T-Cell Correlates of Vaccine Efficacy after a Heterologous Simian Immunodeficiency Virus Challenge

Abstract

Determining the "correlates of protection" is one of the challenges in human immunodeficiency virus vaccine design. To date, T-cell-based AIDS vaccines have been evaluated with validated techniques that measure the number of CD8 ؉ T cells in the blood that secrete cytokines, mainly gamma interferon (IFN-␥), in response to synthetic peptides. Despite providing accurate and reproducible measurements of immunogenicity, these methods do not directly assess antiviral function and thus may not identify protective CD8؉ T-cell responses. To better understand the correlates of vaccine efficacy, we analyzed the immune responses elicited by a successful T-cell-based vaccine against a heterologous simian immunodeficiency virus challenge. We searched for correlates of protection using a viral suppression assay (VSA) and an IFN-␥ enzyme-linked immunospot assay. While the VSA measured in vitro suppression, it did not predict the outcome of the vaccine trial. However, we found several aspects of the vaccine-induced T-cell response that were associated with improved outcome after challenge. Of note, broad vaccine-induced prechallenge T-cell responses directed against Gag and Vif correlated with lower viral loads and higher CD4 ؉ lymphocyte counts. These results may be relevant for the development of T-cell-based AIDS vaccines since they indicate that broad epitope-specific repertoires elicited by vaccination might serve as a correlate of vaccine efficacy. Furthermore, the present study demonstrates that certain viral proteins may be more effective than others as vaccine immunogens.

The PTAP Sequence within the p6 Domain of Human Immunodeficiency Virus Type 1 Gag Regulates Its Ubiquitination and MHC Class I Antigen Presentation

“…Several studies indicate differences in the capability of virusspecific T cell clones to interfere with HIV-1 replication. Importantly, it has been demonstrated that an effective CTL response acting specifically against HIV-1 Gag, but not against other viral Ags, can be correlated with a significant reduction in viral load in HIV-1-infected patients (69)(70)(71) or in SIV-1-infected rhesus macaques (72). Therefore, HIV-1 Gag can be considered as an interesting model Ag.…”

The Majority of Freshly Sorted Simian Immunodeficiency Virus (SIV)-Specific CD8+T Cells Cannot Suppress Viral Replication in SIV-Infected Macrophages

“…To extend our findings that freshly sorted SIV-specific CD8 ϩ T cells cannot efficiently suppress viral replication in SIV-infected macrophages, we next tested bulk CD8 ϩ T cells in the viral suppression assay as previously described (17,28). We isolated bulk CD8 ϩ T cells from ECs and naïve animals using an anti-CD8 antibody that recognizes a conformational epitope of the CD8␣␤ heterodimer, thereby excluding natural killer cells, which express only CD8␣ (40,46).…”

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

“…Autologous cryopreserved PBMC were used to perform a virus inhibition assay essentially as previously described (43). Briefly, PBMC samples obtained before the study start and after the last vaccination were magnetically sorted into CD8-depleted PBMC (target cells) and positively selected CD8+ T cells (effector cells) using a non-human primate-specific CD8 Microbead kit (Miltenyi Biotec), according to the manufacturer's instructions.…”