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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