HIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases.

Loss of gut mucosal integrity and an aberrant gut microbiota are proposed mechanisms contributing to chronic inflammation and increased morbidity and mortality during antiretroviral-treated HIV disease. Sexual practice has recently been uncovered as a major source of microbiota variation, potentially confounding prior observations of gut microbiota alterations among persons with HIV (PWH). To overcome this and other confounding factors, we examine a well-powered subset of AGEhIV Cohort participants comprising antiretroviral-treated PWH and seronegative controls matched for age, body-mass index, sex, and sexual practice. We report significant gut microbiota differences in PWH regardless of sex and sexual practice including Gammaproteobacteria enrichment, Lachnospiraceae and Ruminococcaceae depletion, and decreased alpha diversity. Men who have sex with men (MSM) exhibit a distinct microbiota signature characterized by Prevotella enrichment and increased alpha diversity, which is linked with receptive anal intercourse in both males and females. Finally, the HIV-associated microbiota signature correlates with inflammatory markers including suPAR, nadir CD4 count, and prevalence of age-associated noncommunicable comorbidities.

IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques.

Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.

Dysbiotic bacteria translocate in progressive SIV infection.

Infection of gut-resident CD4(+) memory T cells during acute human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection is associated with rapid loss of these cells and damage to the epithelial barrier. Damage to the epithelial barrier allows translocation of microbial products from the intestinal lumen into the body. Immune activation caused by these microbial products has been associated with disease progression. Although microbial translocation has been demonstrated in SIV-infected nonhuman primates, the identity of translocating bacteria has not been determined. In this study we examined the communities of bacteria both within the gastrointestinal (GI) tract and systemic tissues of both healthy and experimentally SIV-infected Asian macaques. Although there were only modest changes in the GI tract-associated microbiome resulting from infection, there is substantial dysbiosis after administration of antiretrovirals. Analysis of bacterial DNA isolated from tissues of infected animals revealed a preference for the phylum Proteobacteria, suggesting that they preferentially translocate. Consistent with this finding, we observed increased metabolic activity of Proteobacterial species within the colonic lumen of SIV-infected animals. Overall, these data provide insights into disease progression and suggest that therapies aimed at altering the composition and metabolic activity of the GI tract microbiome could benefit chronically HIV-infected individuals, particularly those on antiretroviral therapies.

Mucosal immunity in human and simian immunodeficiency lentivirus infections.

Overwhelming evidence indicates that distinct pathological phenomenon occurs within the gastrointestinal (GI) tract of progressively simian immunodeficiency virus (SIV)-infected Asian macaques and HIV-infected humans compared with other anatomical sites. Massive loss of GI tract lamina propria CD4 T cells, alteration in the profile of lymphocytic cytokine production, changes in the landscape of GI tract antigen-presenting cells, and variations to the structural barrier of the GI tract are hallmarks of progressive HIV/SIV infections. The pathology within the GI tract results in translocation of microbial products from the lumen of the intestine into peripheral circulation. These translocated microbial products directly stimulate the immune system and exacerbate immune activation and, thus, disease progression. Initiation of combination antiretroviral therapy (cART) does not restore completely the immunological abnormalities within the GI tract. This incomplete restoration within the GI tract may contribute to the increased mortality observed within HIV-infected individuals treated for decades with cART. Novel therapeutic interventions aimed at enhancing GI tract anatomy and physiology may improve the prognosis of HIV-infected individuals.

Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection.

Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV) disease progression is associated with multifocal damage to the gastrointestinal tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation, but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of interleukin (IL)-17-producing lymphocytes, cells that microarray analysis showed expressed genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ dendritic cells (DCs) after SIV infection, which associated with the loss of IL-17- and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and coculture of CD103+ DCs and naïve T cells led to increased IL17A and RORc expression in differentiating T cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis.

Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection.

Pigtail macaques (PTMs) rapidly progress to AIDS after simian immunodeficiency virus (SIV) infection. Given the strong association between human immunodeficiency virus (HIV) and SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTMs. We found that before SIV infection, PTMs had high levels of microbial translocation that correlated with significant damage to the structural barrier of the gastrointestinal tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of interleukin-17-producing T cells. These data highlight the relationship among mucosal damage, microbial translocation and systemic immune activation in the absence of SIV replication, and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTMs. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation.

Mobile radiography at a music festival.

Limb injuries are common at music festival sites and traditionally patients seen by on-site medical services require referral to hospital emergency departments for radiographic exclusion of bony injury. This takes clinical personnel off site, increases demand on local emergency departments and is inconvenient for revellers. This is an audit of the use of a portable digital radiography system at the Virgin music festival in Staffordshire over a 3-year period.

High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage.

