The lung is one of the major organs affected by HIV disease. In early HIV infection, little virus is detectable in lung cells, but in late disease (when there are few remaining CD4 + T cells) the amount of virus in the lung can become substantial. The effect of antiretroviral therapy on HIB replication in the lung is not well understood. This project will study these issues through four aims; (1) By analyzing the quantity of HIV present in bronchoalveolar lavage cells and fluid both before and after treatment with a rapidly acting inhibitor of the viral protease (such as indinavir), measurements of the half-life of the viral genome in the lung will be obtained. Assuming that a steady-state was present prior to therapy, this will allow the calculation of the daily production of virus in the lung in subjects at different stages of HIV disease. (2) By analyzing the sequences of the viral pol region (which includes reverse transcriptase and protease) that is the target of currently available drugs, the evolution of drug resistant mutants in the lung will be studied. By comparing these sequences with those obtained from viral genomes in the blood, it will be possible to estimate the degree to which viral replication on the lung mirrors that in the blood or whether HIV can replicate autonomously in the lung independent of the systemic influences that have a selective effect on viral evolution in the blood. (3) A key to the cellular immune response in the lung is the expression of CD40 ligand (CD40L), which is critical for the control of infections such as Pneymocystis carnii. CD40L induces macrophages to express CD40 and to respond to CD40l will be studied. (4) Finally, the cellular factors (e.g., from CD8 + T cell) and soluble factors present in bronchoalveolar lavage fluid (e.g., SLPO1, chemokines) that suppress HIV replication in the lung will be studied and correlated with the replication of HIV in the lung (from Aim 1 above) system to control HIV replication in the lung will be better understood, and the evolution of HIV in the lung in response to antiretroviral drugs will be defined. The knowledge gained may suggest improved strategies for suppressing HIV replication in the lung utilizing immune modulators and therapeutic agents, which may lead to better control of the pulmonary complications of HIV infections.
