RANTES INHIBITS HIV-1 REPLICATION IN HUMAN PERIPHERAL-BLOOD MONOCYTESAND ALVEOLAR MACROPHAGES

Infection with human immunodeficiency virus (HIV)-1 most often leads t o the development of acquired immune deficiency syndrome, which may ma nifest with opportunistic infections, many of which occur in the lung. Mononuclear phagocytes infected by HIV-1, being relatively resistant to its cytopathic effects, potentially act as a reservoir for the viru s. The alveolar macrophage (AM), a differentiated lung tissue macropha ge, is readily infected by HIV-1, after which the virus becomes relati vely dormant. C-C chemokines, secreted by CD8(+) T lymphocytes and oth er cells, are known to suppress HIV replication in lymphocytes. In vie w of this observation, and the relative increase in CD8(+) T lymphocyt es during HIV-1 disease, particularly in the lung, we hypothesized tha t C-C chemokines might play a key role in suppressing HIV-1 replicatio n in AM. We examined the effect of the C-C chemokines macrophage infla mmatory protein (MIP)-1 alpha, MIP-1 beta, and regulated on activation normal T cell expressed and secreted (RANTES) singly and in combinati on on HIV-1 replication in peripheral blood monocytes (PBM) and AM inf ected in vitro. Our findings indicate that RANTES suppresses HIV-1 rep lication, as measured by reverse transcriptase activity, in PBM (41.3/-15.2% of control, n=3, P <0.05) and AM (30.3+/-7.8% of control, n=3, P <0.05) in a dose-dependent manner. The other C-C chemokines had no significant effect singly (MIP-1 alpha PBM: 64.8+/-21.9%; AM: 115.0+/- 2.4% of control; MIP-1 beta PBM: 68+/-19.6; AM: 63.3+/-26.2% of contro l) but modestly decreased HIV replication when incubated in addition t o RANTES (24.5+/-6.5% of control). These observations suggest that RAN TES plays a key role in modulating HIV-1 replication in mononuclear ph agocytes in the blood and lung, and this may have therapeutic implicat ions for prevention and/or treatment of HIV disease.