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Curr Opin HIV AIDS. 2008 May;3(3):356-61. The mucosal barrier and immune activation in HIV pathogenesis. Brenchley JM, Douek DC. Source Viral Pathogenesis and Vaccine Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. [email protected] Abstract PURPOSE OF REVIEW: Significant gastrointestinal pathology occurs in progressive HIV and simian immunodeficiency virus (SIV) infections. This review will examine the relationship between the detrimental events to the gastrointestinal tract during the acute phase of infection and disease progression through the chronic phase and, ultimately, AIDS. RECENT FINDINGS: Gastrointestinal tract CD4 T cells are dramatically depleted in acutely HIV-infected humans and SIV-infected rhesus macaques, sooty mangabeys, and African green monkeys. In addition HIV infection of humans and SIV-infection of rhesus macaques are characterized by enteropathy and increased intestinal permeability. While SIV-infected rhesus macaques and HIV-infected humans manifest chronic and systemic immune activation and microbial translocation, and progress to chronic infection and AIDS, however, SIV-infected sooty mangabeys and African green monkeys do not. SUMMARY: Recent studies have increased our understanding of the mechanisms relating structural and immunological damage to the gastrointestinal tract during the acute phase of HIV/SIV infection to immune activation and disease progression in the chronic phase. Supplemental Content PLoS One. 2011 Apr 11;6(4):e18580. Evidence for polymicrobic flora translocating in peripheral blood of HIVinfected patients with poor immune response to antiretroviral therapy. Merlini E, Bai F, Bellistrì GM, Tincati C, d'Arminio Monforte A, Marchetti G. Source Department of Medicine, Surgery and Dentistry, Clinic of Infectious Diseases, San Paolo Hospital, University of Milan, Milan, Italy. Abstract In advanced HIV infection, the homeostatic balance between gastrointestinal indigenous bacteria and gut immunity fails and microbes are able to overcome the intestinal barrier and gain the systemic circulation. Because microbial translocation is not fully controlled by antiviral therapy and is associated with inefficient CD4+ reconstitution, we investigated the profile of translocating bacteria in peripheral blood of 44 HIV-infected patients starting therapy with advanced CD4+ T-lymphopenia and displaying poor CD4+ recovery on virologically suppressive HAART. According to CD4+ reconstitution at 12-months HAART, patients were considered Partial Immunological Responders, PIRs (CD4+≥250/µl, n = 29) and Immunological non Responders, INRs (CD4+<200/µl, n = 15)). We show that PIRs and INRs present similarly elevated plasma levels of lipopolysaccharide (LPS) and its ligand sCD14 that were not lowered by virologically suppressive therapy. Bacterial 16S rRNA gene amplification and sequencing resulted in a highly polymicrobic peripheral blood microbiota both prior and after 12-month HAART. Several differences in bacterial composition were shown between patients' groups, mainly the lack of probiotic Lactobacillaceae both prior and after therapy in INRs. Failure to control microbial translocation on HAART is associated with a polymicrobic flora circulating in peripheral blood that is not substantially modified by therapy. Supplemental Content Curr Opin HIV AIDS. 2010 Mar;5(2):189-93. Th17, gut, and HIV: therapeutic implications. Hunt PW. Source Positive Health Program, San Francisco General Hospital, University of California-San Francisco, 995 Potrero Avenue, San Francisco, CA 94110, USA. [email protected] Abstract PURPOSE OF REVIEW: The purpose of this review is to discuss the apparent impact of persistent-immune activation and inflammation on morbidity and mortality among treated HIV-infected individuals, to explore the potential role of Th17 T-cell depletion in this process, and to discuss potentialtherapeutic implications. RECENT FINDINGS: Although the vast majority of HIV-infected individuals can now achieve and maintain viral suppression with modern-antiretroviral therapy (ART), their life expectancy remains much shorter than the general population and they continue to be at much higher risk for non-AIDSassociated diseases commonly associated with aging (non-AIDS-associated cancer, cardiovascular disease, etc). Abnormal levels of immune activation and inflammation persist despite sustained viral suppression and may drive these clinical events. Although the causes of persistent-immune activation remain incompletely characterized, persistent low-level HIV replication and/or release from latently infected cells in gut-associated lymphoid tissue (GALT) and microbial translocation probably play a major role. Failure to restore Th17 cells in GALT during ART might impair both the recovery of the gut mucosal barrier and the clearance of microbial products. SUMMARY: Insights from recent-pathogenesis studies might suggest novel-therapeutic approaches designed to restore Th17 cells in GALT, thereby decreasing microbial translocation, immune activation, and ultimately morbidity and mortality during treated HIV infection. Supplemental Content J Infect Dis. 2009 Apr 15;199(8):1177-85. