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.