HIV-seropositive individuals are at an increased risk for an accelerated form of emphysema. The purpose of this study was to determine the distribution of HIV-1 RNA in lung tissues and correlate this with the histologic findings and expression of matrix metalloproteases (MMPs). Reverse transcriptase (RT) in situ PCR analysis was performed on 11 AIDS lung autopsy specimens which showed varying degrees of emphysematous changes. In each lung, HIV-1 RNA was detected. In areas of histologically normal lung, very rare HIV-1-infected cells were evident. In contrast, many HIV-1-infected cells were noted in areas of emphysema. HIV-1 gag RNA was evident primarily in macrophages; infected pneumocytes were also seen. Similarly, MMP mRNA and protein, primarily MMP-9, localized to the areas of emphysema. Colabeling experiments documented that MMP expression was found primarily in cells that were HIV-1 negative and adjacent to HIV-1-infected macrophages. These results suggest that AIDS-related emphysema may be due, in part, to direct infection by HIV-1 of, primarily, alveolar macrophages, and concomitant up-regulation of MMP expression in the neighboring, noninfected cells.