Background:  Our previous studies have demonstrated that severe CD4⁺ T cell depletion occurred in gut-associated lymphoid tissue (GALT) in primary HIV-1 infection that was not reflected in peripheral blood. Similar observations have been reported in simian immunodeficiency virus (SIV)-infected rhesus macaques. Gene expression profiling in GALT during primary SIV infection indicated that dysregulation of cell cycle progression and proliferation-related processes occurred. To determine the molecular basis of virus-induced pathology in GALT, we examined T cell homeostasis, immune activation, viral burden, and host gene expression during primary HIV-1 infection and compared the results to those from the SIV model.

Methods:        Jejunal biopsies and blood samples were obtained from 2 HIV-- infected individuals with 6 weeks of exposure to the virus. T cell depletion (flow cytometry), viral burden (Real-time PCR), antigen-specific responses (intracellular cytokine staining), and gene expression (DNA microarray) in infected subjects were measured and compared to values obtained from 4 healthy, uninfected controls. Similar analyses were performed in 4 macaques following 2 weeks of SIV infection.

Results:  While a dramatic reduction in CD4⁺ T cells was observed in GALT of both HIV infected humans and SIV-infected macaques during primary infection, CD4⁺ T cell levels were stably maintained in the peripheral blood. Expression profiling demonstrated that genes involved in innate and acquired immune responses, as well as inflammation were consistently up regulated in both humans and macaques. Both species also down regulated transcription of genes associated with digestive/epithelial physiology and cell-cell signaling. Molecular and immunologic analyses demonstrated activation induced cell death, dysregulation of cell cycle progression contribute to the CD4⁺ T cell depletion in primary HIV and SIV infections, leading to the disruption of intestinal structure and function.

Conclusions:  Molecular and immunologic analyses of gut-lymphoid tissue provided insights into the mechanisms of viral pathogenesis during primary HIV and SIV infections. Better understanding of the pathogenic mechanisms during early in HIV infection, may lead to the identification of potential novel targets for therapeutic intervention.

Keywords: Microarray; CD4+ T cell; GALT