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ProblemThe effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T-cell frequency, phenotype, and HIV-specific T-cell responses in the endocervix and endometrium of HIV-infected women, comparing these tissues to the GIT.Method of studyMucosal samples and blood were obtained from 18 women: four who were HIV-positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV-uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T-cell frequency, phenotypes, and HIV-specific T-cell responses were analyzed by multiparameter flow cytometry.ResultsT-cell activation, measured by CD38/HLA-DR co-expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV-specific CD8+ T-cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART.ConclusionOur findings reveal differences in CD4+ T-cell frequencies, immune activation, and HIV-specific T-cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART.

ProblemThere is little information regarding the impact of the intrauterine device on immune parameters of the upper female reproductive tract related to risk of HIV acquisition.Method of studyWe collected cervical and endometrial samples from women using the hormonal intrauterine device to study its effects on endocervical cytokines/chemokine concentrations, phenotypic markers of T cells, responses of endometrial T cells to activation, and alterations of endometrial cellular infiltrates.ResultsHormonal intrauterine device use was associated with: increased concentrations of inflammatory cytokines/chemokines (endocervix); increased coexpression of CXCR4 and CCR5 (endocervix and endometrium); increased coexpression of CD38 and HLADR (endocervix and endometrium); increased intracellular IL-10 production after T-cell stimulation (endometrium); and increased density of T cells, most notably regulatory T cells (endometrium).ConclusionHormonal intrauterine device use resulted in both inflammatory and immunosuppressive alterations. Further research is needed to determine the significance of these changes for HIV risk.

Background: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) and Care Transitions Measure (CTM-3) scores are patient experience measures used to determine hospital value-based purchasing reimbursement. Interventions to improve 30-day readmissions have met with mixed results, but less is known about their potential to improve the patient experience among older ethnically and linguistically diverse adults receiving care at safety-net hospitals. In this study, we assessed the effect of a nurse-led hospital-based care transition intervention on discharge-related patient experience in an older multilingual population of adults hospitalized at a safety-net hospital. Methods: We randomized 700 inpatients aged 55 and older at an academic urban safety-net hospital. In addition to usual care, intervention participants received inpatient visits by a language-concordant study nurse and post-discharge phone calls from a language-concordant nurse practitioner to reinforce the care plan and to address acute complaints. We measured HCAHPS nursing, medication, and discharge communication domain scores and CTM-3 scores at 30 days after hospital discharge. Results: Of 685 participants who survived to 30 days, 90 % (n = 616) completed follow-up interviews. The mean age was 66.2 years; over half (54.2 %) of the participants had cognitive impairment, and 33.8 % had moderate to severe depression. The majority (62.1 %) of interviews were conducted in English; 23.3 % were conducted in Chinese and 14.6 % in Spanish. Study nurses spent an average of 157 min with intervention participants. Between intervention and usual care participants, CTM-3 scores (80.5 % vs 78.5 %; p = 0.18) and HCAHPS discharge communication domain scores (74.8 % vs 68.7 %; p = 0.11) did not differ, nor did HCAHPS scores in medication (44.5 % vs 53.1 %; p = 0.13) and nursing domains (67.9 % vs 64.9 %; p = 0.43). When stratified by language, no significant differences were seen. Conclusion: An inpatient standalone transition-of-care intervention did not improve patient discharge experience. Older multi-lingual and cognitively impaired populations may require higher-intensity interventions post-hospitalization to improve discharge experience outcomes.

ProblemThe goal of this study was to investigate the phenotype and functional responsiveness of CD4(+) and CD8(+) T-cells in the upper reproductive tract of healthy premenopausal women. The lower reproductive tract is frequently studied as a site of sexually transmitted infections; however, the upper reproductive tract may also be a portal of entry and dissemination for pathogens, including HIV-1.Method of studyEndometrial biopsy, endocervical curettage, cytobrush, and blood were collected during mid-luteal phase from 23 healthy women. T-cells were isolated and analyzed by flow cytometry.ResultsAs compared with their counterparts in blood, endometrial and endocervical T-cells had enhanced CCR5 expression, and were enriched for activated, effector memory cells. Endometrial T-cells were more responsive to polyclonal stimuli, producing a broad range of cytokines and chemokines.ConclusionThese findings underscore the responsiveness of endometrial T-cells to stimulation, and reveal their activated phenotype. These findings also suggest susceptibility of the upper reproductive tract to HIV-1 infection.

