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Effects of interferon-α treatment on anti-HIV-1 intrinsic immunity in vivo
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Journal of Virology, published online ahead of print on 23 October 2013
Mohamed Abdel-Mohsen1,4, Xutao Deng2, Teri Liegler1, John C. Guatelli35 , Mohamed S. Salama4, Hussam El-din A. Ghanem4, Andri Rauch5, Bruno Ledergerber66 , Steven G. Deeks1, Huldrych F. Gunthard6, Joseph K. Wong1,7, and Satish K. Pillai1, 2, 7, 8
9 Department of Medicine, University of California San Francisco, San Francisco,
10 California, United States of America; 11 Blood Systems Research Institute, San Francisco, California, United States of America; 12 University of California San Diego, La Jolla, California, United States of America; 13 Faculty of Science, Ain Shams University, Cairo, Egypt; 14 Department of Infectious Diseases, Bern University Hospital and University of Bern, 15 Switzerland; 16 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 17 University of Zurich, Zurich, Switzerland; 18 Department of Medicine, San Francisco Veterans Affairs Medical Center, San 19 Francisco, California, United States of America.
"The antiretroviral activity of IFN-a was demonstrated in vitro soon after the discovery of HIV-1 (3), and several studies have reported that exogenous IFN-a treatment potently suppresses HIV-1 in vivo (4-8). Moreover, IFN-a therapy was recently associated with significant reduction in the size of the HIV-1 latent reservoir (9), suggesting that interferon-associated pathways may be exploited to achieve HIV-1 eradication. In this study, we perform a comprehensive analysis of the effects of exogenous IFN-a treatment on all as yet established anti-HIV-1 host restriction factors and HIV-1 viremia in vivo."
ABSTRACT
Interferon-α suppresses HIV-1 replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of interferon-α/ribavirin treatment (IFN-α/riba) on 34 anti-HIV-1 restriction factors in vivo. Several anti-HIV-1 restriction factors were significantly induced by IFN-α/riba in HIV/HCV-coinfected individuals. Fold-induction of cumulative restriction factor expression in CD4+ T cells was significantly correlated with viral load reduction during IFN-α/riba (r2=0.649; p<0.016). Exogenous interferon-α induces supraphysiologic restriction factor expression, associated with a pronounced decrease in HIV-1 viremia.
ABSTRACT
Interferon-α suppresses HIV-1 replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of interferon-α/ribavirin treatment (IFN-α/riba) on 34 anti-HIV-1 restriction factors in vivo. Several anti-HIV-1 restriction factors were significantly induced by IFN-α/riba in HIV/HCV-coinfected individuals. Fold-induction of cumulative restriction factor expression in CD4+ T cells was significantly correlated with viral load reduction during IFN-α/riba (r2=0.649; p<0.016). Exogenous interferon-α induces supraphysiologic restriction factor expression, associated with a pronounced decrease in HIV-1 viremia.
These data support the concept that the induction of particular intrinsic immune
mechanisms may constitute a promising antiretroviral strategy, complementing our previous in vitro work (21) and our translational studies of restriction mechanisms in HLA-B*57-positive individuals (22) and HIV-1 elite controllers (11).
Several recent reports have rejuvenated interest in deciphering the molecular pathways associated with the antiviral effects of IFN-a (6, 7, 9, 14-16). In particular, two recent reports on LCMV infection suggest that IFN-a is associated with both beneficial and detrimental disease outcomes, and the overall balance between the various, diverse effects of type I interferon ultimately determines the course of disease (14, 15). This is mirrored in studies of interferon within the context of HIV-1 infection, whereby IFN-a is known to induce several antiretroviral mechanisms that suppress viral replication, but may result in poor disease outcomes due to association with T cell activation and inflammation (17-19). Taken together, these observations suggest that additional work needs to be performed to dissect interferon-associated molecular pathways to identify critical antiretroviral mechanisms and to avoid possible pro-inflammatory consequences.
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