Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs

Abstract

A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…Although MCM models indicate that elite control can potentially be attributed to innate immunity, the majority of innate immune cells has been understudied in both rhesus and cynomolgus macaque models in the context of elite control. SIV-infected NHP models have many advantages over human studies including the ability to experimentally deplete specific immune cells ( 117 ), the availability of tissue samples ( 117 , 118 ), and the carefully-controlled design of the studies with clear definition of acute and chronic infection ( 118 ). It would be beneficial to investigate whether specific depletion of innate effector cells, such as monocytes, neutrophils, and NK cells, would alter the outcome of SIV infection in macaques expressing protective MHC alleles.…”

A Single Dose SARS-CoV-2 Replicon RNA Vaccine Induces Cellular and Humoral Immune Responses in Simian Immunodeficiency Virus Infected and Uninfected Pigtail Macaques

“…Animals were monitored for Simian AIDS as defined by the WaNPRC guidelines (24). Briefly, weights, complete blood counts, and peripheral blood CD4 counts were monitored at each specimen collection timepoint.…”

“…Briefly, weights, complete blood counts, and peripheral blood CD4 counts were monitored at each specimen collection timepoint. SIV plasma viremia was evaluated by quantitative real time reverse transcription polymerase chain reaction (RT-PCR) by the Virology and Immunology Core at the WaNPRC, as previously described (24). Peripheral CD4 counts were determined from complete blood counts (12) (University of Washington Department of Laboratory Medicine) using flow cytometry based methods by the Virology and Immunology Core at the WaNPRC, as previously described (25).…”

Transient T cell expansion, activation, and proliferation in therapeutically vaccinated SIV+ macaques treated with N-803

“…In ART treated SIV+ macaques, several vaccine modalities have induced high-frequency cellular immune responses against multiple SIV proteins (i.e. Gag, Pol, and Env) (23, 29, 30). High magnitude Gag-specific responses have also been detected in therapeutic vaccine strategies delivering Gag immunogens only (24, 25).…”