Protection against repeated vaginal SHIV challenges by a combination of VRC01 and an anti-{alpha}4{beta}7 antibody

Passive transfer of VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Protection against repeated rectal challenges decreases with decreased antibody levels weeks after infusion. Protection against repeated vaginal challenges has not been tested; however, it is expected to decrease similarly. Infusion of a simianized anti-4{beta}7 mAb (Rh-4{beta}7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and minimized the decline of CD4+ T cells. To investigate the impact of combining VRC01 and Rh-4{beta}7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-4{beta}7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000TCID50) of SHIVAD8-EO. The combination Rh-4{beta}7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-4{beta}7-treated macaques maintained higher CD4+ T cell counts compared to macaques in the other groups and exhibited lower rectal SIV-DNA loads compared to the controls. Interestingly, VRC01-Rh-4{beta}7-treated macaques had less IL-17 producing cells in blood and gut tissue during the acute phase and higher T cell responses to the V2-loop of the SHIVAD8-EO envelope compared to the other groups. The combination of suboptimal amounts of VRC01 and Rh-4{beta}7 delayed infection, altered anti-viral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-4{beta}7 on SIV/HIV infection and anti-viral immune responses is warranted and may lead to novel preventive and therapeutic strategies.