title: Inteleukin-23 promotes interferon-α responsiveness in hepatitis C virus/HIV-coinfected patients.
abstract: Patients coinfected with HIV and hepatitis C virus (HCV) have poor to modest rates of response with interferon-based therapies, which remain a backbone of the treatment in HIV/HCV-coinfected patients. The mechanisms responsible for poor responsiveness to interferon are not well described. In this study a targeted proteomic analysis of plasma from 42 patients infected with both HIV and HCV and undergoing therapy for HCV with peginterferon and ribavirin was performed. Higher baseline plasma levels of interleukin (IL)-23 were associated with sustained virologic response. Further investigation of how IL-23 facilitates interferon (IFN) responsiveness, as evidenced by a >2-fold increase in most interferon-stimulated genes (ISGs), revealed that IL-23 indirectly enhances IFN signaling in peripheral blood mononuclear cells and HCV continuous culture system by preventing the down-regulation of the IFNAR2 receptor after exposure to IFN-α. These findings suggest a unique role of the IL-23 pathway in enhancing host response to type I interferons, thereby facilitating eradication of HCV. Low levels of IL-23 present in plasma of nonresponders may reflect an impaired immune state that in the case of HIV/HCV-coinfected subjects could potentially lead to disruption of TH17 CD4(+) T cells. This study suggests a major role for HIV-associated immune dysregulation present in HIV-infected subjects that subsequently determines the overall responsiveness to exogenous interferon-α-based HCV therapy.
authors.affiliation: 1 Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases , Bethesda, Maryland.
authors.forename: Madeline
authors.initials: M
authors.lastname: Odigie
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.forename: Lisa
authors.initials: L
authors.lastname: Barrett
authors.forename: Kerry
authors.initials: K
authors.lastname: Townsend
authors.forename: Honghui
authors.initials: H
authors.lastname: Wang
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Suffredini
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000150:complications*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D053759:Interleukin-23 / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D053633:Receptor, Interferon alpha-beta / Q000096:biosynthesis; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D053759:Interleukin-23; D053633:Receptor, Interferon alpha-beta; D012254:Ribavirin