Viremic slow progressors (VSP) are a rare subset of HIV-infected persons who exhibit slow immunologic progression despite high viremia. The mechanisms associated with this slow progression remain to be defined. Clinical characteristics of VSP are similar to those of natural hosts for simian immunodeficiency virus (SIV), such as sooty mangabeys (SM) and African green monkeys (AGM), who maintain near-normal CD4 counts despite high-level viremia but maintain low immune activation. Immune activation is a powerful predictor of disease progression, and we hypothesized that low immune activation might also explain the VSP phenotype. Using multiparameter flow cytometry, we assessed levels of T cell activation and regulatory T cells (Treg) in blood and rectal mucosa of VSP, typical progressors, virologic controllers, and seronegative controls. We also assessed Treg function and CD4 T cell proliferative capacity in VSP. Contrary to expectations, we found that VSP subjects have high levels of T cell activation in the gastrointestinal mucosa. The ratio of Treg to CD3+ T cells in the mucosa of VSP was relatively low, potentially contributing to increased immune activation. Nonetheless, CD4+CD25- T cells isolated from these individuals displayed a comparatively weak proliferative response to anti-CD3 stimulation. These data reveal that the VSP phenotype is associated with elevated markers of mucosal immune activation and low numbers of mucosal Treg, suggesting that factors other than immune activation account for this phenotype.

AbstractBackgroundInfection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal.MethodsThis was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (1010 each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14.ResultsMicrobial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study.ConclusionsSynbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection.Trial registrationClinical Trials.gov: NCT00688311

Gastrointestinal (GI) dysfunction has been reported in a substantial number of children with autism spectrum disorders (ASD). Activation of the mucosal immune response and the presence of abnormal gut microbiota are repeatedly observed in these children. In children with ASD, the presence of GI dysfunction is often associated with increased irritability, tantrums, aggressive behaviour, and sleep disturbances. Moreover, modulating gut bacteria with short-term antibiotic treatment can lead to temporary improvement in behavioral symptoms in some individuals with ASD. Probiotics can influence microbiota composition and intestinal barrier function and alter mucosal immune responses. The administration of probiotic bacteria to address changes in the microbiota might, therefore, be a useful novel therapeutic tool with which to restore normal gut microbiota, reduce inflammation, restore epithelial barrier function, and potentially ameliorate behavioural symptoms associated with some children with ASD. In this review of the literature, support emerges for the clinical testing of probiotics in ASD, especially in the context of addressing GI symptoms.

Gastrointestinal (GI) dysfunction has been reported in a substantial number of children with autism spectrum disorders (ASD). Activation of the mucosal immune response and the presence of abnormal gut microbiota are repeatedly observed in these children. In children with ASD, the presence of GI dysfunction is often associated with increased irritability, tantrums, aggressive behaviour, and sleep disturbances. Moreover, modulating gut bacteria with short-term antibiotic treatment can lead to temporary improvement in behavioral symptoms in some individuals with ASD. Probiotics can influence microbiota composition and intestinal barrier function and alter mucosal immune responses. The administration of probiotic bacteria to address changes in the microbiota might, therefore, be a useful novel therapeutic tool with which to restore normal gut microbiota, reduce inflammation, restore epithelial barrier function, and potentially ameliorate behavioural symptoms associated with some children with ASD. In this review of the literature, support emerges for the clinical testing of probiotics in ASD, especially in the context of addressing GI symptoms.

BackgroundThe intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear.Methods and findingsWe evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p