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. 2024 Sep 18;20(9):e1012526.
doi: 10.1371/journal.ppat.1012526. eCollection 2024 Sep.

HIV-1 diversity in viral reservoirs obtained from circulating T-cell subsets during early ART and beyond

Yuepeng Zhang  1 , Fabian Otte  1 , Marcel Stoeckle  2 , Alexander Thielen  3 , Martin Däumer  3 , Rolf Kaiser  4   5 , Katharina Kusejko  6 , Karin J Metzner  6   7 , Thomas Klimkait  1 ; and the Swiss HIV Cohort Study
Affiliations

HIV-1 diversity in viral reservoirs obtained from circulating T-cell subsets during early ART and beyond

Yuepeng Zhang et al. PLoS Pathog. .

Abstract

Even during extended periods of effective immunological control, a substantial dynamic of the viral genome can be observed in different cellular compartments in HIV-1 positive individuals, indicating the persistence of active viral reservoirs. To obtain further insights, we studied changes in the proviral as well as in the viral HIV-1 envelope (Env) sequence along with transcriptional, translational and viral outgrowth activity as indicators for viral dynamics and genomic intactness. Our study identified distinct reservoir patterns that either represented highly sequence-diverse HIV-1 populations or only a single / few persisting virus variants. The single dominating variants were more often found in individuals starting ART during early infection phases, indicating that early treatment might limit reservoir diversification. At the same time, more sequence-diverse HIV reservoirs correlated with a poorer immune status, indicated by lower CD4 count, a higher number of regimen changes and more co-morbidities. Furthermore, we noted that in T-cell populations in the peripheral blood, replication-competent HIV-1 is predominantly present in Lymph node homing TN (naïve) and TCM (central memory) T cells. Provirus genomes archived in TTM (transitional memory) and TEM (effector memory) T cells more frequently tended to carry inactivating mutations and, population-wise, possess changes in the genetic diversity. These discriminating properties of the viral reservoir in T-cell subsets may have important implications for new early therapy strategies, underscoring the critical role of early therapy in preserving robust immune surveillance and constraining the viral reservoir.

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Conflict of interest statement

K.J.M. has received travel grants and honoraria from Gilead Sciences, Roche Diagnostics, GlaxoSmithKline, Merck Sharp & Dohme, Bristol-Myers Squibb, ViiV and Abbott; and the University of Zurich received research grants from Gilead Science, Novartis, Roche, and Merck Sharp & Dohme for studies that Dr Metzner serves as principal investigator, and advisory board honoraria from Gilead Sciences and ViiV.

Figures

Fig 1
Fig 1. Longitudinal characterization of 9 HIV-1-infected individuals followed from the day of diagnosis.
(A) Longitudinal HIV-1 viral loads and CD4+ T cell counts. Black arrows denote the start time of ART treatment, purple arrows highlight time points for Viral outgrowth (VOA) sampling, and the red dotted line marks the limit of detection/full viral suppression. Viral load (RNA copies/ml) in red left y-axis, CD4+ T cell counts (cells/μL) in blue right y-axis. (B) Dynamics of reservoir diversity over time. Pie charts show HIV-1 proviral V3 loop diversity obtained by NGS. Respective sampling time points are shown above each pie chart in days after therapy with number of variants above 0.1% relative abundance. Variants with a proportion below 1% are jointly summarized in black and only the top 5 variants are shown in color with respective abundances shown in the legend below the pie chart. Each color represents one separate virus variant. The number inside the pie charts highlights how many sequences have a relative abundance of >1%. For individual P8, one conservative amino acid change in the V3 loop of the dominant variant on day 139, is indicated by an asterisk. In scatterplots, a black line denotes HIV-1 proviral DNA load, red lines reflect HIV-1 pA loads, a green line depicts TTV load, and red arrows mark the limit of HIV-1 pA detection. The red dotted line indicates the detection threshold (<10 copies). Each individual ID is stated above respective plots.
Fig 2
Fig 2. Dynamics of the HIV-1 reservoir in memory T cell subsets.
Proviral V3 loop diversity, determined by NGS 5 days post-stimulation, represented by pie charts for bulk CD4 T cells and each memory T cell subset. (A) Variants with a proportion below 1% were separated and only the top 5 variants are shown in color with respective abundances shown in the legend below the pie chart. Each color represents one separate virus variant. The number inside the pie charts highlights how many sequences have a relative abundance of >1%. Each participants ID is stated above each plot. B,C: NGS V3 loop diversity of viral RNA from viral outgrowth positive wells. (B) Reactivated virus of TN and TCM form P1, (C): Reactivated virus of TN form P7.
Fig 3
Fig 3. HIV-1 viral dynamics and immune competence.
(A-E) Immunological comparison of the ’high diversity group’ and the ’low diversity group’. (A) Lymphocyte count. (B) CD4 count. (C) CD8 count. (D) TTV load. (E) HIV polyA / HIV DNA. Averaged values were plotted for each individual and time interval. Black line denotes median value. Two-way ANOVA was performed with Geisser-Greenhouse correction and Bonferroni’s multiple comparison test.
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Substances

Grants and funding

YZ was financially supported by the China Scholarship Council (CSC201906170031). FO was paid through research funds of the Molecular Virology Laboratory, University of Basel, Basel, Switzerland. The work was supported by the University of Basel, Basel, Switzerland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.