Passive transfer of VRC01, the first in a family of a new generation of broadly anti-HIV neutralizing antibodies (bNAb), protects macaques from SHIV acquisition. However, protection against repeated challenges rapidly decreases with decreased antibody availability. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 protected macaques from vaginal SIV acquisition.
To determine if addition of Rh-α4β7 would increase the protective activity of VRC01, 3 groups of animals were treated with 1) VRC01-alone or 2) a combination of VRC01 + Rh-α4β7 or 3) control antibodies prior to the initiation of weekly vaginal exposures to SHIV-AD8. Inoculations with Rh-α4β7 continued every 3 weeks through the acute and early-chronic phase of infection.
Rh-α4β7 did not increase the protective effect of VRC01 against SHIV-AD8 acquisition. However, VRC01-Rh-α4β7-treated animals had a viral set-point 1 Log10 lower, on average, than animals receiving VRC01 alone. Moreover, the inclusion of Rh-α4β7 provided complete protection of blood CD4 T cell counts. While rectal SIV-DNA loads were slightly higher in VRC01-pre-treated animals from both VRC01-groups around 4 weeks post-infection, they significantly decreased over time in Rh-α4β7-treated animals compared to the controls. No significant differences were noted in SIV DNA and RNA loads in other tissues at necropsy. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17 producing cells in blood and rectal tissue during the acute phase of infection than the controls. Moreover, blood T cells from the VRC01-Rh-α4β7 group released more IFNγ in response to peptides derived from the 2nd variable loop (V2-loop) of the SHIV-AD8 envelope compared to the other 2 groups. In contrast, T cell responses to a pool of envelope consensus B peptides were decreased and there were no differences in the response to gag peptides. At necropsy (~20 weeks post-infection), VRC01-Rh-α4β7-treated macaques had significantly more IFNγ-producing T cells in the gut. Differences in T cell subsets in inguinal lymph nodes were present in both treatment groups compared to the controls.
The combination of VRC01 and Rh-α4β7 decreased chronic viral load and altered immune responses against SHIV-AD8. Further exploration of the effect of combining other bNAbs with Rh-α4β7 on SIV/HIV infection is warranted and may lead to novel preventive and therapeutic strategies.