HIV/TB interaction in the lung has focused on regulation of HIV-1 replication in alveolar macrophages (AM), the major source of viral replication in tuberculosis (TB). Work performed in this laboratory has demonstrated: 1) Production of inhibitory C/EBPbeta is an interferon (IFN) effect. It is also induced by other innate immune mediators such as SP-a. Once expressed, inhibitory C/EBPbeta suppresses HIV-1 replication and most proinflammatory cytokine promoters in resting AM. 2) As monocytes differentiate to macrophages, they gain the ability to produce a dominant negative C/EBPbeta transcription factor. 3) During TB, contact between lymphocytes and AM drives high-level HIV-1 replication in AM. Both lymphocyte/AM contact and cytokines are required for maximal LTR activation. Lymphocyte/AM contact down-regulates the dominant negative C/EBPbeta, de-repressing the HIV-1 LTR; while cytokines activate NF-kappaB, stimulating the HIV-1 LTR. 4) In mice, CD40 expression is required for de-repression during sepsis. Preliminary data now demonstrate that PU.1 and CREM are expressed in resting AM but not during TB. Both PU.1 and CREM are transcriptional repressors in other systems. In addition, a subset of AIDS patients with TB demonstrates neutrophil (PMN) predominant inflammation. PMN stimulate HIV-1 replication and mutation in vivo and in vitro. Full induction of HIV-1 replication and LTR function requires PMN contact and soluble factors. Like lymphocytes, PMN express CD40L and CD28. Unlike lymphocytes, PMN express LFA- 1, which binds macrophage ICAM-1, and PMN-derived peroxide is a soluble factor that activates NF-kappaB. PMN contact down-regulates inhibitory C/EBPbeta, CREM and PU. 1 in AM. TB patients have elevated levels of soluble ICAM-1, which recruits CD40L to PMN lipid rafts. Antibodies to CD40L, CD28 and CD11a inhibit the activity of PMN lipid rafts. PMN lipid rafts and cross-linking antibodies to CD40, B7 and ICAM-1 aggregate macrophage CD40, B7 and ICAM-1 and abolish inhibitory C/EBPbeta expression. These data led to the hypothesis that inhibitory C/EBPbeta is one of multiple repressors inhibiting HIV LTR activity in resting AM. Further, PMN are a cellular component of the innate immune response that can de-repress the LTR by cellular contact and activate the LTR by soluble factors. This two-step process contributes to high-level HIV-1 replication in AM during opportunistic infection. This proposal will investigate the role of PU. 1 and CREM as inhibitors of HIV-1 replication in AM and the role of PMN in enhancing HIV-1 replication in the lung.
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