Advances in Pediatric HIV-1 Cure Therapies and Reservoir Assays

Abstract

Significant advances in the field of HIV-1 therapeutics to achieve antiretroviral treatment (ART)-free remission and cure for persons living with HIV-1 are being made with the advent of broadly neutralizing antibodies and very early ART in perinatal infection. The need for HIV-1 remission and cure arises due to the inability of ART to eradicate the major reservoir for HIV-1 in resting memory CD4+ T cells (the latent reservoir), and the strict adherence to lifelong treatment. To measure the efficacy of these cure interventions on reservoir size and to dissect reservoir dynamics, assays that are sensitive and specific to intact proviruses are critical. In this review, we provided a broad overview of some of the key interventions underway to purge the reservoir in adults living with HIV-1 and ones under study in pediatric populations to reduce and control the latent reservoir, primarily focusing on very early treatment in combination with broadly neutralizing antibodies. We also summarized assays currently in use to measure HIV-1 reservoirs and their feasibility and considerations for studies in children.

Immune activation and exhaustion marker expression on T-cell subsets in ART-treated adolescents and young adults with perinatal HIV-1 infection as correlates of viral persistence

“…Most studies of HIV-1 persistence focus on measures of HIV-1-infected cell concentrations, largely using total HIV-1 DNA. Recent developments in viral reservoir assays, including the IPDA and TILDA, have improved the ability to further quantify intact and defective proviruses, and the induced reservoir, especially in the context of therapeutics aimed at ART-free remission and cure ( 15 ). This is especially true in infants living with perinatally acquired HIV-1, where early and very early ART causes dramatic reductions in the proviral load and an accurate quantification of the latent reservoir is crucial ( 33 ).…”

“…Multiple assays are used to measure HIV-1 reservoir size in children and adults living with HIV-1 ( 15 , 16 ). Total HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) is the most studied ( 17 ), with the caveat that total HIV-1 DNA substantially overestimates HIV-1 reservoir size as >90% of the proviruses persisting on ART are defective and therefore non-infectious ( 18 ).…”

Age at ART initiation and proviral reservoir size in perinatal HIV-1 infection: considerations for ART-free remission

“…Recent studies [39][40][41][42][43] have emphasized the need for a comprehensive understanding of potential differences in reactivation based on characteristics including age, sex, and resource setting. Identification of virological and immunological biomarkers predictive of ART-free remission are also crucial to advancing the field of HIV-1 cure research for a diverse population [44]. Perinatal HIV-1 offers a distinct opportunity to investigate the efficacy of HIV-1 remission interventions in relation to the timing of both transmission event, ART initiation and remission therapeutics.…”

“…The Quantitative Viral Outgrowth Assay (QVOA) is considered the gold standard for quantifying the induced replication-competent reservoir [44]. However, this assay often requires higher blood volumes that cannot feasibly be extracted from pediatric populations living with HIV-1.…”