Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy
Rajesh T. Gandhi, Joshua C. Cyktor, Ronald J. Bosch, Hanna Mar, Gregory M. Laird, Albine Martin, Ann C. Collier, Sharon A. Riddler, Bernard Macatangay, Charles R. Rinaldo, Joseph J. Eron, Janet D. Siliciano, Deborah K. McMahon, John W. Mellors, Evelyn Hogg, Rebecca LeBlanc, Christine Scello, David Palm, Monica Gandhi, Courtney V. Fletcher, Anthony T. Podany, Fran Aweeka, Lou Halvas, Joan Dragavon, Jeymohan Joseph, Rose Lagattuta, Leyi Lin, Susan Pederson, Kevin A. Robertson, Leah H. Rubin, Davey M. Smith, Serena Spudich, Athe Tsibris
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.