Intrinsic CD4? T cell barriers to HIV-1 latency reversal

The National Institute of Allergy and Infectious Diseases awarded Brigham & Women's Hospital Inc. $894,998 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate intrinsic CD4 T cell barriers to HIV-1 latency reversal.

The research addresses HIV-1 persistence in CD4 T cells despite effective antiretroviral therapy by examining post-transcriptional mechanisms that constrain productive viral gene expression. The investigator will integrate rRNA-depleted and poly(A)-selected RNA sequencing, multimodal single-cell analyses, metabolic pathway inference, and targeted biochemical perturbations to identify cellular states and pathways permitting productive HIV-1 RNA maturation. The work will establish kinetics linking RNA processing to viral protein expression, virion production, and immune effector function, with findings intended to inform rational design of latency reversal strategies that enable productive viral gene expression while preserving immune function.

The award is designated as a Project Grant with a period of performance from September 1, 2026, through August 31, 2027. Work is performed in Boston, Massachusetts.

Abstract

HIV-1 latency remains a major barrier to cure, as the virus persists in CD4⁺ t cells despite effective antiretroviral therapy. Although latency is often conceptualized as transcriptional silence, HIV-1 RNA is frequently detected in treated individuals without accompanying viral protein or virion production. This suggests that post-transcriptional mechanisms may impose critical constraints on productive viral gene expression. Our preliminary data demonstrate that in resting human CD4⁺ t cells, transcription and RNA maturation are frequently uncoupled: host transcripts exhibit extensive intron retention and incomplete polyadenylation, and HIV-1 unspliced RNA greatly exceeds polyadenylated RNA during suppressive therapy. These findings support a model in which HIV-1 latency reflects a failure of RNA maturation-particularly splicing and polyadenylation-rather than an absence of transcription. The overall objective of this proposal is to define the host-cell mechanisms that restrict HIV-1 RNA processing during latency and to determine how these barriers can be selectively overcome. We will integrate paired rrna-depleted and poly(a)-selected RNA sequencing, multimodal single-cell analyses, metabolic pathway inference, and targeted biochemical perturbations to identify the cellular states and pathways that permit productive HIV-1 RNA maturation. We will further establish the kinetics linking RNA processing to viral protein expression, virion production, and immune effector function. By reframing HIV-1 latency as a problem of post-transcriptional regulation imposed by host CD4⁺ t-cell biology, this work addresses a central knowledge GAP in the field. The proposed studies will inform the rational design of latency reversal strategies that enable productive viral gene expression while preserving immune function, advancing efforts toward an HIV cure.