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100 Fcgamma-Mediated Suppression of HIV-1 Infection in Macrophages
D. Perez-Bercoff*, A. David, F. Barré-Sinoussi, and G. Pancino
Unité de Biologie des Rétrovirus, Inst. Pasteur, Paris, France
Background: Cells of the monocyte/macrophage lineage are thought to play a crucial role in HIV-1 persistence and propagation. The state of differentiation of these cells and their activation level directly modulate their susceptibility to HIV-1 infection. Activation of monocytes by exogenous stimuli, such as bacterial lipopolysaccharides (LPS), has been shown to increase viral transcription in vitro. On the contrary, viral replication is strongly inhibited in macrophages upon activation by LPS as well as by some cytokines. In vivo, a low susceptibility of intestinal macrophages to HIV-1 infection has been suggested to be related to high concentrations of LPS in tissue environment. The impact of naturally occurring stimuli, such as circulating immune complexes, on HIV-1 infection of macrophages still needs to be clarified.
Methods: We addressed this issue in a model of macrophage activation by Fc receptors to IgG (FcgammaR), stimulating monocyte-derived-macrophages (MDM) with immobilized human IgG (hIgG).
Results: Infection of MDM with monocytotropic (R5) HIV-1 strains is strongly suppressed upon FcgammaR-activation. FcgammaR cross-linking with human or goat IgG, but not with human or goat IgG F(ab)2 fragments, inhibits HIV-1 replication, indicating that this inhibition is mediated by the Fc portion of IgG. HIV-1 infection was not only suppressed in preactivated MDM, but also in MDM activated after infection. The inhibition induced by FcgammaR cross-linking is observed with both HIV-1 virions pseudotyped with HIV-1 R5 envelopes and VSV-G as well. This suggests that, at least in the first round of infection, a post-entry mechanism might be involved in the inhibition of HIV replication. PCR analysis of viral DNA forms confirmed this hypothesis and indicated that neither reverse transcription nor nuclear translocation of viral DNA is restricted.
Conclusions: Our findings support the hypothesis that stimulation of macrophages by immune complexes may result in a control of HIV-1 infection and thus should be considered as a potential mechanism contributing to natural protection against HIV/AIDS, in particular in individuals frequently exposed to multiple infections in the developing world.
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