Abstract
The HIV latent reservoir in resting memory CD4+ T cells precludes cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not yet in pediatric populations. We determined, ex vivo, the inducibility of the latent reservoir in perinatal infection as compared with adult infections using the Tat/rev induced limiting dilution assay (TILDA), in which a single round (12 hours) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression with multiply spliced HIV RNA production. Markers of immune activation and exhaustion were measured to assess interactions with inducibility. Although rates of T cell activation with PMA/ionomycin were similar, the latent reservoir in perinatal infection was slower to reactivate and of lower magnitude compared with adult infection, independent of proviral load. An enhanced TILDA with the addition of phytohemagglutin and a duration of 18 hours augmented proviral expression in perinatal but not adult infection. The baseline HLA-DR+CD4+ T cell level was significantly lower in perinatal compared with adult infections, but not correlated with induced reservoir size. These data support the hypothesis that there are differences in kinetics of latency reversal and baseline immune activation in perinatal compared with adult infections, with implications for latency reversal strategies toward reservoir clearance and remission.
Highlights
1.7 million children under the age of 15 are living with HIV worldwide, with an estimated 160,000 new infections in children in 2018 [1]
We identified that the induced latent reservoir for HIV in CD4+ T cells of adolescents with perinatal infections on long-term effective antiretroviral therapy (ART) was significantly more resistant to reactivation despite similar proviral loads and rates of cellular activation in response to PMA/ionomycin in standard Tat/rev induced limiting dilution assay (TILDA) conditions
The addition of PHA, a T cell receptor signaling molecule, and a longer duration of stimulation of 18 hours led to a 1.5-fold increase in the detected inducible reservoir in the perinatally acquired compared with the adult infections, where no increase in multiply spliced RNA–producing units per million (msRUPM) was observed
Summary
1.7 million children under the age of 15 are living with HIV worldwide, with an estimated 160,000 new infections in children in 2018 [1]. Treatment of HIV with combination antiretroviral therapy (ART) in both children and adults can lead to durable virologic suppression for decades but does not eradicate the infection due to early establishment of a latent HIV reservoir in resting memory CD4+ T cells [2,3,4,5]. Identifying strategies to eliminate the latent reservoir is a rapidly evolving field of HIV therapeutics with hopes for long-term ART-free remission [14], and these include reversing latency to reactivate latent proviruses in order to promote clearance of HIV-infected cells (referred to as the “shock and kill” approach) [15, 16]. Ex vivo studies of the latency reversal effects of various biologics on HIV-infected resting CD4+ T cells have informed the use of these agents in clinical trials in adults [17,18,19]; similar studies in perinatal infections have not begun
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