Abstract
HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.
Highlights
HIV-1 transmission occurs primarily through virus infection of genitourinary (GU) or gastrointestinal (GI) mucosae following sexual exposure (UNAIDS, 2014a, UNAIDS, 2014b, UNAIDS, WHO in Partnership with UNICEF and UNAIDS, 2014)
Findings in recent years indicate that non-neutralizing Abs may exert significant anti-HIV functions (Milligan et al, 2015, Barouch et al, 2015) facilitated through Fc-mediated interactions with Fc receptors (FcRs) expressed on innate cells in the mucosa (Alter and Moody, 2010, Li et al, 2014, Chung et al, 2015)
Several Ab functions may contribute to mucosal protection against vaginal HIV-1 infection, many of which are dependent on effector cell engagement via appropriate Fc receptors (FcRs)
Summary
HIV-1 transmission occurs primarily through virus infection of genitourinary (GU) or gastrointestinal (GI) mucosae following sexual exposure (UNAIDS, 2014a, UNAIDS, 2014b, UNAIDS, WHO in Partnership with UNICEF and UNAIDS, 2014). Anti-V1V2 IgG Abs capable of mediating Abdependent cellular cytotoxicity (ADCC) were induced by the candidate HIV-1 vaccine regimen in the RV144 trial (Pollara et al, 2014), which at relatively high levels correlated with reduced infection risk (Haynes et al, 2012, Yates et al, 2014) These observations provided optimism that vaccine-induced non-neutralizing, type-specific Abs may contribute substantially to vaccine-induced protection and could be a more achievable goal for vaccine designs (Haynes and McElrath, 2013, Barouch et al, 2015). Defining the key roles and comparing the efficacy of bnAb vs. nnAb functions in relevant models has been a major focus of recent investigations
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