Background:  HIV-1 and simian immunodeficiency virus (SIV) infections lead to chronic inflammation and immune activation in lymphoid organs, including gut-associated lymphoid tissue (GALT). The manifestation of this enteropathogenesis, together with massive and sustained CD4⁺ T cell loss occurs rapidly during acute stage infection. We hypothesize that the extent of CD4⁺ T cell depletion from GALT and local tissue damage resulting from uncontrolled immune responses directly influence the rate of disease progression. Recently, we have acquired and analyzed GALT samples isolated from a rhesus macaque infected for longer than 10 years with SIV_mac239 without any overt display of clinical manifestations of disease. Utilizing flow cytometry, real-time polymerase chain reaction (PCR), and gene expression profiling, we have compared the levels of CD4⁺ T cell depletion and inflammation in this long-term non-progressor (LTNP) to the levels in macaques with SAIDS and healthy uninfected controls.

Methods:  Total RNA was isolated from jejunal tissue samples, amplified, labeled with phycoerythrin, and hybridized to rhesus specific Affymetrix GeneChips. Statistical analysis of differential gene expression (at least 1.5-fold up- or down-regulation, p value ≤0.05) was performed with Array Assist^© and dChip software packages. Statistical analysis of molecular pathways enriched in the microarray data was performed using Pathway Assist^© and EASE software. T-cell subset levels were analyzed by flow cytometry.

Results:  In contrast to increased expression of lymphocyte activation and pro-inflammatory markers found in SAIDS animals, the LTNP macaque displayed increased transcription of anti-inflammatory molecules and up genes involved in tissue repair and regeneration. Genes mediating digestive processes were similarly down-regulated in both the SAIDS and LTNP animals.

Conclusions:  Patterns of host gene expression indicate that natural suppression of disease progression in SIV infection may be dependent on the ability to control inflammatory processes and reduce the level of local cytotoxicity, apoptosis, and destruction of the GALT microenvironment. However, although the reduction of these pathologies may increase overall survival, chronic impairment of epithelial cell/enterocyte function appears to be independent of viral suppression and thus may ultimately contribute to progression to AIDS, even in LTNP.