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Interferon-gamma-induced downregulation of CD4 inhibits the entry of human immunodeficiency virus type-1 in primary monocytes.

Laboratory of Molecular Virology, Food and Drug Administration, Rockville, Md., USA.
Pathobiology (Impact Factor: 2.48). 02/1995; 63(2):93-9.
Source: PubMed

ABSTRACT

We have previously shown that the treatment of monocytes with interferon-gamma (IFN-gamma) 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(s) underlying IFN-gamma-induced inhibition of HIV infection of monocytes. To examine the effect of IFN-gamma on HIV entry, the first event in the infectious cycle of the virus, we amplified HIV-gag sequences in the genomic DNA and RNA of IFN-gamma 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-gamma-treated monocytes after their exposure to HIV. Stimulation of IFN-gamma-treated monocytes 6 days postinfection with tumor necrosis factor-alpha (TNF-alpha), 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-gamma-treated monocytes. Treatment of monocytes with IFN-gamma, TNF-alpha, 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-gamma to be independent of NO2(-)-mediated killing of HIV or HIV-infected monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

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    • "Finally, only IFN-γ exhibited full antiviral properties by decreasing both susceptibility and virus spread in macrophage cultures. Several groups have reported the inhibitory effect of IFNγ on HIV infection or replication (Denis and Ghadirian, 1994; Dhawan et al., 1995; Emilie et al., 1992; Fan et al., 1994; Hammer et al., 1986; Hartshorn et al., 1987; Kornbluth et al., 1989, 1990; Koyanagi et al., 1988). Some controversies remain in the literature, but it can be reminded that most of the studies that showed a positive effect of IFN-γ on HIV replication were not performed using primary human macrophages (Biswas et al., 1992; Han et al., 1996; Vyakarnam et al., 1990) that may explain these discrepancies. "
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    ABSTRACT: Macrophages are pivotal for the regulation of immune and inflammatory responses, but whether their role in HIV infection is protective or deleterious remains unclear. In this study, we investigated the effect of pro- and anti-inflammatory stimuli on macrophage sensitivity to two different aspects of HIV infection: their susceptibility to infection stricto sensu, which we measured by endpoint titration method, and their ability to support virus spread, which we measured by using an RT activity assay in infection kinetics. We show a partially protective role for pro-inflammatory agents as well as for IL-4. We also illustrate that various different stimuli display differential effects on macrophage susceptibility to HIV and on virus replication that occurs thereafter. On the other hand, HIV replication strongly repressed CD206 and CD163 expression, thus clearly orientating macrophages towards a pro-inflammatory phenotype, but independently of TNF. Taken together, our results emphasize that HIV infection of macrophages sets up inflammation at the cell level but through unexpected mechanisms. This may limit target susceptibility and participate in virus clearance but may also result in tissue damage.
    Full-text · Article · Jun 2006 · Virology
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    • "These include blockade of viral genome nuclear integration, augmented b-chemokine secretion, and reduced CCR-5 coreceptor expression [20, 21, 49, 50] . Another possible early event affected by IL-18 includes modulation of the HIV-1 receptor CD4 expression, since previous reports showed that HIV-1 inhibition by exogenous IFN-g involved down-regulation of CD4 expression [39, 51, 52]. Using flow cytometry analysis, we showed that IL-18 reduced cell surface expression of CD4 in the PBMC. "
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    ABSTRACT: Interleukin (IL)–18 is an interferon (IFN)–γ-inducing factor and contributes to the Th1 immune response. IL-18 added after infection of peripheral blood mononuclear cells (PBMC) with monocyte-tropic human immunodeficiency virus type 1 (HIV-1) inhibited p24 antigen production by a maximum of 72%. IFN-γ levels in these cultures were increased, and a significant inverse relationship between HIV-1 production and IFN-γ levels was observed. A neutralizing anti–IFN-γ antibody reversed the IL-18 inhibitory effect. Preincubation of PBMC with IL-18 before infection inhibited p24 without additional IL-18 (64%). However, compared with the degree of IL-18 inhibition observed after a 4-day culture, no additional IL-18 inhibitory effect was observed during days 5–13. IL-18 also reduced cell surface expression of the HIV-1 receptor CD4. These results demonstrate that IL-18 inhibited HIV-1 production in PBMC through intermediate IFN-γ. Furthermore, inhibition was present during the early stages of viral infection and was associated with reduced HIV-1 receptor expression
    Preview · Article · Oct 2001 · The Journal of Infectious Diseases
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