Faculty Bibliography

Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6(+) CD4(+) T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1beta (IL-1beta) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6(+) and Th17-depleted CCR6(-) CD4 T cell cultures and noted that Th17-enriched CCR6(+) cells expressed higher levels of alpha4beta7 and bound HIV envelope in an alpha4beta7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6(-) cells. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1beta (CCL4), increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV.

Aim: To identify factors that affect outpatient colonoscopy attendance in a tertiary care center. Methods: A retrospective review of the electronic medical record system was performed for patients scheduled for outpatient colonoscopies from July to October 2008 at the Manhattan VA Hospital. Patient age, gender, ethnicity, marital status, gender of referring healthcare provider (HCP), distance from hospital (in miles), living situation (e.g. apartment vs. shelter, alone vs. with others), employment status, smoking history, appointment time, day of the week, month, proximity to holiday (in days), family history of gastrointestinal malignancy, prior colon procedures, indication for current procedure, comorbidities (diabetes, hypertension, hyperlipidemia, obesity, pathologies of the major organ systems, psychiatric disorders, and history of cancer) were compared. Statistical analysis using t- and +/-2-tests was performed, with p values 0.05 denoting statistical significance. Results: A total of 517 patients were identified, comprised of 358 patients who presented for their scheduled colonoscopies ("shows") and 159 patients who did not ("no shows"). Patients were more likely to attend their procedure if the referring HCP was female rather than male (p<0.001, Figure 1a). A higher percentage of employed patients presented at their scheduled time compared with patients who were not employed (p<0.005, Figure 1b). Fewer active smokers attended compared with non-smokers. A higher percentage of "shows" who quit smoking attended compared with that of "no shows" (p<0.05, Figure 1c). Patients were less likely to attend the morning time slots from 8-11:30am compared with the afternoon/ early evening time slots from 12-5:30pm (p<0.05, Figure 1d). Patients with neurological conditions (Figure 2, footnote) were less likely to show up at their scheduled appointments (p<0.05, Figure 1e). A greater percentage of "no shows" showed up for future outpatient colonoscopies at the VA Hospital compared with "shows" (p<0.00!

A 38-year-old man with a history of HIV infection virologically suppressed on antiretroviral therapy presents to his gastroenterologist for evaluation of iron deficiency anemia and weight loss. A diagnostic colonoscopy demonstrates a two-centimeter ulcerated mass in the cecum. Biopsies of the lesion return moderately differentiated adenocarcinoma that is wild type for the KRAS mutation by real-time PCR.

Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15-24 months post initiation of cART. At the 2(nd) biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2(nd) GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART.