Paucity of intact non-induced provirus with early, long-term antiretroviral therapy of perinatal HIV infection

Citation: Rainwater-Lovett K, Ziemniak C, Watson D, Luzuriaga K, Siberry G, Petru A, Chen Y, Uprety P, McManus M, Ho YC, Lamers SL, Persaud D. Paucity of intact non-induced provirus with early, long-term antiretroviral therapy of perinatal HIV infection. PLoS One. 2017 Feb 8;12(2):e0170548. PMID: 28178277; PMCID: PMC5298215

Access full article:

https://www.ncbi.nlm.nih.gov/pubmed/28178277

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.

Categories

CRS
Topics

Clinical Trials

A5273: Multicenter Study of Options for Second-Line...

The study is being done with people who are taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse...

Read More

A5288: MULTIOCTAVE, Management Using the Latest Technologies...

The study is being done to: test a strategy of using a resistance test to choose anti-HIV drugs. Resistance tests look at the...

Read More

P2005: A Phase I/II Open-Label, Single-Arm Study to Evaluate...

This study is currently on hold. The study is designed to characterize the pharmacokinetics of DLM using a model-based...

Read More

A5274: REMEMBER, Reducing Early Mortality and Early...

This study is being done in people who are starting HIV treatment and who live in areas where the TB infection rate is high. The...

Read More

A5282: A Randomized, Phase II Trial to Compare an HPV...

The investigators are looking for a better way to prevent cervical cancer. This study is comparing two different methods to...

Read More