We have previously shown that the treatment of monocytes with interferon-γ (IFN-γ) prior to exposure with human immunodeficiency virus type-1 (HIV) results in complete inhibition of HIV infection of monocytes. In the present report, we have extended this study to obtain information on the mechanism) underlying IFN-γ-induced inhibition of HIV infection of monocytes. To examine the effect of IFN-γ on HIV entry, the first event in the infectious cycle of the virus, we amplified WIN-gag sequences in the genomic DNA and RNA of IFN-γ treated monocytes, and found no evidence for the presence of either proviral DNA or HIV RNA sequences. These results were consistent with the absence of intracellular HIV particles either in the latent or actively replicating state as determined by flow-cytometric analysis of these cells. Furthermore, no HIV-induced cytopathic effects, such as multinucleated giant cell formation or cell death, were observed in IFN-γ-treated monocytes after their exposure to HIV. Stimulation of IFN-γ-treated monocytes 6 days postin-fection with tumor necrosis factor-α (TNF-α), which is known to augment HIV replication in the infected cells, did not result in the induction of the HIV indicating the absence of latent HIV infection in IFN-γ-treated monocytes. Treatment of monocytes with IFN-γ, TNF-α, or with a combination of the two agents which is known to induce antimicrobial free radical nitric oxide (NO2- in the murine system did not induce NO2- production human monocytes suggesting the antiviral activity of IFN-γ to be independent of NO2--mediated killing of HIV or HIV-infected monocytes. Interestingly, CD4 expression on the surface of monocytes was substantially downregulated by IFN-γ treatment, and was directly related to intracellular HIV-p24 levels. These results indicate that IFN-γ-mediated inhibition of HIV infection of monocytes was not due to virus latency or killing of these cells, but was primarily due to down-regulation of CD4 expression resulting in the inhibition of HIV entry into monocytes.

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