Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors

Abstract

Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4 ؉ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4 ؉ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4 ؉ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.

Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers

“…In a smaller expression profiling study of GALT tissue, long-term nonprogressors had higher expression levels of many immune response genes, although the levels of expression of these genes were even greater in the noncontrollers. 19 It is possible that the controllers in our study have higher expression levels of immune response genes relative to HIV-negative healthy persons, but the levels are still relatively low with respect to the noncontrollers. Finally, it will be of interest to characterize the same set of parameters in HAART-suppressed patients who have undetectable viral loads as a result of drugmediated viral suppression as opposed to natural resistance.…”

“…6,19,25 Our analysis has validated some parameters of such activation that are concordant between the peripheral blood and rectosigmoid biopsy tissue. Using several forms of analysis, we have also For personal use only.…”

“…Whereas transcriptional profiling has been conducted on GALT tissue from long-term nonprogressors 19 and flow cytometric studies have been conducted on controllers, 6 this is the first time that gene expression patterns have been correlated with immune parameters in peripheral blood and in GALT of controllers and noncontrollers. By reducing the dimensions of our flow cytometry data through principal component analysis (PCA), 20 we were able to associate immune parameters with specific molecular markers that distinguish these 2 groups of subjects.…”

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

“…The persistence of HIV reservoirs in the gut-associated lymphoid tissue (GALT) has been well documented, and detectable levels of HIV replication (RNA, DNA, and p24 protein) have been reported in tissue biopsy specimens from the upper and lower intestinal tracts (3)(4)(5). Studies have shown that ART-naive or treated subjects with HIV show decreased intestinal tissue expression of genes involved in mucosal repair and regeneration, while expression of genes regulating inflammation and immune activation is increased (2,(5)(6)(7). In addition, the expression of genes involved in intestinal epithelial integrity and barrier function, such as tight junctional proteins, as well as in nutrient and xenobiotic absorptive and digestive functions, such as drug-metabolizing enzymes, is also decreased in HIV-infected subjects compared to HIV-negative healthy volunteers (6).…”

“…Studies have shown that ART-naive or treated subjects with HIV show decreased intestinal tissue expression of genes involved in mucosal repair and regeneration, while expression of genes regulating inflammation and immune activation is increased (2,(5)(6)(7). In addition, the expression of genes involved in intestinal epithelial integrity and barrier function, such as tight junctional proteins, as well as in nutrient and xenobiotic absorptive and digestive functions, such as drug-metabolizing enzymes, is also decreased in HIV-infected subjects compared to HIV-negative healthy volunteers (6). Collectively, these data suggest that HIV infection leads to the disruption of the integrity of the intestinal epithelial barrier and alteration in nutrient and drug absorption.…”