Twist in the Tail: Escape from HIV Neutralising Antibodies at a Single Site Confers Broad Susceptibility to Others

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An efficacious vaccine for HIV remains elusive. Numerous groups have isolated antibodies from HIV infected individuals that can bind and neutralise antigenically diverse HIV strains, so-called broadly neutralising antibodies (bNAbs) (Wibmer et al., 2015). HIV bNAbs target several conserved regions on the viral envelope (Env; a heterotrimer composed of gp120 and gp41 subunits) including the CD4 binding site, peptidoglycan associated with either the V1/V2 or the V3 loops, and the gp120-gp41 interface or the membrane proximal external region (MPER) of gp41. Possessing broad and potent antiviral activity, bNAbs may have utility in HIV immunotherapy, and are also an attractive template to guide the rational design of vaccines to generate analogous humoral immunity. However, bNAbs arise in only a minority of infected individuals and have been associated with extended periods of viremic infection and more recently, perturbations in the follicular and regulatory CD4 T cell compartment (Moody et al., 2016). Analysis of isolated bNAb lineages reveals genetic and structural features that likely contribute to their scarcity, including very high rates of somatic mutation, restricted germline selection, frequent genetic insertions and deletions, extended CDR-H3 regions and a propensity for poly- or autoreactivity. The complicated immunological contexts that underpin bNAb development are unlikely to be recapitulated by vaccination. Indeed, generating serum antibody responses able to combat neutralisation-resistant viral isolates (so-called tier 2 viruses) has not been consistently demonstrated by immunisation. Clearer insights into what governs neutralisation sensitivity to bNAbs should help speed further development of bNAb-based immunisation strategies and HIV immunotherapy.