Mechanisms of immune protection against simian immunodeficiency virus

Abstract

The lack of an effective HIV vaccine calls for efforts to investigate the mechanism of protective immunity against AIDS viruses. It has been previously demonstrated that the live replication-competent modified vaccinia virus Tiantan (MVTT) is superior to non-replication vaccinia MVA in inducing high levels of neutralizing antibodies against SARS-CoV infection via mucosal vaccination. Therefore, the hypothesis was that MVTT could be a better HIV vaccine vector given its highly attenuated phenotypes such as no neurovirulence and safe in severe combined immunodeficiency disease (SCID) mice. Here, a recombinant MVTT expressing SIVmac239 Gag-Pol and Env (rMVTTSIVgpe) was constructed and its immunogenicity was assesed when administered via different routes using homologous prime-boost strategies or in heterologous regimens boosted with a recombinant adenovirus-based vaccine inserted matched SIVmac239 genes (rAd5SIVgpe). Results show that the heterologous prime-boost immunization with rMVTTSIVgpe and rAd5SIVgpe induces significantly greater humoral and T cell responses specific to SIV Gag, Pol and Env than homologous inoculations in mice with remarkable improvements in quality and quantity. The further study comparing different combinations of rMVTTSIVgpe and rAd5SIVgpe demonstrates that the rMVTTSIVgpe prime-rAd5SIVgpe boost regimens elicit systemic CD8+ T cell responses with augmented magnitude and polyfunctionality, as compared with rAd5SIVgpe-rMVTTSIVgpe and rAd5SIVgpe-rAd5SIVgpe regimens. Priming with rMVTTSIVgpe also increases frequencies of gut-homing Gag-specific CD8+ T cells (CCR9+47+ and CCR6+47+) and levels of CD8+ T cell ELISPOT responses against Gag, Pol and Env in mesenteric lymph nodes (MLNs) post-boost. The mucosal route of immunization is essential for rMVTTSIVgpe to induce rectal IgG with detectable neutralizing activity against SIVmac1A11. Furthermore, the regimen involving mucosal prime with rMVTTSIVgpe followed by systemic boost with rAd5SIVgpe proves to be efficient in protecting monkeys from mucosal challenge of a high dose of SIVmac239, a CCR5-tropic strain with high pathogenicity and neutralization-resistance. SIV-specific T cell ELISPOT responses specific to Gag and Pol but not Env and the frequency of Gag-specific IFN-+TNF-+CD8+ effector memory T cells (TEM) are likely associated with virological control after challenge. Mucosal immunity induced by this vaccination strategy also has important implications to the effectiveness of protection against disease progression. A hypothesis was generated that removal of non-protective but immune dominant determinant of SIVmac239 Env may drive antibody responses to protective domains. It was found that the neutralization-resistance of SIVmac239 could be partially explained by its high immunogenicity in eliciting CD4-induced neutralizing antibodies, which are unable to protect the CCR5-binding site due to the conformational masking and steric restriction. It was discovered that the immunodominance of CD4-induced neutralizing antibodies on SIV envelope is determined by a single highly conserved N-linked glycosylation site (N277) in the C2 domain. Substitution of this N-linked site abolishes viral entry and the immunogenicity of the CD4i domain while promotes V2-specific antibody responses, which have recently been identified as an important immunological correlate to HIV-1/SIV protection. Our findings demonstrate the concept that B cell immunodominance is relative and eliminating the dominant antigenic region can result in redirection of B cell recognition, which have critical implications for immunogen design and the development of protective antibody-based HIV vaccine.