Regulation of interferon-α-inducible cellular genes in human immunodeficiency virus-infected monocytes

Abstract

Cellular mechanisms that control susceptibility to opportunistic infection in human immunodeficiency virus (HIV)-infected individuals remain poorly understood. HIV may induce certain cellular genes that restrict HIV replication and protect cells against other superinfecting viral pathogens. Indeed, HIV-infected monocytes resist infection by vesicular stomatitis virus (VSV). HIV-induced VSV interference in monocytes increases with time after HIV infection. Such interference was evident 6 h after HIV infection and reached maximal levels at 14 days. Monocytotropic but not T cell-tropic HIV strains elicited these effects, signaling a requirement for viral entry and/or replication. Viral interference was independent of interferon (IFN) and was unaffected by addition of neutralizing IFN-alpha and -beta antibodies. The well-described IFN-alpha-inducible antiviral pathways were examined to determine their relationship to the cellular mechanism(s) underlying VSV interference. HIV and IFN-alpha both induced the expression of 2-5A synthetase and Mx gene. In contrast, the guanylate-binding protein (GBP), 6-16, and 9-27 cellular genes were up-regulated by IFN-alpha but not HIV. MxA was detected in HIV-infected monocytes but not in uninfected monocytes. The association between Mx expression and resistance to VSV, coupled with previously described anti-VSV activities by human MxA, suggested that Mx may be an effector molecule for the HIV-induced anti-VSV activities. These results, taken together, suggest that HIV can induce antiviral cellular gene expression, independent of IFN.

Unique inflammatory RNA profiles of microglia in Creutzfeldt–Jakob disease

“…Although previous experiments have failed to find active IFN in scrapie (34), up-regulation of IFN-related genes in CJD might involve other factors. This latter type of IFNindependent transcriptional induction has already been noted in monocytes infected with HIV (35); it can also be caused by direct interactions between viral proteins and host transcriptional machinery (36). Conventional viral elements could conceivably be involved in the transcriptional program observed in CJD microglia, given the continued failure of PrP-res to elicit all of the changes associated with infection.…”

Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene

“…Indeed, it had been demonstrated earlier, in a cellular model, that IFN-a inhibited HBV replication by reducing transcription of viral genes driven by the HBV enhancers (Tur-Kaspa et al, 1990). In a previous model, Baca et al (1994) showed that HIV-1 was able to induce expression of antiviral IFN-astimulated genes 29-59 oligo-adenylate synthetase and MxA as a means of protecting cells against other superinfecting viral pathogens (Baca et al, 1994). Such a mechanism may be suggested in an HBV/HDV context, and the effects could be exerted in an autocrine or paracrine manner.…”

The Relationship between Simian Immunodeficiency Virus RNA Levels and the mRNA Levels of Alpha/Beta Interferons (IFN-α/β) and IFN-α/β-Inducible Mx in Lymphoid Tissues of Rhesus Macaques during Acute and Chronic Infection

“…HIV-1 tat can inhibit PKR, an antiviral effector molecule that, like Mx, is induced by IFN-␣/␤ (94). Monocytes from HIV-infected patients can produce Mx after in vitro HIV infection and thereby effectively prevent superinfection of these cells by other viruses without interfering with the replication of HIV (6). It has recently been demonstrated that Mx had no inhibitory effect on the replication of another complex human retrovirus (90).…”

“…Furthermore, expression of IFN-␣/␤ is transient, while Mx continues to be expressed after IFN-␣/␤ are no longer detectable (53,54). In addition, Mx can be induced independently of IFN-␣/␤ in monocytes isolated from HIV-1-infected patients (6). In fact, viral proteins alone, in the absence of viral replication, can induce Mx (43,52).…”