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 language | English (US) |
|---|---|
| Pages (from-to) | 899-910 |
| Number of pages | 12 |
| Journal | Journal of Immunology |
| Volume | 203 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 15 2019 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Swainson, Louise A.
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.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070390565&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070390565&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1801649
DO - 10.4049/jimmunol.1801649
M3 - Article
C2 - 31285277
AN - SCOPUS:85070390565
VL - 203
SP - 899
EP - 910
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -