HIV and SIV specific cellular immunity in macaque models

Abstract

Cellular immunity is believed to be an important prerequisite for an effective HIV vaccine. Accruing data from individuals able to contain HIV-1 replication during natural infection underscores the contribution of CD8+ T cells in viral control. Accordingly vaccine strategies designed to generate these types of immune responses are now being explored. We established a chromium release assay adapted for the detection of HIV-1, HIV-2 and SIV specific CD8+ T cells.

We further evaluated combinations of monoclonal antibodies to human cytokines for their cross-reactivity with rhesus and cynomolgus macaque cytokines and compared spontaneous and mitogen-induced cytokine production in peripheral blood mononuclear cells (PBMC) from all species, using ELISA as well as enzyme-linked immune spot assay (ELISpot). The proportional distribution of the different cytokines in terms of PBMC synthezising different cytokines, were similar in all species. These methods were used together with a proliferation assay for the monitoring of cellular immune responses following vaccination or infection.

A prime boost immunization protocol including HIV-2 recombinant avipox vaccine (ALVAC) followed by HIV-2 gp125 protein or V3 peptides induced protection in 4 of 10 immunized monkeys. None of the 4 monkeys receiving ALVAC HIV-2 alone were protected. No correlation was found between any of the studied immunologic parameters and protection. However, among 6 investigated macaques lymphocyte proliferative responses to V3 peptides were detected in 2 protected but in none of 4 non-protected animals. In another study we assessed immune responses in macaques vaccinated with a DNA prime MVA boost HIV/SIV vaccine either intramuscularly and mucosally or intramuscularly only.

In this study we found a correlation between the breadth of elicited immune responses prior to SHIV challenge and the viral load 14 days after challenge. In addition, earlier control of viral replication was observed in animals immunized both mucosally and intramuscularly than in animals immunized intramuscularly only. A further support for the important role of cellular immunity comes from studies of highly HIV exposed uninfected individuals. HIV-specific CD8+ and CD4+ T cell responses have been observed in these individuals but no serum antibodies. Virus-specific CTL was detected in 2 of 3 multiple HIV-2 exposed seronegative monkeys in our study. Following intrarectal challenge with SIVsm, one monkey was completely protected and two monkeys showed suppressed viral replication. SIV specific CTL as well as SIV specific lymphoproliferation was demonstrated in monkeys exposed to low doses of SIVsm, in the absence of antibodies and detectable virus. Despite the presence of cellular immune responses the animals became infected after an intrarectal challenge with a higher dose of SIVsm.

In conclusion our data show the importance of inducing a broad and strong immune response consisting of both cellular and humoral immunity for control of virus replication. Especially functional CD8+ T cells seem to be of vital importance.