The replication-competent HIV reservoir is a genetically restricted, younger subset of the overall pool of HIV proviruses persisting during therapy, which is highly genetically stable over time
Aniqa Shahid, Signe MacLennan, Bradley R. Jones, Hanwei Sudderuddin, Zhong Dang, Kyle D. Cobarrubias, Maggie C. Duncan, Natalie N. Kinloch, Michael J. Dapp, Nancie M. Archin, Margaret A. Fischl, Igho Ofotokun, Adaora A. Adimora, Stephen J. Gange, Bradley E. Aouizerat, Mark H. Kuniholm, Seble Kassaye, James I. Mullins, Harris Goldstein, Jeffrey B. Joy, Kathryn Anastos, Zabrina L. Brumme, the MACS/WIHS combined cohort study (MWCSS), Ighovwerha Ofotokun, Anandi N. Sheth, Gina M. Wingood, Todd T. Brown, Joseph B. Margolick, Kathryn Anastos, David B. Hanna, Anjali Sharma, Deborah Gustafson, Tracey E. Wilson, Gypsyamber DʼSouza, Stephen J. Gange, Elizabeth Topper, Mardge H. Cohen, Audrey L. French, Steven M. Wolinsky, Frank J. Palella, Valentina Stosor, Bradley E. Aouizerat, Jennifer C. Price, Phyllis C. Tien, Roger Detels, Matthew J. Mimiaga, Seble Kassaye, Daniel Merenstein, María L. Alcaide, Margaret A. Fischl, Deborah L. Jones, Jeremy Martinson, Charles R. Rinaldo, Mirjam-Colette Kempf, Jodie Dionne‐Odom, Deborah Konkle‐Parker, James B. Brock, Adaora A. Adimora, Michelle Floris-Moore
Abstract
-based observations, indicating that our observations are not influenced by the HIV region studied. Our results underscore the remarkable genetic stability of the distinct proviral sequences that persist in blood during ART. Our results also suggest that the replication-competent HIV reservoir is a genetically restricted, younger subset of this overall proviral pool.IMPORTANCECharacterizing the genetically diverse HIV sequences that persist in the reservoir despite antiretroviral therapy (ART) is critical to cure efforts. Our observations confirm that proviruses persisting in blood on ART, which are largely genetically defective, broadly reflect the extent of within-host HIV evolution pre-ART. Moreover, on-ART clonal expansion is not appreciably accompanied by the loss of distinct proviral lineages. In fact, on-ART proviral genetic composition remained stable in all but one participant, in whom, after 12 years on ART, proviruses dating to around near ART initiation had been preferentially eliminated. We also identified recombinant proviruses between parental sequence fragments of different ages. Though rare, such sequences suggest that reservoir cells can be superinfected with HIV from another infection era. Overall, our finding that the replication-competent reservoir in blood is a genetically restricted, younger subset of all persisting proviruses suggests that HIV cure strategies will need to eliminate a reservoir that differs in key respects from the overall proviral pool.