Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection

Abstract

We recently found that a new pathogenic chimeric simian-human immunodeficiency virus (SHIV) elicited heterologous human immunodeficiency virus type-1 (HIV-1) neutralizing antibodies (nAbs) in therapy-naïve young rhesus macaques (RMs) following neonatal SHIV infection. Moreover, a subset of the SHIV-infected young RMs spontaneously controlled viremia. Here we evaluated humoral and cellular immunity and plasma biomarkers associated with spontaneous viremia suppression in a new model of young SHIV-infected RMs that generated heterologous HIV-1 nAbs independent of viremia control to gain insights into pediatric immunity that may be harnessed by appropriate therapies in HIV-1-infected infants and children. We determined the levels of 31 plasma analytes (cytokines, chemokines, and growth factors) in SHIV-infected RMs over the course of infection and found that six analytes with chemoattractant or pro-inflammatory activities had significantly lower levels in plasma of RMs that controlled viremia compared to non-controllers. Single-cell transcriptomics of blood-derived immune cells demonstrated that RMs with viremia control had upregulated genes associated with immune activation and cytotoxic functions, whereas non-controllers had upregulated genes associated with immune cell exhaustion and dysfunction. In addition to CD8 T and natural killer cells, monocytes with upregulation of inhibitory genes previously reported only in cytotoxic cells constituted the immunologic environment associated with viremia suppression. These data implicated a complex immunologic milieu of viremia suppression that is not fully defined in pediatric subjects. Understanding immune cell subsets that may be harnessed to control viremia will provide insights into future designs of HIV-1 therapeutic strategies. IMPORTANCE Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.

Pediatric immunotherapy and HIV control

“…[ 55 ] developed a pig-tailed macaque model of vertical transmission in which ten pregnant dams were intravenously infected with SHIV-SF162P3 in their second trimester. Passive transfer of anti-HIV antibodies was reported in plasma of infants at birth until at least 5 weeks, and maternal neutralizing antibodies were proposed to have influenced the rate of vertical transmission as well as pathogenesis following infection [ 56 ▪ ]. These results led to the hypothesis that purposely inducing more and specific maternal antibodies through vaccination during pregnancy could provide protection to exposed infants.…”

“…To consider additional immunologic factors associated with viral suppression in CLWH, Evangelous and colleagues conducted a study in ART-naïve SHIV.CH848.10.17 DT.E169K-infected infant rhesus macaques that spontaneously controlled viremia. They identified reduced levels of several pro-inflammatory cytokines in addition to a profile of activated and/or cytotoxic CD8 + T cells, NK cells, and monocytes in the controllers [ 56 ▪ ].…”