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Kynurenine 3-monooxygenase inhibition during acute SIV infection lowers PD-1 expression and improves post-cART CD4+ T cell counts and body weight
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July 08 2019
Source: J Immunol. 203(4):899-910
Details:
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Alternative Title:J Immunol
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Description:The kynurenine pathway (KP) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. In HIV infection, KP activity is consistently associated with reduced CD4 T cell counts and elevated levels of T cell activation and viral load; it also independently predicts mortality and morbidity from non-AIDS events. Kynurenine 3-monooxygenase (KMO) is a therapeutically important target in the KP. Using the nonhuman primate model of SIV infection in rhesus macaques, we investigated whether KMO inhibition could slow the course of disease progression. We used a KMO inhibitor, CHDI-340246, to perturb the KP during early acute infection and followed the animals for 1 y to assess clinical outcomes and immune phenotype and function during pre-combination antiretroviral therapy acute infection and combination antiretroviral therapy-treated chronic infection. Inhibition of KMO in acute SIV infection disrupted the KP and prevented SIV-induced increases in downstream metabolites, improving clinical outcome as measured by both increased CD4| T cell counts and body weight. KMO inhibition increased naive T cell frequency and lowered PD-1 expression in naive and memory T cell subsets. Importantly, early PD-1 expression during acute SIV infection predicted clinical outcomes of body weight and CD4| T cell counts. Our data indicate that KMO inhibition in early acute SIV infection provides clinical benefit and suggest a rationale for testing KMO inhibition as an adjunctive treatment in SIV/HIV infection to slow the progression of the disease and improve immune reconstitution.
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Pubmed ID:31285277
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Pubmed Central ID:PMC6684450
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Funding:U19 AI096109/NIAID NIH HHS/National Institute of Allergy and Infectious Diseases Extramural Activities/United States ; P51 OD011092/ODCDC CDC HHS/Office of the Director/United States ; HHSN261200800001C/CCR NIH HHS/Center for Cancer Research/United States ; HHSN261200800001E/NCI NIH HHS/National Cancer Institute/United States
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