Paucity of Intact Non-Induced Provirus with Early, Long-Term Antiretroviral Therapy of Perinatal HIV Infection
Authors
Rainwater-Lovett, KaitlinZiemniak, Carrie
Watson, Douglas
Luzuriaga, Katherine
Siberry, George
Petru, Ann
Chen, YaHui
Uprety, Priyanka
McManus, Margaret M.
Ho, Ya-Chi
Lamers, Susanna L.
Persaud, Deborah
UMass Chan Affiliations
Department of Pediatrics, Division of Immunology/Infectious DiseaseProgram in Molecular Medicine
Document Type
Journal ArticlePublication Date
2017-02-08Keywords
HIVAntiretroviral therapy
perinatal infection
UMCCTS funding
Immune System Diseases
Infectious Disease
Pediatrics
Therapeutics
Virus Diseases
Metadata
Show full item recordAbstract
The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults. Whether formation and persistence of Intact, NIPG is thwarted by early ART initiation and long-term virologic suppression in perinatal infection is unclear. Here, we show that the latent reservoir in 11 early treated, long-term suppressed perinatally infected children and adolescents was not inducible by QVOA and dominated by defective, NIPG. Single genome analysis of 164 NIPG from 232 million cultured resting CD4+ T cells revealed no replication-intact, near-full length sequences. Forty-three (26%) NIPG contained APOBEC3G-mediated hypermutation, 115 (70%) NIPG contained large internal deletions, one NIPG contained nonsense mutations and indels, and 5 (3%) NIPG were assigned as "Not Evaluable" due to multiple failed sequencing attempts that precluded further classification. The lack of replication competent inducible provirus and intact NIPG in this cohort indicate early, long-term ART of perinatal infection leads to marked diminution of replication-competent HIV-1 reservoirs, creating a favorable state towards interventions aimed at virologic remission.Source
PLoS One. 2017 Feb 8;12(2):e0170548. eCollection 2017. Link to article on publisher's site
DOI
10.1371/journal.pone.0170548Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40260PubMed ID
28178277Related Resources
Rights
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.Distribution License
http://creativecommons.org/publicdomain/zero/1.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0170548
Scopus Count
Except where otherwise noted, this item's license is described as This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.