Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation.

Author summary While antiretroviral therapy (ART) has improved disease outcome and reduced HIV-1 transmission, it is not a cure, as interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to induce HIV-1 remission in the absence of ART would be highly beneficial to children living with HIV-1, sparing them from the associated adherence requirements, side effects, and cost of ART. Here, we used our previously established pediatric model of oral SIV infection and ART suppression of viremia in infant rhesus macaques (RMs) to evaluate the safety and efficacy of an Ad48-SIV prime, MVA-SIV boost therapeutic vaccine approach plus TLR-7 stimulation. Our study demonstrates this vaccination strategy is immunogenic in infants; however, unlike previously reported results in adult RMs using a similar approach, vaccination did not result in a difference in the level of CD4(+) T cell-associated SIV DNA or viral rebound dynamics after ART interruption when compared to control infant RMs. These results highlight the importance of pre-clinical studies using pediatric models and indicate potential HIV-1 cure strategies may differentially impact adults and children. Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1-infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-gamma spot forming cells (SFC) per 10(6) PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8(+) and CD4(+) T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4(+) T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.