Origins of a Vaccine-Induced, Human Anti-HIV-1 Antibody

A broadly effective HIV-1 vaccine would greatly contribute towards pathway deepens our understanding of the level of somatic prevention of the 2.1 million new HIV-1 infections estimated to occur annually. Six HIV-1 vaccine efficacy trials in humans have thus far been conducted. Whereas most vaccines showed no efficacy in preventing from HIV-1 infection – and two actually increased infection rates in vaccine recipients – the RV144 Thai phase III HIV-1 vaccine trial is to date the only one to have shown efficacy, albeit marginally (31.2% decrease in HIV-1 acquisition at 42 months post-vaccination) (reviewed in (Kim et al., 2015)). Surely, this level of efficacy is insufficient; but these results gave hope that correlates of protection could be identified and improved upon as a path towards amore effective HIV-1 vaccine. In this issue, Nicely et al. present atomic-level details of thematuration pathway taken by a RV144 vaccine-induced antibody, CH58. The regimen administered to RV144 Thai trial volunteers consisted of four interspersed ALVACTM-HIV doses (canarypox-based viral vectorwith env/gag/pol components) boosted twice with AIDSVAX® B/E (bivalent monomeric gp120 protein) over six months (Rerks-Ngarm et al., 2009). Rigorous efforts to uncover correlates of protection in vaccine recipients revealed that IgG binding to a V1/V2 scaffold (HIV-1 gp120 variable loops 1 and 2 displayed on the murine leukemia virus gp70 protein) inversely correlated with infection. Two isolated antibodies from vaccine recipients, CH58 and CH59, bind to lysine 169 in gp120 V2 (Liao et al., 2013), a position implicated by sieve analysis in blocking sequencematched HIV-1 strains. Interestingly, these antibodies only neutralize HIV-1 weakly, but mediate effective antibody-dependent cell-mediated cytotoxicity (ADCC) as the mechanism to thwart HIV-1. Upon exposure to foreign antigens, precursor B cells undergo affinity-based selection and hypermutation of variable domains to gain in affinity and proliferate — a process termed affinity maturation. To shed light into the maturation pathway of the RV144 vaccine-induced CH58 antibody, Nicely and colleagues inferred its precursor sequence, and performed comparative structural and biophysical studies of the germline antibody and its mature counterpart. Only 11mutations separate the precursor sequence from the mature antibody — a maturation pathway driven by the multivalent, prime-boost RV144 vaccine regimen. Conversely, the development of broadly neutralizing antibodies (bnAbs) in naturalHIV-1 infection often requiresmore extensive affinity maturation. As an example, bnAb VRC01, which neutralizes ~90% of circulating HIV-1 isolates, has 66 residue alterations encoded in its variable light and heavy genes (Zhou et al., 2010). The CH58 affinity maturation