Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

• Published in: The Journal of infectious diseases Vol. 212; no. 4; pp. 596 - 607
• Main Authors: von Stockenstrom, Susanne, Odevall, Lina, Lee, Eunok, Sinclair, Elizabeth, Bacchetti, Peter, Killian, Maudi, Epling, Lorrie, Shao, Wei, Hoh, Rebecca, Ho, Terence, Faria, Nuno R., Lemey, Philippe, Albert, Jan, Hunt, Peter, Loeb, Lisa, Pilcher, Christopher, Poole, Lauren, Hatano, Hiroyu, Somsouk, Ma, Douek, Daniel, Boritz, Eli, Deeks, Steven G., Hecht, Frederick M., Palmer, Sarah
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.08.2015
• Subjects: Anti-HIV Agents - therapeutic use; Cell Proliferation; DNA, Viral - genetics; DNA, Viral - isolation & purification; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - genetics; HIV/AIDS; Human immunodeficiency virus 1; Humans; Longitudinal Studies; Lymph Nodes - virology; Major and Brief Reports; Medicin och hälsovetenskap; Phylogeny; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - physiology; T-Lymphocyte Subsets - virology; HIV-1 persistence; HIV-1 reservoir; memory T cells
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiv092

Background. The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART). Methods. Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4⁺ T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologie suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months. Results. DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens. Conclusions. Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.