High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection

George, Michael; Sankaran, Sumathi; Reay, Elizabeth; Gelli, Angela C; Dandekar, Satya

doi:10.1016/s0042-6822(03)00207-1

Cited by 65 publications

(85 citation statements)

References 28 publications

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“…Indeed, patients with heightened LPS levels showed substantially accelerated disease progression, with a median time to clinical event of 1.5 years, versus 4 years for patients with lower levels (41). As a possible complement to these findings, previous data strongly suggested a correlation between intestinal immune dysfunction and intestinal functionality, as suggested both by gene expression profiling that associated gut CD4 ϩ T-cell depletion with downregulated expressions of genes involved in mucosal function (110,111) and by earlier clinical data on malabsorption and nutritional complications in SIV-infected RM (111) and HIV-infected humans (112). Along the same lines, a nested-control study from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial by Sandler et al reported that plasma levels of sCD14 are independent predictors of overall mortality in HIV disease (37).…”

Section: Clinical Implications Of Microbial Translocation In Hiv Disementioning

confidence: 88%

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

2013

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SUMMARYIn pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species.In vivostudies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4+depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Directin situevidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.

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Section: Clinical Implications Of Microbial Translocation In Hiv Disementioning

confidence: 88%

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

2013

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“…4B) in intestinal mucosa that are required for normal maturation of enterocytes. In the SIV model, multiple growth factors as well as genes mediating intestinal epithelial (enterocyte) repair and regeneration have been shown to be dysregulated in GALT during primary acute and chronic stages of infection (6)(7)(8)(9)(10). Moreover, SIV-infected macaque studies have demonstrated impaired nutrient digestive and adsorptive functions during primary SIV infection (6).…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was isolated from the tissue samples, and double-stranded cDNA was synthesized as described (8). Biotin-labeled cRNA was hybridized with Affymetrix U95Av2 GeneChips.…”

Section: Methodsmentioning

confidence: 99%

Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors

Sankaran

Guadalupe

Reay

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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140

126

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Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4 ؉ T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4 ؉ T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4 ؉ T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.

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“…We inoculated four macaques (MK3, MK4, MK6 and MK10) intravenously with previously titrated frozen stocks of SIV mac251. We determined plasma viral loads as previously described 49 . Macaques were pre-anesthetized with ketamine (10 mg/kg; Parke- NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Davis), followed by placement of an endotracheal tube and maintenance of the anesthesia with isofluorane.…”

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confidence: 99%

Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

Raffatellu

Santos

Verhoeven

et al. 2008

Nat Med

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510

557

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Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (T H 17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by T H 17 responses, including the expression of interleukin-17 (IL-17) and IL-22. T H 17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted T H 17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract. A.G. served as consultant for the presentation of NTS bacteremia in African subjects. J.K.K. served as collaborator on studies with Il17ra −/− mice and provided useful comments on the experimental design. S.D. designed and supervised the SIV infections of rhesus macaques, blood sample scheduling, macaque protocols, processing and cell isolations for flow cytometry and DNA microarray analyses. A.J.B. was responsible for the experimental design and supervision of mouse studies, ligated ileal loop experiments in rhesus macaques, macaque protocols and analysis of host responses to Salmonella infection. A.J.B. collected tissue during the ligated ileal loop surgery and was responsible for the final manuscript preparation. A.J.B. and S.D. provided financial support for the study and equally contributed to the experimental design, supervision and data interpretation. Although nontyphoidal Salmonella serotypes (NTS) are common agents causing acute foodborne disease worldwide, it is unusual to isolate them from the blood of adults, because in immunocompetent individuals these pathogens remain localized to the intestine and cause a self-limiting gastroenteritis 1 . However, in people with underlying immunosuppression, NTS may spread beyond the intestine and reach the bloodstream, a serious complication known as NTS bacteremia2. The rise in the number of people with AIDS in sub-Saharan Africa has led to a dramatic increase in the frequency of NTS bacteremia3. In marked contrast to the pre-AIDS era4, NTS is currently a leading cause of hospital admission of adults and among the most common bacterial blood isolates from hospitalized adults in sub-Saharan Africa5, the vast majority of whom are HIV positive 3 . NTS infection in HIV-positive African adults is associated with high acute mortality rates (47%) 6 . Although the occurrence of NTS bacteremia in HIV-positive people is well documented, there are no reports inv...

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High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection

Cited by 65 publications

References 28 publications

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors

Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

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