Speaker
Description
Despite the success of antiretroviral therapy (ART), HIV-1 remains incurable. Most people living with HIV (PLWH) continue treatment for the rest of their lives to prevent rapid viral rebound and HIV-related disease. Understanding the host immune dynamics in response to recrudescing virus is critical to HIV cure efforts, however, the early immune response to viral rebound remains understudied. Here, we characterize the innate interferon response to low level viral replication immediately preceding detectable viral rebound.
We performed analyses on a cohort of donors with HIV-1 who participated in an observational analytical treatment interruption (ATI). We performed single cell RNAseq on peripheral blood mononuclear cells (PBMCs) from a subset of 10 donors and analyzed soluble protein levels in plasma using three Olink 92-plex panels on 19 donors. For the purposes of analysis, we compared three distinct timepoints: on-ART (before ATI), pre-rebound (during ATI, before detectable viremia), and post-rebound (detectable viremia).
In these PLWH, we found a significant increase in monocyte subsets prior to detectable viral rebound. As a proportion of total PBMCs, non-classical inflammatory CD14-CD16++ monocytes increased from 2.6% to 4.1% (p=0.008) while classical CD14++CD16- monocytes increased from 16.6% to 18.9% (p=0.054). Pathway analysis indicated enrichment for IFNγ, IFNα, and inflammatory response pathways within monocyte subsets. Olink analysis indicated a post-rebound increase in soluble inflammatory plasma proteins related to immune activation (PD-L2, TRAIL), cytokine signaling (TNF, LAG3, GZMB), and NFkB signaling (CXCL9, CXCL10, IL12).
Our data suggest that prior to detectable viremia, a subset of circulating monocytes activate and expand in response to low level viral replication. These immune dynamics match what has been observed in acute HIV infection and in AIDS but has not before been described in viral rebound. Further studies into this phenotype may guide HIV-1 cure strategies.
