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. 2021 Feb 3;223(2):225-233.
doi: 10.1093/infdis/jiaa532.

Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy

Rajesh T Gandhi  1 , Joshua C Cyktor  2 , Ronald J Bosch  3 , Hanna Mar  3 , Gregory M Laird  4 , Albine Martin  4 , Ann C Collier  5 , Sharon A Riddler  2   6 , Bernard J Macatangay  2   6 , Charles R Rinaldo  6   7 , Joseph J Eron  8 , Janet D Siliciano  9 , Deborah K McMahon  2   6 , John W Mellors  2 ; AIDS Clinical Trials Group A5321 Team
Collaborators, Affiliations

Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy

Rajesh T Gandhi et al. J Infect Dis. .

Abstract

Background: HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well defined in people on ART.

Methods: We separately quantified intact and defective proviruses, residual plasma viremia, and markers of inflammation and activation in people on long-term ART.

Results: Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life, 7.1 years; 95% confidence interval [CI], 3.9-18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6-75). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART time point to about 5% at the last. Intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation.

Conclusions: Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.

Keywords: HIV proviruses; HIV reservoirs; immune activation; inflammation; residual viremia.

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Figures

Figure 1.
Figure 1.
Study time points. Abbreviation: ART, antiretroviral therapy.
Figure 2.
Figure 2.
Intact proviruses at time point 1 by pre-ART CD4+ T-cell count. Boxes display quartile 1, median and quartile 3. Abbreviation: ART, antiretroviral therapy.
Figure 3.
Figure 3.
Intact proviral DNA declines in people with HIV-1 on long-term ART whereas defective proviruses do not. (A) intact proviral DNA; (B) hypermutated/3′ defective proviruses; (C) 5′ defective proviruses; (D) total defective/hypermutated proviruses (sum of hypermutated/3′ defective and 5′ defective proviruses); (E) total HIV-1 proviruses. Colored lines display median decay; grey lines represent longitudinal measurements for individual participants. Abbreviations: ART, antiretroviral therapy; n.d., not detected.
Figure 4.
Figure 4.
Percent change in HIV-1 proviral DNA per year. Boxes display quartile 1, median and quartile 3.
Figure 5.
Figure 5.
Total HIV-1 proviruses (grey bars) and the percentage of intact proviruses (red lines, displaying median, quartile 1, and quartile 3), by time point. Time point 1 is median 7.1 years on antiretroviral therapy (ART). Time point 2 is median 3.7 years later. Time point 3 is median 5.5 years after time point 1 and a median 12 years after starting ART. See online version for color figure.
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