Azam, W. | Search bioRxiv

bioRxiv2026

Early immune responses anticipate HIV rebound and precede viral control

Sustained viral suppression following antiretroviral treatment (ART) cessation is a major goal of HIV cure research1. Rare individuals mount immune responses able to control viral rebound without intervention2,3, however, the earliest moments in which these responses form remain poorly defined. We performed an intensively sampled, prospective analytical treatment interruption (ATI) to study the initial immune response to rebound and to understand its role in defining subsequent virus control. Profiling of peripheral blood mononuclear cells and plasma revealed consistent immune activation prior to systemic rebound, including upregulation of antiviral transcriptional pathways, expansion of CD16++ non-classical monocytes, and increases of inflammatory and antiviral soluble plasma proteins. Individuals with prior viral control (controllers) diverged from non-controllers with a slower slope of rebound, a longer period of immune activity prior to rebound, and engagement of a multifaceted immune program with less systemic inflammation. An intermediate immune signature emerged in a separate ATI cohort of individuals who experienced delayed rebound after receiving broadly neutralizing antibodies4, suggesting that immunotherapy can induce a potentially protective pre-rebound immune response. Together, these data resolve the earliest systemic host immune responses to HIV rebound and demonstrate broad immune differences associated with HIV control phenotypes.

immunology↗

bioRxiv2025

Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies.

Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process. We find that 10-1074 escape is restricted to a small number of previously documented pathways seen across participants, but these escape mutations 1) emerge via extensively recurrent mutation, 2) are not equally preferred, and 3) can pre-exist at low frequency in intra-host viral populations before therapy, although their detection does not predict rebound timing. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one intra-host population rarely emerge or spread in other populations, except among highly related viruses. Despite this, 3BNC117 escape mutations often still emerge recurrently within their host. Our findings map longitudinal in vivo antibody escape across 20 diverse clade B HIV intra-host populations and reveal clinically relevant resistance dynamics that highlight how combination bNAb therapies will need to contend with extensively recurring escape mutations and dependence on genetic background. Significance StatementUsing recently developed techniques that capture viral genetic diversity and associations between mutations at depth, we deeply sequenced HIV from two clinical trials of broadly neutralizing antibody (bNAb) monotherapies, 3BNC117 and 10-1074. We computationally characterized HIV populations longitudinally with unprecedented resolution as they escaped these therapies in people living with HIV. Intra-host tracking of individual HIV genetic backgrounds reveals extensively recurrent mutations driving escape and suggests that HIV escape routes from certain bNAbs can depend sensitively on the genetic background of the virus. Our findings highlight the difficulties in evaluating pre-treatment resistance, provide an analysis blueprint for future trials, and inform the design of emerging combination antibody therapies to maximize the likelihood of durable efficacy.

molecular biology↗

bioRxiv2024

Inflammatory Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia

The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16++ monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.

immunology↗