|Title / Titel||Antiviral role of APOBEC3 in HIV/HCV coinfected patients: survey of peginterferon-treated individuals in the SHCS|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||Background: The goal of this research proposal is to investigate the effects of elevated APOBEC3 expression on HIV-1 in vivo. The human cytidine deaminases APOBEC3G and APOBEC3F serve as innate antiviral defense mechanisms by introducing C-to-U changes in the minus strand DNA of retroviruses during replication (resulting in G-to-A mutations in the genomic sense strand sequence). The HIV-1 genome, however, encodes the 23 kilodalton protein Vif (virion infectivity factor) which specifically counteracts this defense by promoting the proteolytic degradation of APOBEC3G and APOBEC3F in the host cell. Consequently, the Vif-APOBEC interaction is emerging as an attractive target for pharmacological intervention. To date, all data describing the manipulation of the Vif-APOBEC interaction have been generated using in vitro model systems. A legitimate evaluation of the therapeutic potential of APOBEC3 will require manipulation of the Vif-APOBEC relationship in vivo.
Study Aims/design: The current standard of treatment for HCV infection is combination therapy with ribavirin and the immunomodulatory cytokine interferon-G (IFN-G). IFN-G treatment strongly induces the expression of APOBEC3 in several tissues and cell types, and typically results in a pronounced reduction in HIV-1 viral load in addition to its intended antiviral effect against HCV. We propose to characterize the antiviral role of APOBEC3 by studying peginterferon-treated HIV/HCV coinfected individuals in the SHCS.
Aim 1: Assess the extent to which IFN-G treatment induces APOBEC3G and APOBEC3F expression in vivo.
Hypothesis 1: APOBEC3G and APOBEC3F expression will be elevated in HIV/HCV coinfected individuals during the peginterferon treatment period.
Aim 2: Characterize the influence of IFN- treatment on the population genetics of HIV-1, focusing on APOBEC3-mediated G-to-A hypermutation.
Hypothesis 2: The frequency of G-to-A hypermutation will be elevated during the peginterferon treatment period as a result of enhanced APOBEC3G and APOBEC3F expression.
|Keywords / Suchbegriffe||HIV-1, APOBEC, Hepatitis C, co-infection, G-to-A hypermutation, interferon gamma,|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|SNF (Personen- und Projektförderung), Others
National Institute of Health
|In collaboration with /
In Zusammenarbeit mit
|Duration of Project / Projektdauer||Nov 2008 to Oct 2010|