A Caulobacter crescentus Microbicide Protects from Vaginal Infection with HIV-1JR-CSF in Humanized Bone Marrow-Liver-Thymus Mice

Abstract

Over 2 million people are infected with HIV-1 annually. Approximately half of these new infections occur in women residing in low-income countries, where their access to and control over HIV-1 preventative measures are often limited, indicating that female-controlled prevention options for HIV-1 are urgently needed. Microbicides that can be topically applied to the vaginal tract in advance of sexual activity represent a promising female-controlled prevention option for HIV-1. We have previously described the development of an HIV-1-specific microbicide using the surface or S-layer recombinant protein display capabilities of the nonpathogenic, freshwater bacterium Caulobacter crescentus Recombinant C. crescentus bacteria were created that displayed proteins that interfere with the HIV-1 attachment and entry process and that were able to provide significant protection of TZM-bl cells from infection with HIV-1 pseudovirus. These studies have been expanded to investigate if these recombinant C. crescentus bacteria are able to maintain efficacy with replication-competent HIV-1 and both TZM-bl cells and human peripheral blood mononuclear cells (PBMCs). In addition, we utilized the humanized bone marrow-liver-thymus (BLT) mouse model to determine if vaginal application of recombinant C. crescentus at the time of HIV-1_JR-CSF infection could provide protection from HIV-1 infection. Recombinant C. crescentus bacteria expressing Griffithsin, GB virus C E2 protein, elafin, α-1-antitrypsin, indolicidin, and the fusion inhibitor T-1249 were able to protect 40 to 75% of the BLT mice from vaginal infection with HIV-1_JR-CSF, with C. crescentus bacteria expressing Griffithsin being the most effective. Taken together, these data suggest that a C. crescentus-based microbicide could be a safe and effective method for HIV-1 prevention.IMPORTANCE Human immunodeficiency virus (HIV) disproportionally infects young women in sub-Saharan Africa. Current HIV-1 prevention options have had limited success among women, suggesting that alternative, female-controlled prevention options need to be developed. Microbicides that can be applied to the vaginal tract are a promising prevention option. In this study, we describe the testing of 15 potential candidates for inhibition of HIV-1 infection in a humanized mouse model of HIV-1 infection. Four of these candidates were able to provide significant protection from vaginal infection with HIV-1, with the most successful candidate protecting 75% of the mice from infection. This study describes the preclinical testing of a new strategy that could be a safe and effective option for HIV-1 prevention in women.

Keywords: Caulobacter crescentus; HIV; humanized mice; microbicide.