In the absence of anti-retroviral therapy (ART), ~50% of HIV-infected children have died by 2yrs. However, ~5% of ART-naïve HIV-infected children maintain normal CD4 counts through childhood. Unlike non-progressing adults, where high CD4 counts are associated with low viremia and protective HLA class I allele expression, non-progressing pediatric infection features high viral loads and a minimal role for HLA I. We here tested the hypothesis that non-progressing children present a similar phenotype to that observed in natural SIV infection; and make broadly neutralising antibody (bNAb) responses in association with persistent high viremia.
We studied 276 ART-naïve HIV-infected children aged >5yrs recruited in South Africa. Phenotypic characterisation of T-cells was undertaken using mAbs specific for CD3, CD4, CD8, HLA-DR, CD38, CD45RA, CCR7, PD-1, CCR5, IL-2, IFNg, and TNFa. Plasma sCD14 and iFABP levels were quantified via Luminex and ELISA. Antibody neutralization was measured in TZM-bl cells using a multi-subtype panel of 16 Env-pseudotyped viruses, with breadth defined as neutralization of >50% of heterologous viruses.
Low immune activation was strongly associated with high absolute CD4 count in ART-naive children. Low levels of plasma sCD14 and iFABP were consistent with limited microbial translocation in slow-progressing children. Immune factors associated with non-progression included high naïve CD4 T cells, low effector memory CD4 cells; upon antigen stimulation, high IL-2 and low IFNg production; and low expression of T-cell exhaustion markers. LASSO and generalized linear models identified CD4 T-cell immune activation as the primary driver of CD4 decline among 16 parameters analyzed; notably, viral load had no significant impact. bNAbs were detected in 70% of slow-progressing pediatric subjects (n=89) compared to 15% of C clade infected adults (n=48) (p=1×10-12). The NAb titres were unusually high in the children often exceeding 1:10,000.
Slow-progressing pediatric HIV infection shows features in common with natural SIV infection. HIV-specific immune responses in these children included high frequency bNAb responses in 85% of subjects. Further evaluation of this non-progressing pediatric group may be of value both in defining mechanisms limiting immune activation in the face of persistent viremia, and also in isolating highly potent bNAbs to facilitate future HIV prevention and cure strategies.