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher AI, Deeks SG, Douek DC, Brenchley JM. Source Case Western Reserve University, Cleveland, Ohio 44106, USA. Erratum in J Infect Dis. 2009 Jul 1;200(1):160. Abstract The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infection remains undefined. We measured LPS levels by use of limulus lysate assay, and DNA sequences encoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiency virus (HIV)-infected subjects than in uninfected subjects, and they correlated with LPS levels. Higher levels of 16S rDNA were associated with higher levels of T cell activation and with lower levels of CD4 T cell restoration during antiretroviral therapy. Antiretroviral therapy reduces but does not fully normalize plasma levels of bacterial 16S rDNA, an index of microbial translocation from the gastrointestinal tract. High levels of 16S rDNA during therapy are strongly associated with reduced increases in the CD4(+) T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection. Comment in J Infect Dis. 2010 Jul 1;202(1):176-7; author reply 178. Supplemental Content Curr Opin HIV AIDS. 2010 Mar;5(2):173-8. Th17 cells, HIV and the gut mucosal barrier. Dandekar S, George MD, Bäumler AJ. Source Department of Medical Microbiology and Immunology, University of California-Davis, CA, USA. [email protected] Abstract PURPOSE OF REVIEW: We will present recent studies on a subset of CD4 T helper cells, Th17 cells, that appears to be critical for regulating gut mucosal immune responses against extracellular microbial pathogens and may serve as a link between innate and adaptive immune responses. Implications of the loss of Th17 CD4 T cells in HIV infection will be discussed in relation to the chronic immune activation and HIV pathogenesis. RECENT FINDINGS: Severe depletion of CD4 T cells occurs in the gut mucosa during primary HIV and simian immunodeficiency virus infections. A pronounced loss of mucosal Th17 CD4 T cells in the simian immunodeficiency virus-infected rhesus macaque model of AIDS is linked to impaired immune responses in the gut mucosa to an enteric pathogen, Salmonella typhimurium, leading to the lack of local control of the pathogen and its translocation. Recovery of the gut mucosal immune system during highly active antiretroviral therapy is slow and incomplete compared with the peripheral blood compartment. Recent studies suggest that the replenishment of Th17 CD4 T cells in the gut mucosa during highly active antiretroviral therapy, or during nonpathogenic simian immunodeficiency virus infections in the nonhuman primate models, correlates with better restoration and function of the gut mucosal immune system. SUMMARY: A better understanding of the role of Th17 CD4 cells in the generation of mucosal immune responses to enteric pathogens and maintenance of the intestinal epithelial integrity in HIVinfected patients will help in the development of novel strategies to modulate and enhance mucosal immune system and its function. Supplemental Content Curr Opin HIV AIDS. 2008 May;3(3):356-61. The mucosal barrier and immune activation in HIV pathogenesis. Brenchley JM, Douek DC. Source Viral Pathogenesis and Vaccine Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. [email protected] Abstract PURPOSE OF REVIEW: Significant gastrointestinal pathology occurs in progressive HIV and simian immunodeficiency virus (SIV) infections. This review will examine the relationship between the detrimental events to the gastrointestinal tract during the acute phase of infection and disease progression through the chronic phase and, ultimately, AIDS. RECENT FINDINGS: Gastrointestinal tract CD4 T cells are dramatically depleted in acutely HIV-infected humans and SIV-infected rhesus macaques, sooty mangabeys, and African green monkeys. In addition HIV infection of humans and SIV-infection of rhesus macaques are characterized by enteropathy and increased intestinal permeability. While SIV-infected rhesus macaques and HIV-infected humans manifest chronic and systemic immune activation and microbial translocation, and progress to chronic infection and AIDS, however, SIV-infected sooty mangabeys and African green monkeys do not. SUMMARY: Recent studies have increased our understanding of the mechanisms relating structural and immunological damage to the gastrointestinal tract during the acute phase of HIV/SIV infection to immune activation and disease progression in the chronic phase. Supplemental Content Patholog Res Int. 2011 Apr 26;2011:247923. Human immunodeficiency virus-associated gastrointestinal disease: common endoscopic biopsy diagnoses. Bhaijee F, Subramony C, Tang SJ, Pepper DJ. Source Department of Pathology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. Abstract