Characterization of the alpha interferon-induced postentry block to HIV-1 infection in primary human macrophages and T cells.
Type I interferon (IFN) inhibits virus replication by activating multiple antiviral mechanisms and pathways. It has long been recognized that alpha interferon (IFN-alpha) can potently block both early and late stages of HIV-1 replication. The mechanistic basis for the early block(s) to infection is unknown, as is the identity of the participating antiviral factor(s). Here, we define the effect(s) of IFN-alpha on HIV-1 infection of primary human macrophages and CD4(+) T cells, as well as several monocytic and T-cell lines. We demonstrate that IFN-alpha treatment of macrophages, THP-1 cells, and, to a lesser extent, primary CD4(+) T cells markedly inhibits infection, whereas the effects are minimal in CD4(+) T-cell lines. Virus entry is essentially unaffected by IFN-alpha, but substantial decreases (sometimes >99%) in nascent cDNA accumulation correlate closely with losses in infectivity. Interestingly, proteasome inhibitors rescue viral cDNA accumulation, revealing a link between the ubiquitin-proteasome system and IFN-alpha-induced viral restriction. We also found that diverse primate and nonprimate retroviruses were susceptible to suppression by IFN-alpha. Importantly, all the primary and immortalized cells used here are proficient at responding to IFN-alpha, as judged by the induced expression of numerous IFN-stimulated genes, including PKR and OAS1, indicating that a general deficiency in IFN-alpha responsiveness does not underlie IFN-alpha's inability to elicit an antiviral state in CD4(+) T-cell lines. Rather, we speculate that IFN-alpha fails to induce antiretroviral factors in these cells and that comparative transcriptional profiling with responsive cells, such as macrophages, invokes a strategy for identifying new host-encoded antiviral effectors.
Goujon
Caroline
C
Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom.
Malim
Michael H
MH
D002478:Cells, Cultured; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D009000:Monocytes / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*
D016898:Interferon-alpha