Background
Understanding how host immune responses during acute HIV infection shape reservoir dynamics is critical for developing curative strategies. The early period after antiretroviral therapy (ART) initiation presents a unique window to investigate mechanisms of reservoir decay, before immune exhaustion.
Methods
We performed single-cell RNA sequencing on 112 peripheral blood mononuclear cell samples from 24 participants in the UCSF Treat Acute HIV cohort, collected longitudinally after ART initiation. We fit multivariate linear mixed-effects models adjusted for baseline CD4 count, viral load, and timing of ART initiation to (1) identify transcriptomic change over time and (2) gene signatures linked to faster HIV intact DNA decay using a biexponential decay model (at an FDR q<0.05).
Results
Overall, we observed significant downregulation of interferon-stimulated genes (ISGs) like IFI27, IFI44, and MX1 in CD4 and CD8 cells during the initial rapid phase of decay. Faster initial HIV intact DNA decay rates were associated with upregulation of genes involved in immune activation, enhanced cytotoxicity, cell cycle (G2M, mitotic spindle), and IFN-γ signaling in CD8 cells; downregulation of metabolic fitness (OX PHOS) in CD4 cells; upregulation of TNF-α/NF-κB signaling in dendritic and plasma cells; and upregulation of cytotoxic readiness (MYC) in NK cells. During the slower second phase of decay, we observed downregulation of cytotoxicity (NKG7, GNLY, PRF1) and upregulation of CDKN1 (limits HIV susceptibility) in CD4 cells, and increased inflammatory responses (SGK1, LTB) in CD8 cells. Faster decay in the second phase was associated with upregulation of genes linked to metabolic adaptation (glycolysis, OX PHOS, PI3K/AKT/mTOR, complement) and downregulation of proliferation (G2M, MYC, E2F) in CD4 cells, upregulation of targeted cytotoxicity pathways (allograft rejection, apical junction) in CD8 cells, and decreased inflammatory and apoptotic signaling in dendritic cells, monocytes, and NK cells.
Conclusions
Faster HIV reservoir decay was linked to phase-specific immune and metabolic programs. Broad immune activation and cytotoxicity in the first phase, and reduced inflammation with targeted cytotoxic responses in the second, were associated with faster intact HIV DNA decay. These findings underscore the potential to target immune-metabolic pathways at distinct stages of acute infection to enhance reservoir reduction in cure strategies.
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