Vesicular Stomatitis Virus-Simian Retrovirus Type 2 Vaccine Protects Macaques from Detectable Infection and B-Cell Destruction

Abstract

Natural infection with simian retrovirus (SRV) has long been recognized in rhesus macaques (RMs) and may result in an AIDS-like disease. Importantly, SRV infections persist as a problem in recently imported macaques. Therefore, there is a clear need to control SRV spread in macaque colonies. We developed a recombinant vesicular stomatitis virus (VSV)-SRV vaccine consisting of replication-competent hybrid VSVs that express SRV gag and env in separate vectors. The goal of this study was to assess the immunogenicity and protective efficacy of the VSV-SRV serotype 2 vaccine prime-boost approach in RMs. The VSV-SRV vector (expressing either SRV gag or env) vaccines were intranasally administered in 4 RMs, followed by a boost 1 month after the first vaccination. Four RMs served as controls and received the VSV vector alone. Two months after the boost, all animals were intravenously challenged with SRV-2 and monitored for 90 days. After the SRV-2 challenge, all four controls became infected, and viral loads (VLs) ranged from 10 6 to 10 8 SRV RNA copies/ml of plasma. Two animals in the control group developed simian AIDS within 7 to 8 weeks postinfection and were euthanized. Anemia and weight loss were observed in the remaining controls. During acute infection, severe B-cell depletion and no significant changes in T-cell population were observed in the control group. Control RMs with greater preservation of B cells and lower VLs survived longer. SRV-2 was undetectable in vaccinated animals, which remained healthy, with no clinical or biological signs of infection and preservation of B cells. Our study showed that the VSV-SRV vaccine is a strong approach for preventing clinically relevant type D retrovirus infection and disease in RMs, with protection of 4/4 RMs from SRV infection and prevention of B-cell destruction. B-cell protection was the strongest correlate of the long-term survival of all vaccinated and control RMs.

Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management

“…Both natural and experimental SRV infections can result in a wide spectrum of diseases ranging from subclinical to severe immunodeficiency with associated opportunistic infections. Common clinical findings include anemia, granulocytopenia, lymphopenia, thrombocytopenia, diarrhea, weight loss, splenomegaly, and lymphadenopathy . SRV‐induced perturbations of immune responses include suppression of T‐and B‐lymphocyte function leading to the down regulation of MHC Class II antigen expression, reduced mitogen‐induced proliferation, decreased immunoglobulin production, and other functional defects.…”

Impact of Recombinant VSV-HIV Prime, DNA-Boost Vaccine Candidates on Immunogenicity and Viremia on SHIV-Infected Rhesus Macaques

“…While the dosage probably played an important role in the fast infection, the design and timing might also matter. Many studies with similar schedules to the current study (4-8 weeks post last immunization) only challenged once, while others delayed challenge until 6 to 12 months after the final boost, but challenged multiple times [5,6,56,57]. Increased time from boost to challenge might help reduce nonspecific immune reactions that favor enhancement, which would therefore be preferable for protection.…”

Simian Retrovirus 4 Induces Lethal Acute Thrombocytopenia in Japanese Macaques

“…It is possible that the majority of Japanese macaques are tolerant of SRV-4 and cannot produce antibodies against it, especially for SU Env. Alternatively, SRV-4 may impair the function of B cells, as observed in SRV-2 infection in rhesus macaques (22). Primates have antiretroviral restriction factors, such as APOBEC3, TRIM5␣, and tetherin, that serve as an intrinsic line of defense (23).…”