OA30.05
Background: To assess the ability of immunogens to elicit broadly neutralizing antibodies (bNAbs) against HIV-1, an appropriate animal model is necessary. It has been previously established that the CCR5-tropic SHIV-AD8-EO molecular clone is a pathogenic and mucosally transmissible virus in Rhesus macaques. Furthermore, some macaques infected with this SHIV develop bNAbs; however the mechanism of eliciting bNabs in this model remains unclear.
Methods: One macaque, JG7, slowly developed breadth on a multi-clade 21-virus panel from weeks 47–131 post-infection. Frequency of antigen-specific germinal center B cells and T-follicular helper (TFH) cells were evaluated at the early wk47 time-point as well as somatic hypermutation in these B cell receptors (BCRs). Monoclonal antibodies were isolated and characterized by ELISA binding and neutralization profile.
Results: By wk47, JG7 had high viral load, and high levels of antigen-specific TFH and IgG+B cells in the germinal center. A fingerprint analysis of sera neutralization data suggested a CD4-induced (CD4i) specificity at the early wk47 time-point. BCR sequencing revealed a large clonal family distinguished by high V-gene mutation frequency and long heavy chain CDR3s of 31 amino acids. Four BCRs were cloned and found to recapitulate most of the serum breadth at this time. Furthermore, these monoclonals competed with 17b for binding to gp120 and had enhanced neutralization activity in the presence of soluble CD4, confirming the CD4i prediction.
Conclusions: Our findings support the hypothesis that in the presence of high antigen levels and T cell help, Rhesus macaques can develop cross-neutralizing anti-HIV antibodies with high levels of mutation and long CDRH3s akin to bNAbs isolated from HIV infected humans. These data highlight the utility of the SHIV model for studying development of bNAbs in Rhesus macaques.
