Influence of Age at Virologic Control on Peripheral Blood Human Immunodeficiency Virus Reservoir Size and Serostatus in Perinatally Infected Adolescents

Abstract

Importance Combination antiretroviral therapy (cART) initiated within several weeks of HIV infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure. Objectives To quantify peripheral blood proviral reservoir size in perinatally HIV-infected adolescents and to identify correlates of limited proviral reservoirs. Design, Setting, and Participants A cross-sectional study including 144 perinatally HIV-infected (PHIV+) youth (median age: 14.3 years), enrolled in the US-based Pediatric HIV/AIDS Cohort Study, on durable (median: 10.2 years) cART, stratified by age at virologic control. Main Outcome and Measures The primary endpoint was peripheral blood mononuclear cell (PBMC) proviral load following virologic control at different ages. Correlations between proviral load and markers of active HIV production (HIV-specific antibodies, 2-long terminal repeat (2-LTR) circles), and markers of immune activation and inflammation were also assessed. Results Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control by age 1 year (4.2 [interquartile range, 2.6-8 6] copies per 1 million PBMCs) compared to those who achieved virologic control between 1-5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after age 5 years (−(70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .00l). A proviral burden <10 copies/million PBMCs was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control at ages <1 year, 1-5 years, and >5 years, respectively (p<0.001). Lower proviral load was associated with undetectable 2-LTR circles (p<0.001) and HIV negative or indeterminate serostatus (p<0.001), but not with concentrations of soluble immune activation markers CD14 and CD163. Conclusions and Relevance Early effective cART along with prolonged virologic suppression after perinatal HIV infection leads to negligible peripheral blood proviral reservoirs in adolescence and is associated with negative or indeterminate HIV serostatus. These findings highlight the long-term effect of early effective control of HIV replication on biomarkers of HIV persistence in perinatal infection and the utility of HIV serostatus as a biomarker for small proviral reservoir size, though not necessarily of cure.

Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed

“…Younger age at starting ART in children has been found to be strongly related to the size of the viral reservoir. 18–21 One study reported that reduced reservoir size was observed in children who suppressed by 12 months of age. 18 Age at viral control is a more complex characteristic to compare between groups as it depends on the frequency of viral load testing once ART is started as well as the age when ART is started.…”

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

“…The lowest HIV DNA levels were observed in patients who had low baseline levels and who received early treatment (107). In children, the HIV DNA level was markedly lower when viral control was achieved before age 1 year than between the ages of 1 and 5 years or after age 5 years (73). This difference is linked to the duration of uncontrolled viral replication between initial infection and effective treatment.…”

“…More recently, an assay that dispenses with the extraction step has been proposed (70). Recent technical progress has permitted the development of HIV DNA quantification by digital droplet PCR (ddPCR), which does not require an external quantification standard (71)(72)(73)(74)(75)(76)(77). However, some false-positive signals have been observed with ddPCR, which can be a problem when this method is used for diagnosis (76).…”

Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination

“…Importantly, it was recently argued by Klein et al (95) that children are ideal candidates for immunotherapeutic interventions to achieve viral remission. The arguments presented by the authors are based on the fact that perinatally infected children for whom antiretroviral (ARV) treatment is initiated early on have a small latent virus reservoir (96,97) and normal development of the memory B cell and T cell compartments (98,99). The potential for viral eradication in children was recently illustrated by the "Mississippi baby."…”