Genetic Subtype-Independent Inhibition of Human Immunodeficiency Virus Type 1 Replication by CC and CXC Chemokines |
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| Authors: | Alexandra Trkola William A. Paxton Simon P. Monard James A. Hoxie Michael A. Siani Darren A. Thompson Lijun Wu Charles R. Mackay Richard Horuk John P. Moore |
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| Affiliation: | The Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 100211.; Hematology-Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania 191042.; Gryphon Sciences Inc., South San Francisco, California 940803.; Leukosite Inc., Cambridge, Massachusetts 021424.; and Department of Immunology, Berlex Biosciences Inc., Richmond, California 948095. |
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| Abstract: | We have studied the breadth and potency of the inhibitory actions of the CC chemokines macrophage inhibitory protein 1α (MIP-1α), MIP-1β, and RANTES against macrophage-tropic (M-tropic) primary isolates of human immunodeficiency virus type 1 (HIV-1) and of the CXC chemokine stromal cell-derived factor 1α against T-cell-tropic (T-tropic) isolates, using mitogen-stimulated primary CD4+ T cells as targets. There was considerable interisolate variation in the sensitivity of HIV-1 to chemokine inhibition, which was especially pronounced for the CC chemokines and M-tropic strains. However, this variation was not obviously dependent on the genetic subtype (A through F) of the virus isolates. Peripheral blood mononuclear cell donor-dependent variation in chemokine inhibition potency was also observed. Among the CC chemokines, the rank order for potency (from most to least potent) was RANTES, MIP-1β, MIP-1α. Some M-tropic isolates, unexpectedly, were much more sensitive to RANTES than to MIP-1β, whereas other isolates showed sensitivities comparable to those of these two chemokines. Down-regulation of the CCR5 and CXCR4 receptors occurred in cells treated with the cognate chemokines and probably contributes to anti-HIV-1 activity. Thus, for CCR5, the rank order for down-regulation was also RANTES, MIP-1β, MIP-1α. |
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