The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit.
We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations.
Best-in-class single bnAbs for potency and breadth were CAP256-VRC26.25 (V2-glycan), 10-1074V (V3-glycan), VRC07-523 (CD4bs) and 10E8 (MPER). Optimal bnAb combinations were identified based on breadth and potency of neutralization, as well as other relevant measures such as the extent of complete neutralization and instantaneous inhibitory potential. By these criteria, VRC07-523 + CAP256-VRC26.25, VRC07-523 + CAP256-VRC26.25 + 10-1074V and VRC07-523 + CAP256-VRC26.25 + 10-1074V + 10E8 were identified as the best 2, 3, and 4 bnAb combinations, respectively. Triple and quadruple combinations of bnAbs were significantly more effective than the best double combinations. Quadruple bnAb combinations were predicted to be similar to triple combinations by some metrics, and significantly better by others. Importantly, increasing the total number of bnAbs in combinations improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo.
Combinations with higher numbers of bnAbs are advantageous in providing increased potency, breadth, complete neutralization, and active coverage against HIV-1 clade C. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.