveolar macrophages in HIV persistence and lung disease.

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T cells, and particularly memory CD4+ T cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory coinfections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.

CAR-T Therapy in HIV: Pioneering Advances and Navigating Challenges

Abstract Chimeric antigen receptor T (CAR-T) cell therapy, renowned for its successes in cancer treatment, is now entering the field of human immunodeficiency virus (HIV) therapy, presenting both opportunities and challenges. With the emergence of broadly neutralizing antibodies, multi-target CARs, and T cell receptor–like antibodies aimed at increasing specificity in targeting HIV reservoirs, CAR-T therapy is synergizing with other cutting-edge treatments, including gene-editing technologies, therapeutic vaccines, and latency-reversing agents, in pursuit of a potential functional cure. In this review, we delve into the role of CAR-T therapy in HIV treatment, highlighting its potential to overcome clinical obstacles. We discuss advancements in targeting strategies within CAR constructs and the intricate regulation of T cell proliferation and chemotaxis. Moreover, we explore the use of diverse immune cells, such as gamma-delta T cells and natural killer cells. We review advanced biotechnologies, manufacturing innovations, viral mechanisms, and immune microenvironments. We also discuss the current research landscape and potential future applications of CAR-T therapy against HIV, which remains a critical global health challenge.

Advanced Therapies for Human Immunodeficiency Virus.

Human Immunodeficiency Virus (HIV) remains a significant global health challenge with approximately 38 million people currently having the virus worldwide. Despite advances in treatment development, the virus persists in the human population and still leads to new infections. The virus has a powerful ability to mutate and hide from the human immune system in reservoirs of the body. Current standard treatment with antiretroviral therapy effectively controls viral replication but requires lifelong adherence and does not eradicate the virus. This review explores the potential of Advanced Therapy Medicinal Products as novel therapeutic approaches to HIV, including cell therapy, immunisation strategies and gene therapy. Cell therapy, particularly chimeric antigen receptor T cell therapy, shows promise in preclinical studies for targeting and eliminating HIV-infected cells. Immunisation therapies, such as broadly neutralising antibodies are being investigated to control viral replication and reduce reservoirs. Despite setbacks in recent trials, vaccines remain a promising avenue for HIV therapy development. Gene therapy using technologies like CRISPR/Cas9 aims to modify cells to resist HIV infection or eliminate infected cells. Challenges such as off-target effects, delivery efficiency and ethical considerations persist in gene therapy for HIV. Future directions require further research to assess the safety and efficacy of emerging therapies in clinical trials. Combined approaches may be necessary to achieve complete elimination of the HIV reservoir. Overall, advanced therapies offer new hope for advancing HIV treatment and moving closer to a cure.

Effective in vivo reactivation of HIV-1 latency reservoir via oral administration of EK-16A-SNEDDS

The latent reservoir of human immunodeficiency virus (HIV) is a major obstacle in the treatment of acquired immune deficiency syndrome (AIDS). The “shock and kill” strategy has emerged as a promising approach for clearing HIV latent reservoirs. However, current latency-reversing agents (LRAs) have limitations in effectively and safely activating the latent virus and reducing the HIV latent reservoirs in clinical practice. Previously, EK-16A was extracted from Euphorbia kansui, which had the effect of interfering with the HIV-1 latent reservoir and inhibiting HIV-1 entry. Nevertheless, there is no suitable and efficient EK-16A oral formulation for in vivo delivery and clinical use. In this study, an oral EK-16A self-nanoemulsifying drug delivery system (EK-16A-SNEDDS) was proposed to “shock” the HIV-1 latent reservoir. This system aims to enhance the bioavailability and delivery of EK-16A to various organs. The composition of EK-16A-SNEDDS was optimized through self-emulsifying grading and ternary phase diagram tests. Cell models, pharmacokinetic experiments, and pharmacodynamics in HIV-1 latent cell transplant animal models suggested that EK-16A-SNEDDS could be absorbed by the gastrointestinal tract and enter the blood circulation after oral administration, thereby reaching various organs to activate latent HIV-1. The prepared EK-16A-SNEDDS demonstrated safety and efficacy, exhibited high clinical experimental potential, and may be a promising oral preparation for eliminating HIV-1 latent reservoirs.

Impact of Variable Sampling on Estimates of HIV-1 Reservoir Formation Dates.

Timing of human immunodeficiency virus-1 (HIV-1) reservoir formation is important for informing HIV cure efforts. It is unclear how much of the variability seen in dating reservoir formation is due to sampling and gene-specific differences. We used a Bayesian extension of root to tip regression (bayroot) to reestimate formation date distributions in participants from Swedish and South African cohorts, and assessed the impact of variable timing, frequency, and depth of sampling on these estimates. Significant shifts in formation date distributions were only observed with use of faster-evolving genes, while timing, frequency, and depth of sampling had minor or no significant effect on estimates.

HIV Reservoirs and Treatment Strategies toward Curing HIV Infection.

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the "Shock and Kill", and "Block and Lock" strategies.

HIV-Infected Hepatic Stellate Cells or HCV-Infected Hepatocytes Are Unable to Promote Latency Reversal among HIV-Infected Mononuclear Cells.

