Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation
Jaimy Joy, … , Helen Horton, Lisa M. Frenkel
Jaimy Joy, … , Helen Horton, Lisa M. Frenkel
Published June 4, 2024
Citation Information: J Clin Invest. 2024;134(14):e159569. https://doi.org/10.1172/JCI159569.
View: Text | PDF
Research Article AIDS/HIV Virology Article has an altmetric score of 4

Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation

Abstract

Despite effective antiretroviral therapy (ART), persons living with HIV harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute ART initiators would be integrated into antiviral genes, whereas integration sites (ISs) in chronic ART initiators would favor genes associated with cell proliferation and exhaustion. We found that the HIV DNA distribution across HIV-specific versus herpesvirus-specific CD4+ T cells was as hypothesized. HIV ISs in acute ART initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α–mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. ISs in chronic ART initiators were enriched in a gene set controlling EZH2 histone methylation, and methylation has been associated with diminished long terminal repeat transcription. These differences that we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.

Authors

Jaimy Joy, Ana Gervassi, Lennie Chen, Brent Kirshenbaum, Sheila Styrchak, Daisy Ko, Sherry McLaughlin, Danica Shao, Ewelina Kosmider, Paul T. Edlefsen, Janine Maenza, Ann C. Collier, James I. Mullins, Helen Horton, Lisa M. Frenkel

×

Figure 2

HIV DNA levels in antigen-specific CD4+ T cells of participants initiating ART during acute or chronic HIV infection.

Options: View larger image (or click on image) Download as PowerPoint
HIV DNA levels in antigen-specific CD4+ T cells of participants initiati...
(A and B) HIV DNA levels (y axis) in CD4+ T cells reactive (CD3+CD8–CD137+) to HIV or various herpesviruses (x axis) 11 days after peptide antigen stimulation are shown for participants initiating ART during acute (A) or chronic (B) HIV infection. The ART-acute-HIV cohort (n = 7) was defined as 1.5 months or less between estimated time of infection and ART initiation and the ART-chronic-HIV cohort (n = 4) was defined as more than 6 months between estimated time of infection and ART initiation. HIV DNA loads were measured by amplification of HIV genomic regions (env, gag, LTR) multiplexed with the human gene transferrin gene (hTFR) by qPCR. HIV DNA is represented as LTR copies per 106 cells. Each solid circular symbol is the mean log(LTR/hTFR) of 2 replicate measures, with bars indicating 2 standard errors. When only one replicate was above the limit of detection, an open circular symbol is shown, and when neither replicate was above the limit of detection, an open square at 1 is shown. Dotted lines represent equivalent of 1 copy of HIV per million cells (see Methods). (C) Comparison of within-participant differences of HIV DNA in HIV-specific CD4+ T cells versus highest HIV DNA among herpesviruses-specific CD4+ T cells across ART-acute-HIV and ART-chronic-HIV groups. Wilcoxon’s P = 0.79. (D) The HIV DNA enrichment factor (y axis, defined as the HIV DNA load in HIV-specific cells divided by the herpesviruses-specific cells with the greatest HIV DNA load) versus time from acute HIV infection to ART initiation (x axis); Spearman’s δ (P = 0.04) shows a negative correlation.