Mechanisms of early-life immunity associated with induction of heterologous HIV-1 neutralizing antibodies 9283

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Abstract Description A goal of an HIV-1 vaccine is induction of broadly neutralizing antibodies (bnAbs) that prevent infection of different strains. Previous studies have shown that infants and children living with HIV-1 generate bnAbs more frequently than adults. Studying neonate and adult rhesus macaques (RM) infected with simian-HIV (SHIV), we interrogated the permissive immunological environment for bnAb induction in pediatric populations. We studied 11 pairs of SHIV-infected RMs (N = 22), collecting blood and tissue samples up to 24 months post-infection. Viral load was quantified via qPCR of SIV gag RNA copies/mL of plasma. Blood-derived monoclonal (m) Abs and plasma samples were tested for HIV/SHIV neutralization by TZM-bl assay. Lymph node-derived germinal center (GC) B and T cell phenotyping was via flow cytometry. Neonates and adults had similar viral peaks, but neonates maintained 1-2 logs higher mean viremia over time. By 24 months, 7/11 (64%) neonates developed plasma heterologous HIV-1 nAbs, in contrast to 2/11 (18%) adults. From a young RM, we isolated (BEAM-Ab assay 10X Genomics) three mAbs that neutralized up to ∼90% of viral particles in heterologous tier 2 HIV-1 strains, of which two neutralized ∼13% of 119 strains (GM IC50=∼8-11µg/ml). Also, neonates had fewer GC CD4+ T regulatory cells than adults. We defined mechanisms of SHIV immunity that may inform future pediatric vaccine strategies in humans to elicit heterologous HIV-1 nAbs that can mature to bnAbs prior to sexual debut. Topic Categories Viral Immunology (VIR)

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