Minor SHIV variants abrogate protective efficacy of broadly neutralizing antibodies in rhesus macaques

Broadly neutralizing antibodies (bNAbs) against HIV have demonstrated robust protective efficacy against sensitive viruses in humans and nonhuman primates. However, the potential of rare resistant viral variants to abrogate bNAb-based protection remains to be determined. Here we show that simian-human immunodeficiency virus (SHIV) challenge containing minor resistant variants can compromise protective efficacy of the V2-specific bNAb PGDM1400 in rhesus macaques. Macaques were infused with PGDM1400 and challenged intrarectally with either 500 monkey infectious dose 50 (MID50) of the PGDM1400-sensitive virus SHIV-325C or with 500 MID50 of SHIV-325C mixed with a sub-infectious 0.5 or 0.05 MID50 dose of the PGDM1400-resistant virus SHIV-SF162P3. All PGDM1400-treated animals challenged with SHIV-325C were protected as expected, but animals that received the mixed SHIV challenge were productively infected either with the resistant virus SHIV-SF162P3 or with rare resistant clones in the SHIV-325C challenge stock. These data demonstrate that minor resistant viral variants comprising just 0.01-0.1% of the challenge stock, at sub-infectious doses when administered alone, effectively abrogated bNAb protection against SHIV challenge in rhesus macaques. These findings suggest rare resistant variants may be more important than previously appreciated as a mechanism of virologic failure, emphasizing the importance of utilizing bNAb cocktails for HIV prevention.