[The mechanism of HIV replication at the site of inflammation coinfected with HIV and M. tuberculosis]

Abstract

HIV-1 replication is remarkably augmented in macrophages at the site of inflammation due to tuberculosis. Reduction of expression of an inhibitory C/EBP beta transcription factor and activation of NF-kappa B are observed at the site of inflammation. Of 18 paraffin embedded tissue sections of HIV-tuberculosis coinfected autopsy or biopsy samples, 9 samples were positive for HIV-p24 staining, which were all derived from patients with blood CD4 cell counts more than 50/mm3. Moreover, the P24 positive cells were morphologically macrophages or epithelioid cells. CD4 positive lymphocytes consistently located near the P24 positive macrophages. Therefore, we hypothesized that lymphocyte-macrophage contact is important for maximal HIV production from macrophages. In vitro experiments showed that contact between lymphocytes and macrophages reduced inhibitory C/EBP beta, activated NF-kappa B and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappa B was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappa B was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed costimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappa B, further enhancing the HIV-LTR.