AIDSWEEKLY Plus, Monday, 28 April 1997
Daniel J. DeNoon, Senior Editor
The rapid pace of AIDS research again has accelerated with the announcement that a modified (beta)-chemokine can block HIV infection.
The naturally occurring (beta)-chemokines RANTES, MIP- 1(alpha), and MIP-1(beta) inhibit HIV infection by primary and macrophage-tropic HIV-1 isolates (Cocchi et al., Science, 1995;270:1811-5), but they cannot prevent infection of primary macrophage cultures. Moreover, their use as AIDS therapies is limited by their natural functions of leukocyte activation and chemotaxis signalling.
Now an international research team reports that a modification to one of these cytokines, RANTES, causes it to completely block the CCR5 receptor needed by HIV to infect macrophages.
"A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)- RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes," wrote Chester Beatty Laboratories researcher Graham Simmons and colleagues. "It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium- inducing, macrophage-tropic HIV-1 strains."
Simmons et al. reported their findings in the journal Science ("Potent Inhibition of HIV-1 Infectivity in Macrophages and Lymphocytes by a Novel CCR5 Antagonist," Science, 1997;276:276-9).
Their report follows close on the heels of the first report of a chemokine antagonist that inhibited HIV-1 infection of activated peripheral blood cells (Arenzana- Seisdedos et al., Nature, 1996;383:400).
Macrophage-tropic (M-tropic) strains of HIV are responsible for an estimated 90 percent of HIV transmission. These strains require the CCR5 receptor to infect cells; T- lymphocyte-tropic (T-tropic) HIV strains usually appear later in the course of HIV disease and require the CXCR4 receptor.
Simmons et al. initially set out to explore the anti-HIV effects of Met-RANTES, a RANTES derivative with a methionine at its NH[2] terminus. Met-RANTES is known to inhibit RANTES signalling.
To create an even more divergent derivative, they developed AOP-RANTES by modifying the NH[2] terminus of RANTES into an aldehyde-like formation and then reacting it with aminooxypentane.
Further experiments demonstrated that:
* AOP-RANTES binds exclusively to the CCR5 receptor.
* AOP-RANTES totally blocks the CCR5 receptor at a 1 nM concentration with a 50% inhibitory concentration (IC[50]) of 0.072 nM.
* AOP-RANTES is 10-fold more potent than RANTES or Met-RANTES in blocking infection of peripheral blood mononuclear cells (PBMC) by five primary, nonsyncytium-inducing (NSI), M-tropic HIV-1 strains. There was complete inhibition of infection with AOP-RANTES concentrations <100 ng/ml.
* AOP-RANTES did not block infection by T-tropic HIV-1 strains.
* Unlike RANTES and Met-RANTES, AOP-RANTES blocked macrophage replication of all four primary, NSI, M-tropic strains tested.
"The AOP modification has succeeded in creating a classical antagonist with a monocomponent high-affinity binding mode," Simmons et al. concluded. "AOP-RANTES or similarly modified chemokines (or even non-peptide antagonists) that achieve full receptor occupancy are therefore suitable candidates for treatment of HIV infected individuals."
The corresponding authors for this study are Paul R. Clapham, Virology Group, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, U.K. and Amanda E.I. Proudfoot, Geneva Biomedical Research Institute, GlaxoWellcome Research and Development SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
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