Kynurenine 3-monooxygenase inhibition during acute simian immunodeficiency virus infection lowers PD-1 expression and improves post–combination antiretroviral therapy CD4+ T cell counts and body weight

Louise A. Swainson, Haelee Ahn, Priya Pajanirassa, Vinod Khetarpal, Claire Deleage, Jacob Estes, Peter W. Hunt, Ignacio Munoz-Sanjuan, Joseph M. McCune

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)899-910
Number of pages12
JournalJournal of Immunology
Volume203
Issue number4
DOIs
StatePublished - Aug 15 2019

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Kynurenine 3-Monooxygenase
Simian Immunodeficiency Virus
Virus Diseases
CD4 Lymphocyte Count
Kynurenine
Body Weight
T-Lymphocytes
Infection
Therapeutics
HIV Infections
Immune Reconstitution Inflammatory Syndrome
Physiological Phenomena
T-Lymphocyte Subsets
Cell Body
Macaca mulatta
Viral Load
Primates
Nervous System
Disease Progression
Morbidity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Kynurenine 3-monooxygenase inhibition during acute simian immunodeficiency virus infection lowers PD-1 expression and improves post–combination antiretroviral therapy CD4+ T cell counts and body weight. / Swainson, Louise A.; Ahn, Haelee; Pajanirassa, Priya; Khetarpal, Vinod; Deleage, Claire; Estes, Jacob; Hunt, Peter W.; Munoz-Sanjuan, Ignacio; McCune, Joseph M.

In: Journal of Immunology, Vol. 203, No. 4, 15.08.2019, p. 899-910.

Research output: Contribution to journalArticle

Swainson, Louise A. ; Ahn, Haelee ; Pajanirassa, Priya ; Khetarpal, Vinod ; Deleage, Claire ; Estes, Jacob ; Hunt, Peter W. ; Munoz-Sanjuan, Ignacio ; McCune, Joseph M. / Kynurenine 3-monooxygenase inhibition during acute simian immunodeficiency virus infection lowers PD-1 expression and improves post–combination antiretroviral therapy CD4+ T cell counts and body weight. In: Journal of Immunology. 2019 ; Vol. 203, No. 4. pp. 899-910.
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AU - Ahn, Haelee

AU - Pajanirassa, Priya

AU - Khetarpal, Vinod

AU - Deleage, Claire

AU - Estes, Jacob

AU - Hunt, Peter W.

AU - Munoz-Sanjuan, Ignacio

AU - McCune, Joseph M.

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