Paucity of Intact Non-Induced Provirus with Early, Long-Term Antiretroviral Therapy of Perinatal HIV Infection

Abstract

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.

HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy

“…The acquisition of new mutations would be especially evident in patients who initiated treatment in early infection with a homogeneous virus population, such as donor 2661. In this donor, the number of HIV-1-infected cells that persisted on ART was small compared with the individuals who initiated ART in chronic infection, consistent with previous reports (34)(35)(36)(37). As a result, all 150 million LNMCs obtained from an entire lymph node were investigated for HIV-1 DNA or RNA.…”

Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration

“…When viral replication is inhibited early with ART, children display low levels of cell-associated HIV DNA and HIV RNA, 56 – 59 shorter half-life of replication-competent virus from latently infected cells, 57 , 60 and their noninduced proviral genomes are mostly defective. 61 Young children have high frequencies of naive CD4 + T cells that are likely more resistant to HIV. 62 Adolescents on ART since infancy with more than a decade of viral suppression are a unique population: their viral reservoirs continue to decay and only traces of HIV can be detected in their blood CD4 + T cells.…”

Severe haematologic toxicity is rare in high risk HIV‐exposed infants receiving combination neonatal prophylaxis

“…Furthermore, there is some controversy regarding whether high‐risk newborns should receive therapeutic rather than prophylactic doses of ARVs. This is based on increasing evidence of the benefits of very early cART initiation in perinatal infection with respect to restricting the viral reservoir .…”