Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 7, Pages 2689-2696Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI93289
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Categories
Funding
- NIH [AI098487, AI106468, AI114235, AI117841, AI120008, AI124776, AI116228, AI078799, HL134539, R3767073, P30 AI060354]
- Collaboration for AIDS Vaccine Discovery - Bill and Melinda Gates Foundation
- International AIDS Vaccine Initiative
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Cancer Institute (NCI)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Heart, Lung, and Blood Institute (NHLBI)
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Institute on Aging (NIA)
- Fogarty International Center (FIC)
- Office of AIDS Research (OAR)
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HIV-1 causes a chronic, incurable disease due to its persistence in CD4(+) T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4(+) T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4(+) T cells, and subsets of functionally polarized memory CD4(+) T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4(+) T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4(+) T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication-and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4(+) T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4(+) T cells.
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