CD4 T cell memory restoration upon antiretroviral initiation in people living with HIV.

Abstract

Abstract HIV infection depletes CD4 T cells and dysregulates formation of long-lived memory CD4 T cells. Studies show that antiretroviral therapy (ART) in people with HIV (PWH) more effectively restores CD4 T cell memory phenotypes when initiated early (< Fiebig V). We used a 31 marker mass cytometry panel to assess CD4 T cell phenotype in PWH treated in acute infection (AHI) (median 2.3 years post ART initiation) and chronic infection (CHI) (median 5.8 years post ART initiation) compared to healthy donors (HD) (n=10 per group). Markers of activation (HLA-DR, CD25), exhaustion (PD-1), survival (Bcl-2) and memory (CD127) were examined. CD4 T cell memory phenotypes of AHI clustered closely with HD whereas CHI had fewer central memory CD4 T cells. We also examined IL-7 signaling in CD4 T cells, measuring STAT5 phosphorylation (pSTAT5) in response to IL-7. CHI exhibited significantly lower pSTAT5 than HD in contrast to AHI who exhibited restored IL-7 signaling. This suggests ongoing and underappreciated functional defects in CD4 T cells in CHI. To examine this further, we are completing detailed analysis of CHI before and after ART initiation (pre-ART, day 2, 7, 10, 14, 28, month 5, 9 and 18). Data will be compared to our recent work showing that CD4 T cell memory subsets, activation and exhaustion markers are highly stable in durably suppressed CHI on ART over 19–27 months. New work is examining CD4 T cell function in immunological non-responders (INR) who fail to restore CD4 counts following ART. Altogether these studies will inform how HIV impacts formation of both CD4 memory and the HIV reservoir (which is largely harbored in long lived memory CD4 T cells) following ART initiation, potentially identifying novel therapeutic targets to accelerate HIV cure in CHI. This work was made possible by the National Institute of Allergy and Infectious Diseases U01 AI131310, Collaboratory of AIDS Researchers for Eradication (UM1 AI164567) and UNC WIHS (U01 AI103390).