HIV-1 Subtype C-Infected Children with Exceptional Neutralization Breadth Exhibit Polyclonal Responses Targeting Known Epitopes

Abstract

An HIV vaccine is likely to require bNAbs, which have been shown to prevent HIV acquisition in nonhuman primates. Recent evidence suggests that HIV-infected children are inherently better at generating bNAbs than adults. Here, we show that exceptional neutralization breadth in a group of viremic HIV-1 subtype C-infected children was due to the presence of polyclonal bNAb responses. These bNAbs targeted multiple epitopes on the HIV envelope glycoprotein previously defined in adult infection, suggesting that the immature immune system recognizes HIV antigens similarly. Since elicitation of a polyclonal bNAb response is the basis of next-generation HIV envelope vaccines, further studies of how bNAb lineages are stimulated in children is warranted. Furthermore, our findings suggest that children may respond particularly well to vaccines designed to elicit antibodies to multiple bNAb epitopes.

Broadly neutralizing plasma antibodies effective against diverse autologous circulating viruses in infants with multivariant HIV-1 infection

“…Despite the high variability in terms of the sequence, glycosylation and length of the V2-apex of HIV-1 envelope, bnAbs directed against V2-apex are elicited relatively early and are one of the most potent classes of bnAbs 1,12 . The findings herein of a high frequency of V2-apex bnAbs in infants with PNA is in consensus with previous observations in infected children 11 . In AIIMS704, dependence on V2-apex and MPER were observed while AIIMS706 showed dependence on V2-apex and V3-glycan ( Figure 1F ).…”

“…Using the HIV-25710-2.43 mutant pseudoviruses, we next delineated the epitope specificities of plasma bnAbs from ENs and BNs. The plasma bnAbs of majority of the infants (8/11) were directed against the V2-glycan, with two ENs (AIIMS704 and AIIMS706) showing multi-epitope dependency, a feature reported to be typically associated with chronic antigenic exposure 8,11 ( Figure 1F ). Despite the high variability in terms of the sequence, glycosylation and length of the V2-apex of HIV-1 envelope, bnAbs directed against V2-apex are elicited relatively early and are one of the most potent classes of bnAbs 1,12 .…”

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

“…In order to identify the neutralizing specificities of AIIMS_329 and AIIMS_330 plasma anti-bodies that may have contributed to their potent neutralizing activity, we tested plasma neu-tralization of mutant pseudoviruses harbouring mutations at key residues of V2-glycan and V3-glycan to assess glycan dependence (5,6), binding reactivity with RSC3 wild type probe and its mutant RSC3Δ371I/P363N (22) for presence of CD4bs dependence and MPER peptides (MPER-B and –C) (23,24) for MPER dependence.…”

“…Significantly high viral loads in context of normal CD4 + T cell counts, rapid disease progression, and generation of potent and polyclonal antibody response earlier in infection than adult counterparts are some of the differences between pediatric and adult HIV-1 infection. Recently, we and others observed the longitudinal evolution of plasma cross-neutralization antibody response with multiple epitope specificities in select antiretroviral naïve HIV-1 clade C (HIV-1C) chronically infected children (5,6). The clade C primary isolates that we established from some of these chronically infected children were relatively resistant to some of the tested second generation adult bnAbs (18).…”

“…Chronically infected children have been shown to have potent plasma bnAbs with diverse epitope specificities (5,6). In our pediatric cohort of antiretroviral naïve HIV-1C infected long term non-progressors (LTNPs) characterized for plasma antibody responses (6,13–18), we identified a pair of antiretroviral naive HIV-1C infected children AIIMS_329 and AIIMS_330, defined herein as genetically identical twins by their identical HLA haplotypes, who had acquired the infection at birth by vertical transmission.…”