Multiple Interventions With Distinct Anti-reservoir Activities in People on Antiretroviral Treatment

The development of effective, convenient, and well-tolerated antiretroviral therapy (ART) that leads to virologic suppression has transformed the natural history of a fatal disease into a chronic condition, allowing an almost normal life expectancy for people with HIV. Nevertheless, contemporary ART fails to eradicate the virus, resulting in a rebound in viremia within days to weeks after cessation of ART. Evidence indicates that disparities in biological and sociocultural characteristics between resource-limited and resource-privileged settings affect treatment outcomes. Consequently, resource-constrained settings must possess the capability to comprehend the mechanisms and drivers of HIV persistence, as well as to devise and evaluate therapies for HIV cure or prolonged remission within local populations. The investigators will employ genomic, metabolomics, and transcriptomics to analyze samples from a successful therapeutic trial the investigators conducted in Brazil, a resource-constrained country, to identify and investigate mechanisms of HIV persistence and we will employ novel latency-reversal agents and advanced in vivo cell therapy. The clinical trial to be conducted will employ a multifaceted intervention strategy to achieve HIV remission through intensified ART to reduce residual HIV replication, a novel combination of latency reversal agents (LRA), and cell therapy utilizing autologous dendritic cells infused with autologous HIV peptides.

Aging PWH increasingly experience HIV as a chronic condition characterized by multimorbidity, including cardiovascular disease, diabetes mellitus, non-AIDS-defining malignancies, and neurocognitive disorders; persistent immune activation and inflammation associated with HIV infection are hypothesized to contribute to accelerated biological aging.

Generalized immune activation and chronic inflammation constitute central hallmarks of HIV pathogenesis. Key drivers of HIV-associated immune activation include persistent viral replication, microbial translocation from the gastrointestinal (GI) tract, and co-infections.

Even under effective (ART), low-level viral replication in anatomical reservoirs such as the GI tract continues to contribute to systemic immune activation and disease burden.7 HIV-associated dysregulation of CD4⁺ T regulatory (Treg) cells further exacerbates this process, resulting in sustained immune activation due to impaired immunomodulatory control.8 The cumulative burden of viral gene products and microbial antigens promotes broad activation of both T and B lymphocytes, accompanied by increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which drive bystander lymphocyte activation and contribute to immunosenescence.

HIV-1 replication per se is a major determinant of immune activation, with higher plasma viral loads directly correlating with increased levels of systemic inflammation.9 Notably, defective HIV proviruses, overwhelming prevalent in individuals receiving long-term suppressive ART, can still produce viral proteins capable of sustaining immune activation despite the absence of replication-competent viruses.10 This persistent inflammatory state is implicated in multiple downstream pathological processes, including accelerated CD4⁺ T-cell depletion, lymphoid tissue fibrosis, and increased risk of end-organ diseases such as chronic kidney disease, liver dysfunction, atherosclerosis, cardiovascular disease, and HIV-associated neurocognitive disorders.

Immunophenotypic and soluble biomarkers provide quantitative measures of in vivo T-cell activation and systemic inflammation. Emerging evidence indicates that the latent reservoir of individuals on suppressive ART is predominantly composed of defective proviruses containing large genomic deletions, which may nevertheless retain transcriptional and translational activity sufficient to drive immune activation. However, it remains uncertain whether curative strategies aimed at reducing reservoir size will effectively attenuate immune activation and inflammation, and thereby mitigate the downstream sequelae of HIV pathogenesis.

Individuals who naturally control HIV in the absence of ART, the so-called elite controllers, might provide insights for HIV cure research. Mechanisms involved include T cells, autologous antibodies targeting archived viruses, interferon sensitivity, and natural killer (NK) cells. More recently, the focus has moved towards the so-called "exceptional controllers, individuals who might be considered as true natural cures. Insights also come from "post-treatment controllers", those who can control viral replication after ART is interrupted. It is necessary to better understand viral dynamics associated with control of HIV replication in the absence of ART and to identify biomarkers that predict it to design more effective strategic ART interruptions.

HIV DNA remains detectable in peripheral blood mononuclear cells (PBMCs) in nearly all PWH on suppressive ART, with the majority of these proviral genomes being replication-defective. However, the precise cellular and anatomical sources of viral rebound following ART interruption remain incompletely characterized. Consequently, a detailed understanding of HIV integration site distribution during long-term ART, as well as the inducibility of proviruses relative to their chromosomal context, is essential. In parallel, identifying robust biomarkers to predict viral rebound in analytical treatment-interruption studies is a critical research priority. Furthermore, defining biomarkers associated with reservoir persistence and developing methodologies to quantify the impact of reservoir-reducing interventions accurately will be instrumental in advancing HIV cure strategies. Importantly, the selective elimination of defective proviruses that remain transcriptionally active and contribute to chronic low-grade inflammation may be necessary to optimize long-term clinical outcomes.

A primary mechanism underlying HIV persistence is the clonal proliferation of infected cells, which can occur independently of ongoing viral replication and leads to substantial expansion of infected cell populations. Therapeutic strategies aimed at limiting cellular proliferation, and thereby reducing HIV clonal expansion, may be required to attenuate chronic inflammation, decrease the risk of malignancies and other comorbidities, and move PWH on ART closer to a functional or sterilizing cure. Emerging evidence suggests that combinatorial approaches targeting multiple aspects of viral persistence are likely to be the most effective. Additionally, the development of sensitive and reproducible assays to quantify HIV reservoirs during suppressive ART and in the context of curative interventions will be essential to accelerate progress in HIV cure research.