Tuberculosis (TB) is the most common co-infection during HIV-1 worldwide, and is associated with significant HIV-related morbidity and mortality. In dually infected subjects, HIV load and heterogeneity are increased both locally and systemically. Mycobacterium tuberculosis (MTB) infection supports HIV replication and dissemination through dysregulations of host cytokines, chemokines and their receptors. Host molecules such as TNFalpha and MCP-1 and TGF-beta sites of MTB infection induce HIV-1 replication in mononuclear cells in part through activation of nuclear factor kappaB. The regulatory component of host P-TEF-beta (Cyclin T1), which is critical to HIV tat activity is inducible in macrophages by bacterial LPS, and therefore its activation during co-infections such as TB. Furthermore, MTB activates alveolar macrophages from HIV-infected subjects with latent HIV-1 infection to viral expression. In addition, the expression of CCR5 is upregulated on macrophages at sites of MTB infection. Furthermore, the concentrations of the HIV- 1 inhibitory chemokines are limited during TB and at sites of MTB infection. The Hypothesis of this proposal is that MTB induces HIV transcription in macrophages by upregulation of P-TEF-[3, and that host molecules produced by macrophages at sites of MTB infection (TNF-alpha, MCP-1, and TGF-beta) are conducive to transcriptional activation of HIV, and antiretroviral therapies are able to contain viral expression from macrophages during HIV/TB.
The Specific Aims are: 1) To determine the basis of transcriptional activation of HIV by MTB in mononuclear phagocytes; to examine the role of activation of P-TEF-I], and transcription factors in augmentation of HIV by MTB in alveolar macrophages and monocytes; 2) To determine mechanisms of transcriptional activation of HIV operative at sites of active MTB infection in HIV/TB patients with pleural TB, and to assess the role of excess cytokines and chemokines in viral production, and the role of new rounds of HIV infection in enhanced HIV activity in situ; 3) To determine whether HIV viral set point, viral heterogeneity, frequency of latently and productively infected CD4 cells and release of virions by macrophages are effectively controlled by antiretroviral therapy during HIV/TB.
In Aim 1, molecular assays will be applied to assessment of transcriptional activation of HIV in human alveolar macrophages obtained from healthy subjects. Mononuclear cells from HIV/TB patients with pleural TB will be used as a model of interaction of these two 9athogens at sites of active TB (Aim 2). For purposes of Aim 3, HIV/TB patients with pulmonary TB enrolled in a placebo-controlled trial of ARV will be assessed longitudinally.
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