INTERFERENCE OF INTERLEUKIN-10 WITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION IN PRIMARY MONOCYTE-DERIVED MACROPHAGES

Previously we demonstrated an inhibitory effect of interleukin-4 (IL-4 ) on establishment of human immunodeficiency virus type 1 (HIV-1) infe ction in primary macrophages. The reported similarities between the bi ological effects of IL-4 and IL-10 prompted us to study the effect of IL-10 on HIV-1 replication. Treatment of primary macrophages with IL-1 0 resulted in inhibition of HIV-1 infection. This inhibitory effect wa s specific for macrophages, since IL-10 did not interfere with HIV-1 r eplication in primary T cells. Semiquantitative PCR analysis excluded an inhibitory effect of IL-10 on virus entry and reverse transcription . Effects of IL-10 on HIV-1 long terminal repeat-driven chloramphenico l acetyltransferase activity also could not be demonstrated in a trans ient expression system in primary derived macrophages. In agreement wi th this, Northern (RNA) blot analysis demonstrated equal amounts of vi ral RNA species irrespective of IL-10 treatment, also excluding an inh ibitory effect on elongation of virus transcription. Monocyte derived macrophages (MDM) treated with IL-10 after EW-I inoculation showed acc umulation of apparently mature p24 protein suggestive of an inhibitory effect at the level of virus assembly. IL-10 treatment of MDM prior t o HIV-1 inoculation did not result in accumulation of p24 protein. Imm unoblot analysis indeed showed the absence of mature p24 and gp120 but accumulation of the Pr53 gag encoded protein in HIV-1-inoculated, IL- 10-pretreated MDM, suggesting an inhibitory effect at the level of pro tein processing. A combination of IL-4 and IL-10 resulted in a cumulat ive inhibitory effect on HIV-1 replication in MDM. The recent observat ion that in the course of HIV-1 infection a shift Occurs in the produc tion of IL-2/gamma interferon toward enhanced IL-4 and IL-10 productio n and the reported shift from preferential macrophage-tropic towards p referential T cell-tropic HIV-1 variants with progression of disease s uggest that cytokines have an important role in the in vivo regulation of HIV-1 tropism.