AEGiS-13IAC: Combination of CCR5 and CXCR4 inhibitors in therapy of HIV-1 infection: in vitro studies in mixed virus infections.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Combination of CCR5 and CXCR4 inhibitors in therapy of HIV-1 infection: in vitro studies in mixed virus infections.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA408)

Rusconi S, La Seta Catamancio S, Citterio P, Bulgheroni E, Croce F, Galli M, Hirsch MS
S. Rusconi, University of Milan, Ospedale Luigi Sacco, Istituto di Malattie Infettive e Tropicali, via GB Grassi 74, 20157 Milan, Italy, Tel.: +39.02.390 42 676, Fax: +39.02.356 09 05, E-mail: rusconi@mailserver.unimi.it

BACKGROUND: Antagonists of chemokine receptors CCR5 and CXCR4 are potential antretroviral agents. We studied the combined effects of a derivative of SDF-1beta, Met-SDF-1beta, and a modified form of RANTES, AOP-RANTES.

METHODS: Inhibitory effects were tested with or without the two fusion inhibitors at virus inhibitory concentrations of 95% or 99% (IC95 or IC99). The viral isolates examined in the present study were derived from two patients with primary HIV-1 infection (PHI) before the start of any antiretroviral treatment: one (RM) was CCR5-tropic and the other (DK) was CXCR4-tropic. Experiments were conducted utilizing single or combined drugs against infection with RM or DK viruses or against mixed infection (50 : 50) with these two viruses. Studies were conducted in peripheral blood mononuclear cells (PBMC) or in U87MG-CD4 CCR5 or CXCR4 cell lines.

RESULTS: AOP-RANTES inhibited R5 viruses but not X4 viruses, whereas Met-SDF-1beta inhibited X4 viruses, but not R5 viruses when used in the appropriate cells at IC95 or IC99 concentrations. Combination of AOP-RANTES and Met-SDF-1beta inhibited dual infections with R5 and X4 viruses (95-99 %), whereas single drugs suppressed dual infections less well (32-61 %). Sequencing studies confirmed the outgrowth of single strain virus in subcultures when only one drug was used, e.g. R5 virus when Met-SDF-1beta was used and X4 virus when AOP-RANTES was used. Subsequent plasmid cloning showed a higher frequency of DNA integration of the CCR5+ isolates in dual HIV-1 infections in the absence of drugs, as well as the maintenance of HIV-1 nucleic acid even in the presence of both dual-target inhibitors.

CONCLUSIONS: Our experiments suggest that use of combined inhibitors of R5 and X4 viruses may be useful to inhibit mixed infections mediated by viruses with a different tropism.

Keywords: AEGIS, HIV Infections, HIV-1, RANTES, Chemokines, CXC, Receptors, Chemokine, Cytokines, Cell Line, aminooxypentane-RANTES, methionine stromal cell-derived factor-1beta, stromal cell-derived factor-1beta, In Vitro, Human, therapy, antagonists & inhibitors
000709
TuOrA408