H.K. Deng, R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. DiMarzio, S. Marmon, R.E. Sutton, C.M. Hill, C.B. Davis, S.C. Peiper, T.J. Schall, D.R. Littman, N.R. Landau, "Identification of a major co-receptor for primary isolates of HIV-1," Nature, 381:661-6, 1996. (Cited in more than 610 papers since publication)
PRESS RUN: Ned Landau of the Aaron Diamond group raced to get confirmation of CCR5 as the HIV M-tropic coreceptor into publication, including a mad dash to an overnight mail office. Four other groups published similar results within weeks.
The progress of knowledge about how HIV enters the cells is akin to the evolutionary theory of punctuated equilibrium: long periods of little progress, followed by breakthroughs that trigger further discovery.
Ned Landau, staff investigator at the Aaron Diamond AIDS Research Center, recalls that the first trigger was tripped 10 years ago, when researchers, experimenting with mouse models learned that the CD4 receptor alone did not allow the virus entry. "That finding caused laboratories all over the world to look for the second factor," Landau recalls. However, the elusive second factor stymied researchers for years. Then, in 1996 a research team from the National Institutes of Allergy and Infectious Diseases led by Edward Berger, chief of the molecular structure section, trapped the CXCR4 cofactor in an exhaustive screen (Hot Papers, The Scientist, 12:11, March 30, 1998). However, AIDS researchers soon learned that the CXCR4 coreceptor only bound to the T-tropic, later-stage virus.
Robert C. Gallo, director of the Institute of Human Virology at the University of Maryland in Baltimore, and colleagues provided another clue. In vitro experiments showed that CC chemokines bound to HIV. "You could put two and two together to figure out that the M-tropic was going to use a CC chemokine receptor," Landau explains. "That finding kicked off a race. We knew that lots of people would figure that out." Only four CC receptors were known at the time. "We were testing them as fast as we could." But none of them worked. "We had suspicions that there was an additional CC receptor--and that would be the right one."
Those suspicions proved correct when Marc Parmentier and colleagues at the University of Brussels in Belgium sequenced CCR5 (M. Samson et al., Biochemistry, 35:3362-7, 1996). "As soon as we had that sequence, just a few days later, we had the finding that that was the key cofactor." Landau still remembers seeing the data that convinced him that CCR5 was, indeed, the coreceptor that HIV uses to gain initial entry into cells. "When we had CCR5 expressed in the cells, the level of infection went up almost 10,000-fold," Landau recalled. "It knocked our socks off."
Landau's team didn't have the luxury of sitting back and contemplating their success, though. They knew that other teams were working on the same problem. Landau recalls the frenetic pace between discovery, writing the paper, and overnighting it to the journal. "We were running through the streets of New York carrying the manuscript," Landau recalls. Four other teams soon published similar findings. Each article has been cited in more than 400 papers. (B.J. Doranz et al, Cell. 85:1149-58, 1996 (415 papers); H. Choe et al., Cell, 85:1135-48, 1996 (465 papers); G. Alkhatib et al., Science, 272:1955-8, 1996 (487 papers); and T. Dragic et al., Nature, 381:667-73, 1996 (593 papers).
The papers have been cited so often because they reveal insight into AIDS pathogenesis, explain the mechanisms the virus uses to invade cells, and open the door to potential new therapies (P. Smaglik, The Scientist, 12:9, March 2, 1998). "Many pharmaceutical companies are screening for chemokine receptor inhibitors," Landau reports.