Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection

Hsu, Denise C.; Sereti, Irini

doi:10.1007/s40265-016-0546-7

Cited by 69 publications

(48 citation statements)

References 241 publications

(216 reference statements)

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“…The direct influence of dysbiosis, microbiota by-products, epithelial barrier and local immune response will need further studies to define their distinctive role on systemic inflammation and subsequent development of non-AIDS comorbidities. Cardiovascular disease, DM, liver steatosis, neurocognitive disorders and cancer represent the most frequent manifestations of non-AIDS comorbidities, which represent a new frontier in the management of PLWH in today's medical practice (19)(20)(21). Thus, in addition to ART, strategies to improve the gut microbial composition and intestinal barrier function are emerging as a research priority.…”

Section: Introductionmentioning

confidence: 99%

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

et al. 2020

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Section: Introductionmentioning

confidence: 99%

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

et al. 2020

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“…Its persistence during effective anti-retroviral therapy (ART) predicts mortality and is associated with a number of co-morbidities (e.g. cardiovascular disease, neurocognitive dementia) linked to chronic immune activation and inflammation[15-17]. …”

Section: Introductionmentioning

confidence: 99%

The gut microbiome and HIV-1 pathogenesis

Dillon

Frank²,

Wilson³

2016

Aids

139

127

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HIV-1 infection is associated with substantial damage to the gastrointestinal (GI) tract resulting in structural impairment of the epithelial barrier and a disruption of intestinal homeostasis. The accompanying translocation of microbial products and potentially microbes themselves from the lumen into systemic circulation has been linked to immune activation, inflammation, and HIV-1 disease progression. The importance of microbial translocation in the setting of HIV-1 infection has led to a recent focus on understanding how the communities of microbes that make up the intestinal microbiome are altered during HIV-1 infection and how they interact with mucosal immune cells to contribute to inflammation. This review details the dysbiotic intestinal communities associated with HIV-1 infection and their potential link to HIV-1 pathogenesis. We detail studies that begin to address the mechanisms driving microbiota-associated immune activation and inflammation and the various treatment strategies aimed at correcting dysbiosis and improving the overall health of HIV-1 infected individuals. Finally, we discuss how this relatively new field of research can advance to provide a more comprehensive understanding of the contribution of the gut microbiome to HIV-1 pathogenesis.

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“…The SIV-associated chronic immune activation is characterized by uncontrolled lymphocyte proliferation, aberrant production of proinflammatory cytokines (i.e., tumor necrosis factor [TNF] and interferon gamma [IFN-␥]), high levels of lymphocyte apoptosis, and irreparable damage to the architecture of lymphoid tissues (2). While HIV-associated immune activation and inflammation are decreased when patients are placed on long-term antiretroviral therapy (ART), the overall levels of immune activation remain higher than those observed in non-HIV-infected age-matched individuals (3)(4)(5)(6). While the causes of HIV/ SIV-associated immune activation are complex and not fully understood, comparative studies of pathogenic SIV infection of macaques and nonpathogenic SIV infection of natural hosts (e.g., sooty mangabeys [7] and African green monkeys [8]) point to chronic activation of the type I interferon (IFN-I) pathway as a potential major contributor to the chronic immune activation that leads to AIDS progression.…”

mentioning

confidence: 99%

Reduced Chronic Lymphocyte Activation following Interferon Alpha Blockade during the Acute Phase of Simian Immunodeficiency Virus Infection in Rhesus Macaques

Carnathan

Lawson

et al. 2018

J Virol

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Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection of humans and rhesus macaques (RMs) induces persistently high production of type I interferon (IFN-I), which is thought to contribute to disease progression. To elucidate the specific role of interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIV infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4 T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α decreased the levels of activated CD4 and CD8 T cells, as well as B cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-α-blockaded animals supports the hypothesis that IFN-α signaling contributes to lymphocyte activation during SIV infection and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals. Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system.

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Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection

Cited by 69 publications

References 241 publications

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

The gut microbiome and HIV-1 pathogenesis

Reduced Chronic Lymphocyte Activation following Interferon Alpha Blockade during the Acute Phase of Simian Immunodeficiency Virus Infection in Rhesus Macaques

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