Variable Sensitivity of CCR5-Tropic Human Immunodeficiency Virus Type 1 Isolates to Inhibition by RANTES Analogs

Vincent S. Torre,1 Andre J. Marozsan,2 Jamie L. Albright,1 Kalonji R. Collins,1 Oliver Hartley,3 Robin E. Offord,3 Miguel E. Quỉones-Mateu,1 and Eric J. Arts1,2,* Division of Infectious Diseases, Department of Medicine,1 and Department of Pharmacology,2 Case Western Reserve University, Cleveland, Ohio 44106, and Department of Medical Biochemistry, University of Geneva, Geneva, Switzerland3
Received 6 October 1999/Accepted 11 February 2000

Aminooxypentane (AOP)-RANTES efficiently and specifically blocks entry of non-syncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) into host cells. Inhibition appears to be mediated by increased intracellular retention of the CCR5 coreceptor- AOP-RANTES complex and/or competitive binding of AOP-RANTES with NSI R5 HIV-1 isolates for CCR5. Although AOP-RANTES and other -chemokine analogs are potent inhibitors, the extreme heterogeneity of the HIV-1 envelope glycoproteins (gp120 and gp41) and variable coreceptor usage may affect the susceptibility of variant HIV-1 strains to these drugs. Using the same peripheral blood mononuclear cells (PBMC) with all isolates, we observed a significant variation in AOP-RANTES inhibition of 13 primary NSI R5 isolates; 50% inhibitory concentrations (IC50) ranged from 0.04 nM with HIV-1A-92RW009 to 1.3 nM with HIV-1B-BaL. Experiments performed on the same isolate (HIV-1B-BaL) with PBMC from different donors revealed no isolate-specific variation in AOP-RANTES IC50 values but did show a considerable difference in virus replication efficiency. Exclusive entry via the CCR5 coreceptor by these NSI R5 isolates suggests that variable inhibition by AOP-RANTES is not due to alternative coreceptor usage but rather differential CCR5 binding. Analysis of the envelope V3 loop sequence linked a threonine or arginine at position 319 (numbering based on the HXB2 genome) with AOP-RANTES resistance. With the exception of one isolate, A319 was associated with increased sensitivity to AOP-RANTES inhibition. Distribution of AOP-RANTES IC50 values with these isolates has promoted ongoing screens for new CCR5 agonists that show broad inhibition of HIV-1 variants.