Background:  Limited information is available on the molecular mechanisms by which long-term HIV-1-infected non-progressors (LTNP) naturally suppress HIV-1 infection and maintain immune functions. The mucosal immune system is an early target for HIV-1 infection, causing severe CD4⁺ T cell depletion that is maintained through the course of infection in the absence of ART. Previous studies have documented high levels of immune activation and inflammatory responses in primary HIV-1 infection. The mechanisms mediating the development of these pathogenicities, their effect on the mucosal microenvironment, and the reasons LTNP patients do not display this phenotype remain unknown.

Methods:  Using DNA microarray technology, real-time polymerase chain reaction, flow cytometry, and immunohistochemistry, we evaluated mucosal T-lymphocyte subsets, virus-specific responses, gene expression profiles, and viral loads in patients with primary HIV-1 infection, LTNP patients, and untreated chronically HIV-1-infected patients with high viral loads and CD4⁺ T cell loss.

Results:  While LTNP had undetectable viral loads and normal CD4⁺ T-cell levels in peripheral blood and mucosal compartments, patients in the early stages of HIV 1 infection had high viral loads in the gut as well as pronounced CD4⁺ T-cell depletion. Oligonucleotide microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of patients with high viral load and patients in early stages of infection as compared to LTNP. Genes associated with cell cycle progression were similarly deregulated in all patient groups. Alterations in gene expression that were common to early patients and LTNP included a group of genes with common upstream transcription factors. Genes associated with lipid metabolism and epithelial cell barrier and digestive functions were down-regulated in both patients with high viral load and LTNP and to varying degrees in early infection.

Conclusions:  Our findings indicate that, in contrast to patients with high viral load, LTNP maintain both peripheral and CD4⁺ T-cell levels and control immune and inflammatory responses. Down-regulation of genes associated with digestive and barrier functions highlight the insidious effects of HIV-1 infection that occur in all patients in all stages of disease progression, regardless of their ability to control viral replication.