There exists a unique group of persons who are able to durably control HIV in the absence of therapy. The mechanisms of control in these persons remain poorly defined. In this study, we examined CD8 ؉ T-cell responses in blood and rectal mucosa from 17 "elite controllers" (viral load < 75 copies/mL), 11 "viremic controllers" (75-2000 copies/mL), 14 noncontrollers (> 10 000 copies/mL), and 10 antiretroviral-treated persons (< 75 copies/mL). Production of interferon-␥, interleukin-

A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4؉ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8؉ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4 ؉ T cells. In this study, we assessed HIV-specific CD4 ؉ T-cell responses in the rectal mucosa of 28 "controllers" (viral load [VL] of <2,000 copies/ml), 14 "noncontrollers" (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had highermagnitude Gag-specific mucosal CD4؉ T-cell responses than individuals on HAART (P < 0. 05), as measured by their ability to produce gamma interferon (IFN-␥), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-␣), and macrophage inflammatory protein 1␤ (MIP-1␤). The frequency of polyfunctional mucosal CD4 ؉ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4؉ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4 ؉ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4 ؉ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8 ؉ T-cell response (Spearman's r ‫؍‬ 0.43, P ‫؍‬ 0.005), suggesting that increased CD4 ؉ T-cell "help" may be important in maintaining strong CD8 ؉ T-cell responses in the gut of HIV controllers.

Gut-associated lymphoid tissue (GALT) is a major site of HIV replication and CD4؉ T cell depletion.

Objectives:To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy.Design:Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study.Methods:HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms.Results:All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but d-xylose absorption increased in seven of eight participants. Mucosal CD4+ lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4+ lymphocyte densities (r = −0.74, P = 0.046).Conclusion:SBI significantly increases intestinal mucosal CD4+ lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy.

The intestinal tract is a lymphocyte-rich site that undergoes severe depletion of memory CD4؉ T cells within days of simian immunodeficiency virus or human immunodeficiency virus type 1 (HIV-1) infection. An ensuing influx of virus-specific CD8 ؉ T cells, which persist throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells or their relationship to the disease course. In this study, we measured CD8 ؉ T-cell responses to HIV-1 peptides in paired rectal and blood samples from chronically infected patients. In both blood and rectum, there was an immunodominant CD8؉ T-cell response to HIV Gag compared to Pol and Env (P < 0.01). In contrast, cytomegalovirus pp65 peptides elicited gamma interferon (IFN-␥) secretion strongly in peripheral blood mononuclear cells (PBMC) but weakly in rectal CD8؉ T cells (P ‫؍‬ 0.015). Upon stimulation with HIV peptides, CD8 ؉ T cells from both sites were capable of mounting complex responses including degranulation (CD107 expression) and IFN-␥ and tumor necrosis factor alpha (TNF-␣) production. In rectal tissue, CD107 release was frequently coupled with production of IFN-␥ or TNF-␣. In patients not on antiretroviral therapy, the magnitude of Gag-specific responses, as a percentage of CD8 ؉ T cells, was greater in the rectal mucosa than in PBMC (P ‫؍‬ 0.054); however, the breakdown of responding cells into specific functional categories was similar in both sites. These findings demonstrate that rectal CD8 ؉ T cells are capable of robust and varied HIV-1-specific responses and therefore likely play an active role in eliminating infected cells during chronic infection.