Due to a common mode of transmission through infected human blood, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is relatively prevalent. In alignment with this, HCV co-infection is associated with an increased size of the HIV reservoir in highly active antiretroviral therapy (HAART)-treated individuals. Hence, it is crucial to comprehend the physiological mechanisms governing the latency and reactivation of HIV in reservoirs. Consequently, our study delves into the interplay between HCV/HIV co-infection in liver cells and its impact on the modulation of HIV latency. We utilized the latently infected monocytic cell line (U1) and the latently infected T-cell line (J-Lat) and found that mediators produced by the infection of hepatic stellate cells and hepatocytes with HIV and HCV, respectively, were incapable of inducing latency reversal under the studied conditions. This may favor the maintenance of the HIV reservoir size among latently infected mononuclear cells in the liver. Further investigations are essential to elucidate the role of the interaction between liver cells in regulating HIV latency and/or reactivation, providing a physiologically relevant model for comprehending reservoir microenvironments in vivo.

Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells

The persistence of CD4+ T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4+ T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.

Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection.

Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.

Role of long noncoding RNA in regulating HIV infection-a comprehensive review.

A complete cure against human immunodeficiency virus (HIV) infection remains out of reach, as the virus persists in stable cell reservoirs that are resistant to antiretroviral therapy. The key to eliminating these reservoirs lies in deciphering the processes that govern viral gene expression and latency. However, while we comprehensively understand how host proteins influence HIV gene expression and viral latency, the emerging role of long noncoding RNAs (lncRNAs) in the context of T cell activation, HIV gene expression, and viral latency remain unexplored. This review dives into the evolving significance of lncRNAs and their impact on HIV gene expression and viral latency. We provide an overview of the current knowledge regarding how lncRNAs regulate HIV gene expression, categorizing them as either activators or inhibitors of viral gene expression and infectivity. Furthermore, we offer insights into the potential therapeutic applications of lncRNAs in combatting HIV. A deeper understanding of how lncRNAs modulate HIV gene transcription holds promise for developing novel RNA-based therapies to complement existing treatment strategies to eradicate HIV reservoirs.

Immunologic and Virologic Parameters Associated With Human Immunodeficiency Virus (HIV) DNA Reservoir Size in People With HIV Receiving Antiretroviral Therapy.

A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial for developing therapies to eradicate the virus. We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size. The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group. Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

DAA-mediated HCV cure reduces HIV DNA levels in HCV/HIV coinfected people.

Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) can control virus replication and prolong the life of people living with HIV (PLWH). However, the virus remains dormant within immune cells in what is called the HIV reservoir. Furthermore, 2.3 million PLWH are also coinfected with hepatitis C virus (HCV) and are at risk of developing chronic liver disease and cancer. HCV treatment with direct acting antivirals (DAA) can completely cure the infection in more than 95% of treated individuals and improve their long-term health outcomes. In this study, we investigated how HCV treatment and cure affect the HIV reservoir. We demonstrate the beneficial impact of DAA treatment as it reduces the HIV reservoirs in particular in people infected with HCV before HIV. These results support the need for early ART and DAA treatment in HIV/HCV coinfections.

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses.

Characterizing the human immunodeficiency virus (HIV) reservoir that endures despite antiretroviral therapy (ART) is critical to cure efforts. We observed that the oldest proviruses persisting during ART were exclusively defective, while intact proviruses (and rebound HIV) dated to nearer ART initiation. This helps explain why studies that sampled sub-genomic proviruses on-ART (which are largely defective) routinely found sequences dating to early infection, whereas those that sampled replication-competent HIV found almost none. Together with our findings that intact proviruses were more likely to be clonal, and that on-ART low-level/isolated viremia originated from proviruses of varying ages (including possibly defective ones), our observations indicate that (i) on-ART and rebound viremia can have distinct within-host origins, (ii) intact proviruses have shorter lifespans than grossly defective ones and thus depend more heavily on clonal expansion for persistence, and (iii) an HIV reservoir predominantly "dating" to near ART initiation will be substantially adapted to within-host pressures, complicating immune-based cure strategies.

Increased Levels of Caspase-1 and IL-1β Among Adults With Persistent Immune Activation After 12 Years of Suppressive Antiretroviral Therapy in the Infectious Diseases Institute HIV Treatment Cohort.

We sought evidence of activated pyroptosis and the inflammasome pathways among human immunodeficiency virus (HIV)-infected adults after 12 years of suppressive antiretroviral therapy (ART) and persistent immune activation in the Infectious Diseases Institute HIV treatment cohort in Uganda. In a cross-sectional study, using peripheral blood mononuclear cells of HIV-infected individuals with high and low immune activation (CD4/CD8+CD38+HLA-DR+ cells) relative to HIV-negative reference group, caspase-1 expression was measured using flow cytometry and plasma interleukin 18 and interleukin 1β (IL-1β) levels using enzyme-linked immunosorbent assay. There was higher expression of caspase-1 by CD4 T cells of ART-treated individuals with high immune activation relative to those with lower immune activation (P = .04). Similarly, plasma levels of IL-1β were higher among ART-treated individuals with high immune activation levels relative to those with low immune activation levels (P = .009). We observed a low positive correlation between caspase-1 expression by CD4/CD8 T cells and immune activation levels (r= 0.497 and r= 0.329, respectively). Caspase-1 and IL-1β were high among individuals with high immune activation despite 12 years of suppressive ART. There is a need to further understand the role of persistent abortive infection and the latent HIV reservoir characteristics as drivers of persistent activation and inflammation and to subsequently intervene to prevent the complications of chronic immune activation during long-term ART.