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. 2017 Apr 20;13(4):e1006285.
doi: 10.1371/journal.ppat.1006285. eCollection 2017 Apr.

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Rajesh T Gandhi  1 , Deborah K McMahon  2 , Ronald J Bosch  3 , Christina M Lalama  3 , Joshua C Cyktor  2 , Bernard J Macatangay  2 , Charles R Rinaldo  4 , Sharon A Riddler  2 , Evelyn Hogg  5 , Catherine Godfrey  6 , Ann C Collier  7 , Joseph J Eron  8 , John W Mellors  2 ; ACTG A5321 Team
Affiliations

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Rajesh T Gandhi et al. PLoS Pathog. .

Abstract

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: EH is employed by a commercial company, Social & Scientific Systems, Inc. JJE is a consultant to Gilead Sciences, Merck & Co, Janssen and ViiV Healthcare. The University of North Carolina receives research grants from Gilead Sciences, Janssen and ViiV Healthcare on which JJE is an investigator. ACC is a member of a Data Safety and Monitoring Board for Merck & Co.-sponsored studies and received support from the International AIDS Society-USA for preparation of an educational presentation. JWM is a consultant for Gilead Sciences and a shareholder of Cocrystal Pharma, Inc.

Figures

Fig 1
Fig 1. Correlations between pre-ART HIV-1 DNA and CA-RNA levels (A) and between pre-ART HIV-1 DNA and CD4+ T-cell counts (B).
Fig 2
Fig 2. In participants on Antiretroviral Therapy (ART) with suppressed plasma viremia, longitudinal decay in HIV-1 DNA (A), cell-associated RNA (B) and proportion with detectable 2-LTR circles (C) over time.
Between initiation of ART and year 4 of therapy, there was a 15-fold drop in HIV-1 DNA and a 525-fold drop in CA-RNA. After year 4 of ART, HIV-1 DNA decayed at 5% per year (half-life of 13 years); there was no further decay in CA-RNA levels.
Fig 3
Fig 3. Pre-ART HIV-1 DNA Levels are correlated with on-ART HIV-1 DNA levels.
Participants with high HIV-1 DNA before ART continued to have high HIV-1 DNA on therapy, despite sustained suppression of plasma viremia.
Fig 4
Fig 4. Longitudinal changes in markers of inflammation after initiation of antiretroviral therapy.
The p-value in each panel is for the change in the log-transformed level of the specified biomarker from pre-ART to year 1.
Fig 5
Fig 5. Correlation between pre- and on-ART levels of inflammatory biomarkers.
The figures show the correlation between the levels of the biomarkers before starting ART and the levels at year 4 after starting therapy. The levels at the other on-ART time points (year 1, years 6–15) also correlated with the levels before starting ART (Table 2).
Fig 6
Fig 6. Longitudinal changes in T cell counts, ratios, activation and cycling after initiation of antiretroviral therapy.
Fig 7
Fig 7. No association between HIV-1 DNA and T cell activation or T cell cycling.
Data in this figure are from year 4 of antiretroviral therapy.
See this image and copyright information in PMC

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