This program supported basic research on the effects of HIV-1 infection on alveolar macrophages and on immune defenses in the lung. Grantees looked at changes in alveolar macrophage function that occur with HIV-1 infection and which may explain the high frequency of infectious pulmonary disease in people with AIDS.
Six grants were supported and the program finished in 1994.
R01 HL43523 - Richard Kornbluth - University of California, San Diego, CA
R01 HL43528 - Ofra Weinberger - Columbia University, New York, NY
R01 HL43529 - David Weissman - University of New Mexico, Albuquerque, NM
R01 HL43571 - Elizabeth Rich - Case Western Reserve University, Cleveland, OH
R01 HL43609 - Paul Luciw - University of California, Davis, CA
R01 HL43628 - David Volsky - St. Luke's Inst. for Health Science, New York, NY
Findings from basic studies in this program support the concept that active TB infection may accelerate the course of HIV disease. When blood monocytes from patients with active TB were infected with HIV, in vitro, the virus replicated more rapidly in these monocytes than in monocytes from matched healthy PPD (a skin test for TB-reactive donors). The increased production of HIV is thought to result from activation of the monocytes by exposure to TB and its products and appeared to be modulated by tumor necrosis factor-alpha. These data support other clinical data from the Pulmonary Complications of HIV Infection study, where more than 50 percent of the patients infected with both HIV and TB have died, despite the fact that none were classified as having AIDS. The potentially adverse impact of smoking cigarettes on the expression of HIV disease in the lung was suggested by an extremely high growth, in vitro, of HIV in alveolar macrophages from smokers compared to nonsmokers. It is likely that smoking cigarettes increases the viral load in the lung by enhancing the production of HIV by alveolar macrophages. The mechanism is yet to be determined; the effect could not be attributed to increased uptake of virus, to changes in the initiation of reverse transcription, or to increased production of tumor necrosis factor.
Another area of investigation within this program focused on understanding viral tropism for alveolar macrophages. Study of macrophage-tropic strains of HIV provided clues about their ability to replicate in macrophages more effectively than in lymphocytes. The process of HIV DNA entry into the nucleus of infected cells has been implicated as one determinant of efficient replication. Nuclear entry appeared to be dependent on the production of a circular form of the DNA in the host cell during infection. When macrophages were infected with either lymphocyte or macrophage tropic strains, the circular DNA was seen only in the infected macrophages. Results of other researchers in this program using cells from non-human primates for in vitro studies indicate that the env gene does not appear to play a significant role in cell tropism.