Biology subjects

Sandel, D. A.

Publications and source records attributed to Sandel, D. A..

3 recordsLinked to original sources

bioRxiv2026

A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control

A key goal in HIV-1 cure research is to understand why some individuals control viral rebound after stopping antiretroviral therapy (ART). Recent human studies have identified responding CD8+ T cells expressing Ki-67 and the transcription factor TCF-1 as correlates of post-treatment control, but the mechanistic basis of this association remains unclear. Using the theoretical framework of Conway and Perelson, we fit mechanistic within-host models to viral load and CD8+ T cell data from 9 individuals in a combination immunotherapy trial following ART interruption. Although Ki-67 and TCF-1 measurements were not used for fitting, the inferred effector cell expansion sensitivity, i.e., the responsiveness of effector expansion to low antigen levels, shows a strong linear relationship with Ki-67 and TCF-1 levels at rebound (Pearsons r {approx} 0.8). Building on this, we show analytically that the post-rebound viral load set point is inversely proportional to the effector cell expansion sensitivity, and thus strongly correlates with cycling (Ki-67+) CD8+ T cells (r {approx} -0.8) at rebound, and a subset that expresses TCF-1 (r {approx} -0.9). In effect, individuals with a larger proportion of CD8+ T cells responding to viral rebound, and a greater representation of TCF-1 expressing cells within the responding subset, achieve markedly lower viral set points through a higher effector cell expansion sensitivity. This mechanism is consistent with prior modeling in a non-intervention ATI setting, suggesting it may generalize across more rebound contexts. Our results provide a mechanistic explanation why both Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset predict post-treatment control, linking clinical correlation to its underlying cause and highlighting Ki-67 and TCF-1 as potential early biomarkers of HIV immunotherapy success.

immunology↗

bioRxiv2026

Immune activation during broadly neutralizing antibody-mediated HIV suppression prior to post-intervention control

Broadly neutralizing antibodies (bNAbs) have been associated with enhancement of HIV-specific T or B cell responses and sustained partial control of HIV replication in some people with HIV (PWH). The mechanisms through which bNAbs may potentiate host immunity in this context are not known. We previously reported the outcomes of a clinical trial in which ten PWH on antiretroviral therapy (ART) received a combination of immunotherapies including two bNAbs administered immediately preceding an analytic treatment interruption (ATI). After bNAb levels waned, seven participants exhibited varying degrees of post-intervention control of HIV linked to a robust expansion of activated CD8+ T cells in response to rebounding virus. To investigate the role of the bNAbs in enhancing endogenous immune responses, we looked for evidence of HIV-specific or broader immune activation during the period after ART was paused and prior to rebound when bNAbs were controlling HIV replication. At a timepoint early post-ART interruption and at least one month before virus emerged in plasma, we detected an increase in levels of plasma inflammatory proteins as well as phenotypic and transcriptional activation of innate and adaptive immune cells. Compared to non-controllers, post-intervention controllers demonstrated unique transcriptional activation patterns as well as differential longitudinal plasma inflammatory protein trends. No enhancement of HIV-specific T cell or antibody responses was observed in this window. This study identifies activated cell types and inflammatory pathways that are recruited early during bNAb-mediated HIV suppression and that may play a role in potentiating long-lasting HIV immune control after bNAb therapy. One Sentence SummaryIn a combination immunotherapy trial with high rates of post-intervention control, bNAb-mediated HIV suppression was associated with increased immune activation compared to HIV suppression by ART.

immunology↗

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↗