Journal of virology 2017 05 24() pii 10.1128/JVI.00498-17
Passive immunotherapies against HIV-1 will most likely require broadly neutralizing antibodies (bnAb) with maximum breadth and potency to assure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross clade pseudoviruses. We evaluated the in-vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically SHIV-SF162P3 infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7 (mean 1.1 log10 RNA copies/ml reduction), while the combination of both antibodies suppressed all animals (mean 0.92 log10 RNA copies/ml reduction). Interestingly, the combination of both antibodies had no additive antiviral effect, compared to a single dose of PGT121, potentially reflecting the nearly 10-fold higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymphnode cells after 10 weeks. Autologous NAb responses and SIV/SHIV specific CD8+ T-cell responses were not significantly enhanced in the bnAb treated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS in-vivo, supporting the further clinical development of this antibody.IMPORTANCE Monocloncal antibodies (mAbs) are being considered for passive immunotherapies of HIV-1 infection. A critical requirement for such strategies is the identification of mAbs that recognize the diversity of variants within circulating but also reservoir viruses and mAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS, that has superior in-vitro antiviral characteristics, alone or in combination with the bnAb PGT121 in rhesus macauqes that are chronically infected with chimeric simian-human immunodeficiency virus (SHIV). The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior than PGT121 alone in delaying time to viral rebound or reducing PBMC or lymphnode cell proviral DNA levels. The occurrence of viral escape variants in an N6-LS mono-treated animal, however, argues for the critical need to maximize breadth and anti-viral efficacy by combining bnAbs for therapeutic indications.