Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 48, Pages E11341-E11348Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1813512115
Keywords
HIV; latent reservoir; sequencing; analytical treatment interruption
Categories
Funding
- National Center for Advancing Translational Sciences (NIH), Clinical and Translational Science Award Program [UL1 TR001866]
- Shapiro-Silverberg Fund for the Advancement of Translational Research
- Heisenberg Program of the Deutsche Forschungsgemeinschaft [KL 2389/2-1]
- European Research Council [ERC795StG639961]
- German Center for Infection Research
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery Grants [OPP1092074, OPP1124068, OPP1168933]
- NIH [1UM1 AI100663, R01AI-129795]
- Einstein-Rockefeller-CUNY Center for AIDS Research [1P30AI124414-01A1]
- BEAT-HIV Delaney Grant [UM1 AI126620]
- Robertson Fund
- Bill and Melinda Gates Foundation [OPP1168933] Funding Source: Bill and Melinda Gates Foundation
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Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4(+) T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti-HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.
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