Regulation of Cytokine and Viral Gene Expression in Monocytes Infected with the Human Immunodeficiency Virus

Abstract

Monocytes treated with interferon-α (IFN-α) at virus challenge show no evidence of human immunodeficiency virus (HIV) infection: no p24 antigen or reverse transcriptase (RT) activity, no viral mRNA and no proviral DNA. Levels of p24 antigen and RT activity in monocytes infected with HIV 1–3 weeks before IFN-α treatment gradually decrease to baseline. HIV-induced cytopathic changes are markedly reduced, as are levels of HIV mRNA: the frequency of productively infected cells is ≤ 1 %. But, levels of proviral DNA in the IFN-α-treated and control HIV-infected cells are indistinguishable, and remain so through 3 weeks. Large quantities of proviral DNA in IFN-α-treated cells with little active transcription suggest true microbiological latency. The major potential source for IFN-α in HIV-infected patients is the macrophage. With any of 15 virus isolates, tumor necrosis factor-α, interleukin-1 β, interleukin-6, IFN-ω or IFN-β are not detected nor the mRNA expressed in HIV-infected or uninfected monocytes. Both uninfected and HIV-infected monocytes produce high levels of these cytokines after treatment with synthetic double-stranded RNA (poly-LC). Uninfected monocytes also produce high levels of IFN-α after treatment with Poly-I:C, Newcastle disease virus or herpes simplex virus. In marked contrast, HIV-infected monocytes express no IFN-α activity or mRNA before or after treatment with any of these agents. The markedly diminished capacity of HIV-infected monocyte to produce IFN-α reflects a specific transcriptional block and may be an adaptive mechanism of virus to alter basic microbicidal functions of this cell. The inevitable result of this HIV-induced cytokine dysregulation is virus replication and persistence in mononuclear phagocytes.

HIV-1 Infection Induces Interleukin-1β Production via TLR8 Protein-dependent and NLRP3 Inflammasome Mechanisms in Human Monocytes

“…We report that HIV-1-induced ROS and cathepsin B were required for the activation of the NLRP3 inflammasome. It has been reported previously that there are no differences in the IL-1␤ pattern in HIV-1-infected versus non-infected monocytes (47)(48)(49). The discrepancy is probably due to the different HIV-1 strains or the lower multiplicity of infection used in previous experiments.…”

Ovine lentivirus is macrophagetropic and does not replicate productively in T lymphocytes

“…Therefore, the reduced virus production may have resulted from inhibition of the development of macrophage precursors into macrophages. Previous studies have shown that lentivirus production in PBMC correlated with development of macrophages in the cultures (16,62), and virus production in these cells is contingent upon transcriptional activation factors that are produced by macrophages but not their precursors (15,55). Both monocytes and dendritic cells in PBMC give rise to phagocytic, adherent macrophages in culture (3, 34,64).…”

Simian Immunodeficiency Virus Infection in the Brain and Lung Leads to Differential Type I IFN Signaling during Acute Infection

“…This pattern has been previously observed in HIV infected monocytes. While they have an impaired ability to produce interferon alpha, production of interferon beta remains normal (20). …”

“…It is thought that this mechanism is responsible for the down regulation of both viral and cytokine gene expression (9). Although the production of interferon beta usually leads to the production of interferon alpha, it has been reported that HIV infected monocytes have a reduced ability to produce interferon alpha while interferon beta levels remain the same (20). This implies that differential interferon signaling patterns may exist, which may not be surprising since interferon alpha and beta have been shown to have different activities, especially in the CNS (21).…”