AIDSWEEKLY Plus; Monday, May 10, 1999
Daniel J. DeNoon, Senior Editor

New drugs under development block the CCR5 coreceptor used by the so-called R5 HIV strains. R5 HIV is tropic for macrophages and is the type of HIV most frequently transmitted. But in vitro studies now show that these potent drugs rapidly select for R4 HIV strains that enter cells via the alternative CXCR4 coreceptor. A switch from a preponderance of R5 HIV to a preponderance of the T-cell-tropic X4 HIV phenotype frequently heralds the onset of AIDS.

"These results reinforce the case for using agents that block all significant HIV-1 coreceptors for effective therapy," wrote Donald E. Mosier of Scripps Research Institute and colleagues.

Mosier et al. reported their findings in the Journal of Virology ("Highly Potent RANTES Analogs either Prevent CCR5-Using Human Immunodeficiency Virus Type 1 Infection In Vivo or Rapidly Select for CXCR4-Using Variants," J Virol 1999 May;73(5):3544-50.

The researchers noted that the natural ligands for the CCR5 receptor are the cytokines macrophage inflammatory protein (MIP)-1(alpha), MIP-1(beta), and RANTES (regulated on T-cell activation, normal T-cell expressed and secreted).

Modification of the RANTES molecule has yielded two novel HIV inhibitors: aminooxypentane (AOP)-RANTES and N-nonanoyl (NNY)-RANTES. AOP-RANTES is manufactured by Gryphon Sciences, South San Francisco, California; NNY-RANTES was developed at France's Institut National de la Sante et de la Recherche Medicale (INSERM).

Mosier et al. explored the in vivo efficacy of the two chemokine receptor antagonists in an animal model of HIV infection: severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice). The drugs were tested for their ability to prevent infection with an R5 strain of HIV-1 (the 242 molecular clone) that requires only one amino-acid mutation to become dually tropic for the CCR5 and CXCR4 coreceptor, and only three mutations to become an X4 virus.

Both drugs were highly potent. AOP-RANTES achieved higher circulating concentrations than NNY-RANTES. Nevertheless, NNY-RANTES was more effective in preventing infection.

"Inhibition of virus infection occurred with the plasma levels of 50 to 113 pM NNY-RANTES and 500 to 630 pM AOP-RANTES during continuous administration of the antagonists, levels that are lower than the average concentration ((approx)2.5 nM) of native RANTES in human plasma and, for NNY-RANTES, levels that were lower than the in vitro 50% inhibitory concentration for the 242H virus isolate," Mosier et al. reported.

NNY-RANTES, administered by infusion or bolus injection, protected 60 percent of challenged hu-PBL-SCID mice from infection. This is the first demonstration that chemokine receptor antagonists can block HIV infection in vivo (another drug of this type, AMD3100, has demonstrated in vitro efficacy).

Still unknown is the duration of the cellular response to CCR5 antagonists. This depends on their precise mode of action. If they work by sequestering CCR5 within cells (one known action of natural RANTES), their effect may be longer-lasting than their very brief plasma half-life. But if they work merely by occupying the external CCR5 receptor, it might be necessary to maintain drug levels at effective concentrations.

Despite, or perhaps because of the unexpected efficacy of NNY-RANTES, coreceptor-switch HIV variants appeared during the one-week treatment period in two challenged animals. Interestingly, these were not the dual-tropic variants a single amino-acid change would have created. In both cases there was the same three-position mutation into an X4 virus. Primary patient isolates may not so quickly occur, but the data suggest that the dangerous switch would indeed take place.

"The emergence of viruses capable of using CXCR4 under the selective pressure of the concentrations of NNY-RANTES used in these experiments demonstrates that the inappropriate use of CCR5 antagonists could generate more pathogenic variants, since there is general agreement that the course of disease progression is accelerated with the switch from R5 to R5X4 viruses," Mosier et al. warned.

"These results strongly reinforce the view that clinical use of blocking agents for CCR5 alone would be unwise and that cocktails of antagonists directed toward known coreceptors or antagonists with broader specificity will be required for safe and effective therapy of HIV-1 infection in humans."

The researchers noted, however, that the potency of the agents tested points to HIV coreceptors as important targets for antiretroviral therapy.

This study was supported by National Institutes of Health grants and a grant from the Swiss National Science Foundation.

The corresponding author for this study is Donald E. Mosier, Department of Immunology-IMM7, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037. Phone: (619) 784-9121. Fax: (619) 784-9190. Email: <dmosier@scripps.edu>.

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