Cutting Edge: Experimentally Induced Immune Activation in Natural Hosts of Simian Immunodeficiency Virus Induces Significant Increases in Viral Replication and CD4+ T Cell Depletion

Pandrea, Ivona; Gaufin, Thaidra; Brenchley, Jason M.; Gautam, Rajeev; Monjure, Christopher; Gautam, Aarti; Coleman, Clint A.; Lackner, Andrew A.; Ribeiro, Ruy M.; Douek, Daniel C.; Apetrei, Cristian

doi:10.4049/jimmunol.181.10.6687

Cited by 132 publications

(142 citation statements)

References 14 publications

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“…Microbial translocation occurs during HIV-1 and pathogenic SIV infection but not during SIV infection of natural host species (5), suggesting that microbial translocation may play a role in viral infection and disease progression. Interestingly, intravenous LPS administration in natural host species infected with SIV does induce systemic immune activation, increase SIV replication, and accelerate CD4 + T cell depletion (14). Mutations that result in constitutively activated EGFR are associated with patient responsiveness to small-molecule EGFR inhibitors in lung cancer; however, these mutations are rarely identified in HNSCC or CRC.…”

Section: Discussionmentioning

confidence: 99%

Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

Shan

Siliciano²

2014

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

Shan

Siliciano²

2014

J. Clin. Invest.

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“…Second, both SIV-infected AGM and SM exhibit significantly reduced levels of activated/ proliferating T lymphocytes in the intestinal mucosa compared to those in SIV-infected macaques (78), thus suggesting a central role for local immune activation in dictating generalized mucosal immune dysfunction and microbial translocation, possibly by reducing the functionality of other arms of the immune system. Importantly, the exogenous administration of LPS to SIV-infected AGM results in increased levels of systemic immune activation, thus indicating that an effective preservation of mucosal barrier function is likely to be key to the ability of AGM to maintain low-level immune activation despite high-level viremia (91).…”

Section: Pathogenesis Of Hiv/siv-associated Microbial Translocationmentioning

confidence: 99%

“…Following multiple literature reports that strongly suggested an association between immune activation and microbial translocation parameters in HIV-infected patients (Table 2), two studies demonstrated that the direct administration of LPS in a natural host of SIV (which lacks chronic immune activation and microbial translocation) results in increased immune activation and viral replication (91,92).…”

Section: Microbial Translocation and Immune Activation: What Is The Cmentioning

confidence: 99%

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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“…We previously modeled microbial translocation experimentally by bypassing the intestinal mucosa through intravenous LPS administration to chronically SIV-infected African green monkeys (8,9), which maintain a healthy mucosal barrier, control chronic immune activation, and do not progress to AIDS (10,11). These interventions increased systemic immune activation, viral replication, and hypercoagulability (8,9), consistent with a key role for microbial translocation in the pathogenesis of AIDS.…”

Section: Introductionmentioning

confidence: 99%

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Kristoff¹,

Haret-Richter²,

Ma³

et al. 2014

J. Clin. Invest.

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Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.

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Cutting Edge: Experimentally Induced Immune Activation in Natural Hosts of Simian Immunodeficiency Virus Induces Significant Increases in Viral Replication and CD4+ T Cell Depletion

Cited by 132 publications

References 14 publications

Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

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