Regulation of HIV-1 expression by cytokine networks in a CD4+ model of chronic infection.
Using the CD4+ model of chronic HIV-1 infection, OM-10.1, we investigated the influence of TNF-alpha regulatory networks on induced viral expression. Previously, OM-10.1 cultures were characterized to respond to exogenous TNF-alpha, as nearly 100% of the cells were activated to express HIV-1 within 24 h. In this study, OM-10.1 cells were pulse-treated, by applying exogenous factors for short periods of time and then washing, to determine if autocrine TNF-alpha could sustain HIV-1 activation in the absence of additional exogenous stimulation. After a TNF-alpha pulse treatment, the progressive increase of HIV-1-expressing OM-10.1 cells was prevented by the continuous presence of anti-TNF-alpha mAb. The inductive activity of supernatant from TNF-alpha pulse-treated OM-10.1 cultures was completely removed by absorption on immobilized anti-TNF-alpha mAb. In addition, TNF-alpha pulse-treated OM-10.1 cells activated HIV-1 expression in untreated OM-10.1 cells when cultured across a permeable membrane indicating paracrine effects. Interestingly, if TNF-alpha pulse-treated OM-10.1 cells were further pulse-treated with anti-TNF-alpha mAb, a marked reduction in autocrine TNF-alpha was observed although the level of newly synthesized TNF-alpha mRNA remained unaffected. A similar degree of inhibition over autocrine TNF-alpha production was observed when soluble TNF receptors were used as the second pulse treatment in these experiments. Although the applicability of these results to in vivo chronically HIV-1-infected cells remains to be realized, these results do indicate that activated HIV-1 expression can be influenced by self-perpetuating mechanisms during periods of limited exogenous stimulation. Furthermore, physiologic mechanisms involving soluble cytokine receptors that counteract autocrine and paracrine activation of HIV-1 expression are shown here to play a regulatory role.
Retrovirus Diseases Branch, Centers for Disease Control, Atlanta, GA 30333.
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Roberts
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis*; D005434:Flow Cytometry; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014775:Virus Activation
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha