Interferon alfa partially inhibits HIV replication in hepatocytes in vitro.

TO THE EDITOR—Interferons are potent antiviral agents that activate expression of numerous interferon-stimulated genes (ISGs) that also have antiviral properties. Interferon alfa is commonly used to treat chronic hepatitis C virus (HCV) infection, although several viral proteins have been implicated in the inhibition of ISGs and/or key components of interferon signaling pathways [1]. In a recent Journal article, Azzoni et al investigated the antiviral effects of pegylated (Peg) interferon alfa-2a on human immunodeficiency virus (HIV) suppression [2]. Twelve weeks of Peg–interferon alfa-2a monotherapy resulted in sustained suppression of HIV in 45% of patients despite interruption of antiretroviral therapy (ART). Other clinical trials also support an approximately 0.5 log reduction in plasma HIV RNA in patients treated with Peg–interferon alfa-2a in the absence of ART [3–6]. We recently reported that HIV infects hepatocyte-derived cell lines, as well as primary human hepatocytes [7]. Integrated HIV proviral DNA was detected in hepatocytes and was inhibited by the integrase inhibitor raltegravir in a dosedependent manner. HIV p24 protein was also detected in cell culture supernatants and was inhibited by zidovudine. Levels of HIV were modest, compared with those in a lymphocyte cell line, suggesting that low-level viral replication occurs in hepatocytes. Given the in vivo data from Azzoni et al and our in vitro findings, we evaluated whether HIV replication in hepatocytes was limited by interferon and/or ribavirin (RBV). The Huh7.5JFH1 cell line, which produces infectious HCV virions [8], was infected with the NL4–3 isolate of HIV as described previously [7]. Incubation with 0.1, 10, or 1000 ng/mL consensus interferon (Infergen, Three RiversPharmaceuticals [CranberryTownship, PA]) and/or 0.1, 1.0, or 10 μg/mL ribavirin (Roche Laboratories [Nutley, NJ]) was performed 1 day before and during HIV infection. At day 3, HIV p24 and HCV core proteins were quantified in cell culture supernatants by enzymelinked immunosorbent assays with lower limits of detection of 4.3 pg/mL (PerkinElmer [Boston, MA]) and 1 ng/mL (Cell Biolabs [San Diego, CA]). As shown in Figure 1, there was a modest dose-response effect of RBV on HIV replication in hepatocytes, resulting in 10.4%, 25.3%, and 37.5% inhibition at RBV doses of 0.1, 1.0, and 10 μg/mL, respectively. Interferon treatment at doses of 0.1, 10, and 1000 ng/mL inhibited HIV replication by 3.7%, 38.5%, and 45.2%, respectively. The combination of RBV plus interferon inhibited HIV replication in