Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model

Abstract

The new generation broadly neutralizing antibody VRC01 against HIV-1 shows great potential as a topically administered microbicide to prevent sexual transmission. We evaluated its efficacy in a RAG-hu humanized mouse model of vaginal HIV-1 transmission. Mice were challenged vaginally with R5 tropic HIV-1 BaL an hour after intravaginal application of the VRC01 (1 mg/ml concentration) gel. A combination of four first generation bNAbs, namely b12, 2F5, 4E10 and 2G12, was used as a positive efficacy control whereas a non-specific dengue MAb 4G2 was used as negative control. Our results showed that seven out of nine VRC01 antibody administered mice and all of the mice receiving the four bNAb antibody combination were protected against HIV-1 challenge. These findings demonstrate the efficacy of the new bNAb VRC01 as a topical microbicide to protect against HIV-1 vaginal transmission and highlight the use of the RAG-hu mouse model for testing HIV prevention strategies.

Figure 1. Vaginal application of VRC01 gel protects humanized mice against vaginal HIV-1 challenge

RAG-hu mice were challenged by vaginal route one hour after vaginal administration of VRC01, combinatorial bNAb, irrelevant antibody or placebo gels as described in Methods. Blood was collected bi-weekly from infected mice and the status of HIV-1 infection was determined by Q-RT-PCR. Kaplan-Meier plots of time course of appearance of viremia in antibody treated versus non-treated virus challenged mice.

Figure 2. Viral RNA loads in mice administered with different bNAb gels

RAG-hu mice were challenged by vaginal route an hour after vaginal application of bNAb gels as described in Methods. Blood was collected bi-weekly. Viral RNA was extracted from plasma and viral RNA loads were determined by Q-RT-PCR as described in Methods. The dotted line represents limit of PCR detection.

Figure 3. CD4 T cell decline in non-protected mice versus protected mice

Levels of CD4 T cells were monitored bi-weekly by FACS to determine their decline in treated versus non-treated mice. Baseline values for each of the mice were established prior to infection as described in Methods and are shown as week 0 values.