The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time
Year: 2013
Type: article
Abstract: The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.
Authors: Lina Josefsson, Susanne von Stockenstrom, Nuno R. Faria, Elizabeth Sinclair, Peter Bacchetti, Maudi Killian, Lorrie Epling, Alice Tan, Terence Ho, Philippe Lemey, Wei Shao, Peter W. Hunt, Ma Somsouk, Will Wylie, Daniel C. Douek, Lisa Loeb, Jeff Custer, Rebecca Hoh, Lauren Poole, Steven G. Deeks, Frederick Hecht, Sarah Palmer
Institutions: Swedish Institute, Karolinska Institutet, KU Leuven, University of California, San Francisco, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, The University of Sydney, Westmead Institute
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: amfAR, The Foundation for AIDS Research, Delaney AIDS Research Enterprise, European Commission, Vetenskapsrådet, National Institutes of Health, Center for AIDS Research, University of Washington, University of California, San Francisco, National Institute of Mental Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, National Center for Complementary and Integrative Health
Awards: Clinical and Translational Science Institute, G1675626477, Impact of HIV-associated inflammation on disease, Preparedness, Prediction and Prevention of Emerging Zoonotic Viruses with Pandemic Potential using Multidisciplinary Approaches, UCSF-GIVI CENTER FOR AIDS RESEARCH, Mentoring and Research in Integrative Medicine, G2881458443, G3181090803, DARE: Delaney AIDS Research Enterprise to find a cure., HIV, Gut Mucosal Turnover and Inflammation, and the Risk of Colorectal Neoplasia, G3954841298, G4456443839, G4713330150, G5418282550, G6043550565, G6444951560, G758528517, G7717753738, G9000100957, G9000271296, G97119092
OpenAlex ID: W2046159404