Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys

Abstract

The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was an about one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01–negative monkeys challenged with SIVsmE660, no CD8+ T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4+ T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanism of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.

Activated CD4 + CCR5 + T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

“…In terms of protection from virus acquisition, the current set of results also are consistent with our previous work on the effect of AdC6 and AdC7 vectors expressing SIVGag/Tat showing no protection from SIV mac acquisition (24). Interestingly, studies of vector regimens including DNA and AdHu5 expressing an Env immunogen showed protection from virus acquisition when the animals were challenged with SIV smmE660 but not when the more stringent SIV mac239 was used (29).…”

How Samhd1 changes our view of viral restriction

“…Crosstalk between restriction factors and immune response should be considered in the development of effective vaccines. Indeed, correlation between the expression of TRIM5α-SIV-restrictive alleles and protection of vaccinated monkeys has been recently reported [73,74]. This may be achieved through Trim5α-mediated limitation of virus replication and/or viral diversity.…”

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

“…The RV144 clinical trial showed modest protection against infection, and this protection apparently correlated with anti-Env bAb, especially IgG antibodies against the V1V2 region (22, 23), but no evidence of vaccine-induced virus control was found in the individuals who became infected. Clearly, a vaccine regimen able to prevent acquisition (11,19,20,24) and reduce viral replication after infection has become possible (11,19,24) using the macaque model. In agreement with those findings, we report that our SIVmac239-based vaccine elicited systemic and mucosal anti-Env humoral immune responses able to significantly delay acquisition of the heterologous SIVsmE660, and SIV-specific cellular responses that efficiently contribute to postacquisition control of viral replication.…”