SYNTHETIC FULL-LENGTH AND TRUNCATED RANTES INHIBIT HIV-1 INFECTION OFPRIMARY MACROPHAGES

Objective: To determine the effect of beta-chemokines on HIV-1 infecti on of primary macrophages, and to search for chemokine derivatives dev oid of biological effects but efficient at protecting CD4+ T lymphocyt es and macrophages against HIV-1. Design: Use of chemically synthesize d molecules devoid of biological contaminants and monocyte-derived mac rophages from healthy donors. Methods: Full-length RANTES was chemical ly synthesized together with three derivatives, truncated of seven, ei ght and nine amino acids at the amino-terminus ([8-68]RANTES, [9-68]RA NTES and [10-68]RANTES), which were tested for their biological activi ty and antiviral effects. Results: Whereas full-length and truncated R ANTES derivatives bound to beta-chemokine receptor CCR-5 with the same affinity as recombinant RANTES, the truncated forms were not chemotac tic and acted as CCR-5 antagonists in this respect, although a partial agonist effect was noted on cell metabolism. Full-length RANTES and [ 8-68]RANTES protected T lymphocytes and macrophages from infection by HIV-1, although 10-fold higher concentrations of the truncated analogu es were necessary to achieve the same effect as full-length RANTES. Wi th regard to the effect of RANTES on HIV-1 infection of primary macrop hages, our results contrast with most previously reported data. Conclu sion: These data indicate that through binding to CCR-5, truncated RAN TES derivatives that are devoid of detectable biological effects may r epresent candidates as drugs to protect both lymphocytes and macrophag es from HIV-1. (C) 1998 Lippincott-Raven Publishers.