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 SwainsonHaelee AhnPriya PajanirassaVinod KhetarpalClaire DeleageJacob D EstesPeter W HuntIgnacio Munoz-SanjuanJoseph M McCunePublished in: Journal of immunology (Baltimore, Md. : 1950) (2019)
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.
Keyphrases
- antiretroviral therapy
- body weight
- liver failure
- hiv infected
- drug induced
- respiratory failure
- human immunodeficiency virus
- poor prognosis
- hiv aids
- hiv positive
- aortic dissection
- hiv infected patients
- clinical trial
- intensive care unit
- squamous cell carcinoma
- ms ms
- oxidative stress
- hepatitis b virus
- papillary thyroid
- mass spectrometry
- long non coding rna
- endothelial cells
- big data
- electronic health record
- risk factors
- extracorporeal membrane oxygenation
- high glucose
- transcription factor
- newly diagnosed
- young adults
- mechanical ventilation
- stress induced
- smoking cessation
- atomic force microscopy