The mechanisms underlying the massive gastrointestinal tract CD4 T-cell depletion in human immunodeficiency virus (HIV) infection are not well understood nor is it clear whether similar depletion is manifest at other mucosal surfaces. Studies of T-cell and virus dynamics in different anatomical sites have begun to illuminate the pathogenesis of HIV-associated disease. Here, we studied depletion and HIV infection frequencies of CD4 T cells from the gastrointestinal tract, bronchoalveolar lavage (BAL), and blood with the frequencies and functional profiles of HIV-specific T cells in these anatomically distinct sites in HIV-infected individuals. The major findings to emerge were as follows: (i) depletion of gastrointestinal CD4 T cells is associated with high frequencies of infected CD4 T cells; (ii) HIV-specific T cells are present at low frequencies in the gastrointestinal tract compared to blood; (iii) BAL CD4 T cells are not massively depleted during the chronic phase; (iv) infection frequencies of BAL CD4 T cells are similar to those in blood; (v) significantly higher frequencies and increased functionality of HIV-specific T cells were observed in BAL compared to blood. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might circumvent global depletion of mucosal CD4 T cells.

HIV infection and the gastrointestinal immune system.

There has recently been a resurgence of interest in the gastrointestinal pathology observed in patients infected with HIV. The gastrointestinal tract is a major site of HIV replication, which results in massive depletion of lamina propria CD4 T cells during acute infection. Highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of gastrointestinal CD4 T cells. The gastrointestinal pathology associated with HIV infection comprises significant enteropathy with increased levels of inflammation and decreased levels of mucosal repair and regeneration. Assessment of gut mucosal immune system has provided novel directions for therapeutic interventions that modify the consequences of acute HIV infection.

Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques.

Loss of CD4(+) T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4(+) T-cell subtypes may be important. We found that CD4(+) T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4(+) T-helper cells, are infected by SIV(mac251)in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.

Transfer of PR1-specific T-cell clones from donor to recipient by stem cell transplantation and association with GvL activity.

BACKGROUND: The curative effects of GvL following transfer of donor-derived T cells during allogeneic stem cell transplantation (SCT) are well established. However, little is known about the nature, origin and kinetics of the anti-leukemic T-cell responses involved. METHODS: We used quantitative real-time PCR (qRT-PCR) for interferongamma mRNA production (IFN-gamma) and PR1/HLA-A*0201 tetramer staining to detect PR1-specific CD8+ T-cell activity in a donor and a patient with CML. Unbiased strand switch anchored RT-PCR was used to further characterize specific clones in PR1 sorted CD8+ T-cell populations. RESULTS: We identified PR1-specific CD8(+) T-cell clones from a donor pre-transplant, and demonstrated their transfer in the recipient's blood post-SCT using molecular tracking of Ag-specific T-cell receptors. PR1-specific CD8(+) T-cell populations were polyclonal, with a range of functional avidities for cognate Ag, and displayed predominantly effector memory phenotype early post-SCT, suggesting active stimulation in vivo. Expansion of these PR1-specific CD8(+) T-cell clones in the recipient was followed by complete remission of CML. DISCUSSION: This report represents the first direct demonstration that PR1-specific CD8(+) T-cell clones can be transferred during SCT, and supports the feasibility of pre-transplant vaccination strategies that aim to boost the number of anti-leukemic T cells in the graft.

An unusual rugby injury.

We describe an unusual sports injury in a young man, a combination of obturator hip dislocation with an ipsilateral anterior cruciate ligament injury. Traumatic non-prosthetic hip dislocations, particularly obturator hip dislocations, are extremely rare sports injuries and have not previously been reported in conjunction with a knee ligament injury. The severe pain and obvious deformity from the hip injury can distract from other injuries, particularly to the ipsilateral knee. This case reinforces the need for a thorough assessment of the knee joint, before hip reduction if possible and certainly after reduction of the dislocation.

Evaluation of focussed assessment with sonography in trauma (FAST) by UK emergency physicians.

OBJECTIVES: To evaluate the introduction of a focussed assessment with sonography in trauma (FAST) scan into the early assessment of trauma patients in the UK. METHODS: The setting was an inner city teaching hospital emergency department (annual attendance 100,000). All patients aged 16 or over admitted to the resuscitation room after blunt trauma were included in a prospective observational study. Patients had a FAST scan performed at the end of the primary survey. Results were compared to results of other investigations, laparotomy, postmortem examination, or observation. RESULTS: 153 patients were entered into the study. The sensitivity of the FAST scan was 78% and specificity was 99%. CONCLUSION: FAST is a highly specific "rule in" technique and is useful in the initial assessment of trauma patients. Emergency physicians can perform FAST after a brief training period.