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

TitleTherapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation.
Publication TypeJournal Article
Year of Publication2020
AuthorsBricker KM, Obregon-Perko V, Uddin F, Williams B, Uffman EA, Garrido C, Fouda GG, Geleziunas R, Robb M, Michael N, Barouch DH, Chahroudi A
JournalPLoS Pathog
Volume16
Issue10
Paginatione1008954
Date Published2020 Oct
ISSN1553-7374
KeywordsAdenoviridae, Animals, Animals, Newborn, CD4-Positive T-Lymphocytes, Female, Genetic Vectors, Macaca mulatta, Male, SAIDS Vaccines, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Toll-Like Receptor 7, Vaccination, Viral Load, Viremia, Virus Replication
Abstract

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-γ spot forming cells (SFC) per 106 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.

DOI10.1371/journal.ppat.1008954
Alternate JournalPLoS Pathog
PubMed ID33104758
PubMed Central IDPMC7644092
Grant ListP01 AI131276 / AI / NIAID NIH HHS / United States
P51 OD011132 / OD / NIH HHS / United States
R01 AI133706 / AI / NIAID NIH HHS / United States
P30 AI050409 / AI / NIAID NIH HHS / United States
P30 CA138292 / CA / NCI NIH HHS / United States