Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.

• Main Authors: Charline Bacchus-Souffan, Mark Fitch, Jori Symons, Mohamed Abdel-Mohsen, Daniel B Reeves, Rebecca Hoh, Mars Stone, Joseph Hiatt, Peggy Kim, Abha Chopra, Haelee Ahn, Vanessa A York, Daniel L Cameron, Frederick M Hecht, Jeffrey N Martin, Steven A Yukl, Simon Mallal, Paul U Cameron, Steven G Deeks, Joshua T Schiffer, Sharon R Lewin, Marc K Hellerstein, Joseph M McCune, Peter W Hunt
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2021-01-01
• Series: PLoS Pathogens
• Online Access: https://doi.org/10.1371/journal.ppat.1009214

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.