This proposal will analyze the pathogenicity and evolution of HIV in the lung by comparing expression of chemokines and chemokine receptors in lung mononuclear cell (LMC) with the genotype/phenotype and quasispecies heterogeneity of HIV-1 isolates resident in the lung of HIV-infected patients. Circulating B chemokines levels in the lung, CCR5 expression of LMC, and other organ/cell-specific restrictive factors may influence viral transmission, evolution and selection of a specific viral phenotype [non-syncytium inducing (NSI)/CCR5-topic(RC) vs. Syncytium inducing (SI)/CXCR4-tropic (X4)]. A potential predominance of NSI/R5 HIV-1 isolates in the lung supports the use of CCR5-antagonist- chemokine analog (such as AOP-RANTES) in the treatment of HIV infection in the lung. Treatment of HIV infection in the lung with AOP-RANTES may be most beneficial during active Mycobacterium tuberculosis infection in HIV+ patients since significant increases in viral load, which may originate from the lung, correlates with the onset of TB. All of these issues, i.e. the pathogenicity/ evolution of HIV in the lung and suitable antiretroviral treatment strategies for HIV+ or HIV+/TB+ patients, will be addressed in the following specific aims: 1) To characterize the expression of chemokine and chemokine receptors in lung mononuclear cells of HIV-infected patients, and to determine the envelope genotype and quasispecies heterogeneity of their lung and blood HIV-1 isolates; 2) To compare the virulence/fitness of lung- and blood-derived HIV-1 isolates in lung and blood lymphocytes, and macrophages, and to test the sensitivity and potential resistance of these viral isolates to AOP-RANTES and other chemokine analogs; and 3) To analyze the expression of chemokine circuits and HIV isolates from the blood and pleural mononuclear cells of HIV infected patients with active tuberculosis, and determine the use of chemokine analogs in inhibition of HIV activity.
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