Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
Calenda, Giulia, Ines Frank, Geraldine Arrode-Bruses, Amarendra Pegu, Keyun Wang, James Arthos, Claudia Cicala, Kenneth A. Rogers, Lisa Shirreff, Brooke Grasperge, James L. Blanchard, Stephanie Maldonado, Kevin Roberts, Agegnehu Gettie, Francois Villinger, Anthony S. Fauci, John R. Mascola, and Elena Martinelli. 2019. "Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques," PLoS Pathogens 15(5): e1007776.