THE GASTROINTESTINAL (GI) TRACT IS A MAJOR SITE OF DISEASE IN HIV INFECTION: almost half of HIV-infected patients present with GI symptoms, and almost all patients develop GI complications. GI symptoms such as anorexia, weight loss, dysphagia, odynophagia, abdominal pain, and diarrhea are frequent and usually nonspecific among these patients. Endoscopy is the diagnostic test of choice for most HIV-associated GI diseases, as endoscopic and histopathologic evaluation can render diagnoses in patients with non-specific symptoms. In the past three decades, studies have elucidated a variety of HIV-associated inflammatory, infectious, and neoplastic GI diseases, often with specific predilection for various sites. HIV-associated esophageal disease, for example, commonly includes candidiasis, cytomegalovirus (CMV) and herpes simplex virus (HSV) infection, Kaposi's sarcoma (KS), and idiopathic ulceration. Gastric disease, though less common than esophageal disease, frequently involves CMV, Mycobacterium avium-intracellulare (MAI), and neoplasia (KS, lymphoma). Small bowel biopsies and intestinal aspirates from HIVinfected patients often show HIV enteropathy, MAI, protozoa (Giardia, Isospora, Cryptosporidia, amebae, Microsporidia), and helminths (Strongyloides stercoralis). Colorectal biopsies demonstrate viral (CMV, HSV), bacterial (Clostridia, Salmonella, Shigella, Campylobacter), fungal (cryptococcosis, histoplasmosis), and neoplastic (KS, lymphoma) processes. Herein, we review HIV-associated GI pathology, with emphasis on common endoscopic biopsy diagnoses. Supplemental Content J Infect Dis. 2008 Aug 15;198(4):456-64. Collagen deposition limits immune reconstitution in the gut. Estes J, Baker JV, Brenchley JM, Khoruts A, Barthold JL, Bantle A, Reilly CS, Beilman GJ, George ME, Douek DC, Haase AT, Schacker TW. Source Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. Abstract Despite suppression of human immunodeficiency virus (HIV) replication by antiretroviral therapy, reconstitution of CD4+ cells is variable and incomplete, particularly in gut-associated lymphatic tissues (GALT). We have previously shown that immune activation and inflammation in HIV-infected and simian immunodeficiency virus-infected lymph nodes results in collagen deposition and disruption of the lymphatic tissue architecture, and this damage contributes to CD4+ cell depletion before treatment and affects the extent of immune reconstitution after treatment. In the present study, we compared collagen deposition and the extent of depletion and reconstitution of total CD4+ cells and subsets in peripheral blood, lymph nodes, and inductive and effector sites in GALT. We show that CD4+ cell depletion in GALT correlates with the rapidity and greater magnitude of collagen deposition in this compartment, compared with that in peripheral lymph nodes, and that although treatment does not restore CD4+ cells to effector sites, treatment in the early stages of infection can increase CD4+ central memory cells in Peyer patches. Comment in J Infect Dis. 2008 Aug 15;198(4):453-5. Supplemental Content PLoS Pathog. 2010 Aug 19;6(8):e1001052. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, Barclay GR, Smedley J, Pung R, Oliveira KM, Hirsch VM, Silvestri G, Douek DC, Miller CJ, Haase AT, Lifson J, Brenchley JM. Source AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA. [email protected] Abstract The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4(+) T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication. Supplemental Content Curr HIV/AIDS Rep. 2010 Nov;7(4):226-33. Alcohol and HIV disease progression: weighing the evidence. Hahn JA, Samet JH. Source Division of Infectious Diseases, Department of Medicine, San Francisco General Hospital, University of California-San Francisco, San Francisco, CA 94143-0811, USA. [email protected] Abstract Heavy alcohol use is commonplace among HIV-infected individuals; however, the extent that alcohol use adversely impacts HIV disease progression has not been fully elucidated. Fairly strong evidence suggests that heavy alcohol consumption results in behavioral and biological processes that likely increase HIV disease progression, and experimental evidence of the biological effect of heavy alcohol on simian immunodeficiency virus in macaques is quite suggestive. However, several observational studies of the effect of heavy alcohol consumption on HIV progression conducted in the 1990s found no association of heavy alcohol consumption with time to AIDS diagnosis, while some more recent studies showed associations of heavy alcohol consumption with declines of CD4 cell counts and nonsuppression of HIV viral load. We discuss several plausible biological and behavioral mechanisms by which alcohol may cause HIV disease progression, evidence from prospective observational human studies, and suggest future research to further illuminate this important issue. Supplemental Content