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Background:  In sharp contrast to HIV infection of humans or simian immunodeficiency virus (SIV) infection of rhesus macaques (RM), SIV infection in sooty mangabeys (SM) is not associated with CD4⁺ T-cell decline, generalized immune activation, or progression to AIDS, despite chronic high levels of viremia. Studies have correlated the resistance of SM to SIV-related pathogenesis with lower T-cell activation during acute and chronic infection. Given the differences in pathogenesis, we hypothesized that global gene expression profiling of peripheral blood mononuclear cells (PBMC) and T-cell subsets during chronic infection would allow for the identification of genes associated with the divergent infection outcomes.

Methods:  Microarray technology was used to measure and compare gene expression in CD4⁺ T cells, CD8⁺ T cells, and total PBMC of SIV-infected and uninfected SM and HIV-infected and uninfected humans. Genes of statistical significance and biological interest, and control genes, were validated with Q-polymerase chain reaction (PCR) and/or flow cytometry.

Results:  While transcriptional profiles of T-cell subsets from HIV-infected humans included numerous established markers associated with immune activation (most notably type I interferon (IN) responses), profiles of T-cell subsets from infected SM reflected neither the breadth nor magnitude of gene-expression patterns associated with this response. Indeed, expression profiles of SM supported previous findings of an attenuated host immune response in SIV infection. SIV-associated SM CD8⁺ T-cell gene expression profiles showed moderate changes in major hystocompatibility complex (MHC) Class II RNA and CD28 RNA expression. However, in sharp contrast to the human gene expression profiles, SM T cells demonstrated a profound lack of type I IN response gene (or other pro-inflammatory cytokine gene) up-regulation. This absence of IN-a response gene expression was underscored by an increase in expression of a transcriptional repressor of type I IN responses. Moreover, expression of genes known to be important for T-cell homeostasis, T-cell co-stimulation, and lymphocyte-dendritic cell communication differed widely between SM and humans, suggesting the possibility of active mechanisms of cell maintenance and/or immune response attenuation in these subjects.

Conclusions:  Transcriptional profiles of SIV-infected SM and HIV-infected human lymphocytes have allowed the identification of genes that may provide clues to the key determinants of disease outcome following viral infection.

Keywords: Sooty Mangabey; Simian Immunodefciency Virus; Microarray