Mycobacterium tuberculosis (MTB) is a global infection whose prevalence has increased in part due to HIV infection. Epidemiological data have demonstrated that HIV-infected individuals are more susceptible to MTB infection and disease. Moreover, it has been shown that MTB disease causes an acceleration in the progression of HIV disease. The purpose of this study was to delineate how MTB modulates HIV infection in vivo and in in vitro models, and thus determine whether it is possible to inhibit this MTB-induced HIV replication. We measured plasma viral load, a direct reflection of viral replication in lymphoid tissue, in HIV-infected individuals before, during, and after MTB disease. An increase in the plasma HIV load was noted during the acute phase of MTB disease compared to either before the onset of the disease or after successful treatment. In contrast, no significant decrease in plasma viremia was observed in patients in whom anti-MTB therapy was not successful due to drug resistance of their MTB isolates and/or non-adherence to therapy. To evaluate the mechanisms involved in the MTB-induced augmentation of HIV replication, we studied the virologic and immunologic responses induced by MTB and the constituent antigen PPD (purified protein derivative) in an in vitro system using primary CD8-depleted peripheral blood mononuclear cells (PBMC) and lymph node cells isolated from HIV+, PPD+ donors. We demonstrated that, in this in vitro system, PPD and MTB increased HIV replication, and this effect correlated with an increase in cellular activation and thus in the production of proinflammatory cytokines and beta-chemokines. To evaluate whether it was possible to inhibit PPD- or MTB-induced HIV replication we used several strategies such as specific inhibition of the activity of a single inflammatory cytokine (using soluble cytokine receptors or cytokine receptor antagonists); blocking more than one cytokine pathway using anti-inflammatory cytokines; or exogenous addition of beta- chemokines. We found that anti-inflammatory cytokines are the most consistent inhibitory factors of PPD or MTB-induced HIV replication, whereas neutralization of individual inflammatory cytokines or the exogenous addition of beta-chemokines has variable effects on viral replication. These findings may be important to further understand the pathogenesis of HIV infection and to develop more effective therapy to control disease progression.
