Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 38, Pages E8958-E8967Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1802028115
Keywords
HIV; latency; reservoir; phylogenetics; evolution
Categories
Funding
- British Columbia Centre for Excellence in HIV/AIDS
- Canadian Institutes for Health Research (CIHR) [PJT-148621, PH-153391, PJT-155990]
- National Institute of Allergy and Infectious Diseases of the NIH [UM1A1126617]
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- NIH Grant [R21A127029]
- Canadian HIV Cure Enterprise Team Grant [HIG-133050]
- CIHR
- Canadian Foundation for AIDS Research
- International AIDS Society
- CIHR Frederick Banting and Charles Best Master of Science Award
- CIHR New Investigator [FRN-130609]
- Michael Smith Foundation for Health Research Scholar Award
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Given that HIV evolution and latent reservoir establishment occur continually within-host, and that latently infected cells can persist long-term, the HIV reservoir should comprise a genetically heterogeneous archive recapitulating within-host HIV evolution. However, this has yet to be conclusively demonstrated, in part due to the challenges of reconstructing within-host reservoir establishment dynamics over long timescales. We developed a phylogenetic framework to reconstruct the integration dates of individual latent HIV lineages. The framework first involves inference and rooting of a maximum-likelihood phylogeny relating plasma HIV RNA sequences serially sampled before the initiation of suppressive antiretroviral therapy, along with putative latent sequences sampled thereafter. A linear model relating root-to-tip distances of plasma HIV RNA sequences to their sampling dates is used to convert root-to-tip distances of putative latent lineages to their establishment (integration) dates. Reconstruction of the ages of putative latent sequences sampled from chronically HIV-infected individuals up to 10 y following initiation of suppressive therapy revealed a genetically heterogeneous reservoir that recapitulated HIV's within-host evolutionary history. Reservoir sequences were interspersed throughout multiple within-host lineages, with the oldest dating to >20 y before sampling; historic genetic bottleneck events were also recorded therein. Notably, plasma HIV RNA sequences isolated from a viremia blip in an individual receiving otherwise suppressive therapy were highly genetically diverse and spanned a 20-y age range, suggestive of spontaneous in vivo HIV reactivation from a large latently infected cell pool. Our framework for reservoir dating provides a potentially powerful addition to the HIV persistence research toolkit.
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