Increased HIV-1 Mucosal Replication Is Associated With Generalized Mucosal Cytokine Activation

Abstract

The purpose of this study was to characterize intestinal mucosal cytokine profiles in subjects with HIV-1 infection and their relation to mucosal viral load (MVL). Intestinal mucosal cytokine mRNA (interleukin [IL]-2, interferon [IFN]-gamma, IL-12, IL-10, IL-1beta, tumor necrosis factor [TNF]-alpha, IL-6, and regulated upon activation, normal T-cell expressed and secreted [RANTES]) and HIV-1 RNA were quantified using real-time polymerase chain reaction (PCR). On the basis of MVL quantification, the HIV-1-infected subjects were divided into 3 groups: undetectable MVL (<50 copies/microg of tissue total RNA), low MVL (>50 but <5000 copies/microg of tissue total RNA), and high MVL (>5000 copies/microg of tissue total RNA). Compared with the control group, significant reductions in RANTES, IL-2, and IFNgamma expression were seen in the undetectable MVL group (P < 0.005). IL-6 was significantly increased in all the HIV groups (P < 0.005), and RANTES, IL-10, and IFNgamma were increased in the high MVL group (P < 0.005). Subjects with high MVL have generalized immune activation with increases in T helper (Th)1, Th2, and proinflammatory cytokines, whereas subjects with undetectable MVL have reduced expression of multiple cytokines. The pathologic basis for these observations is unclear but may relate to the success or failure of antiretroviral therapy in controlling mucosal viral replication.

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

“…Loss of mucosal CD4 ϩ T cell helper activity may contribute substantially to the impairment of virus-specific CD8 ϩ T cell activity. Expression of genes regulating lymphocyte activation and inflammation was dominant in the mucosal tissue of HVL, but not LTNP patients, suggesting that chronic immune activation was ongoing in GALT, potentially leading to mucosal tissue injury and dysfunction (22). Thus, elevated immune and inflammatory responses characterize chronic HIV-1 infection in vivo.…”

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).…”

“…espite improved outcomes for persons with HIV, intestinal complications ranging from diarrhea, weight loss, nausea, vomiting, and abdominal pain to gastrointestinal (GI) bleeding, anorectal disease, and GI tumors continue to be common, even in those who have achieved undetectable viral loads and normal CD4 ϩ lymphocyte counts with the use of combination antiretroviral therapy (ART) (1,2). 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).…”

HIV infection and the gastrointestinal immune system

“…22 In particular, high levels of TNF are thought to cause apoptosis of enterocytes, and treatment with anti-TNF antibodies is of great clinical benefit to individuals with Crohn's disease. 23 With respect to HIV enteropathy, local immune activation likely plays a formative role; indeed, high levels of proinflammatory mediators such as the beta chemokines 24 IL-6, IL-10, and IFN-γ 25 are found in the lamina propria of the colon of HIV-infected individuals. Moreover, the degree of inflammation within the GI tract correlates with viral replication.…”

“…Moreover, the degree of inflammation within the GI tract correlates with viral replication. [25][26][27] Although systemic immune activation is a hallmark of HIV-infection, its etiology has remained elusive. However, it has been reasonably postulated that local bacterial invasion across the damaged tight epithelial barrier may allow microbial products to stimulate the immune system locally, presumably through receptors such as Toll-like receptors.…”