New Entries on HIV Cofactors Clarify Viral Tropism

New Entries on HIV Cofactors Clarify Viral Tropism

Jeremy Cherfas

WHAT'S HOT IN BIOLOGY...

Rank	Paper	Citations This Period Sep- Oct 97	Rank Last Period Jul- Aug 97
1	Y. Feng, et al., "HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor," Science, 272(5263):872-7, 10 May 1996. [NIH, NIAID, Bethesda, MD] *UK757	65	7
2	C.J. Bult, et al., "Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii," Science, 273(5278):1058-73, 23 August 1996. [6 U.S. institutions] *VD428	64	8
3	H. Deng, et al., "Identification of a major co-receptor for primary isolates of HIV-1," Nature, 381(6584):661-6, 20 June 1996. [Howard Hughes Med. Inst., New York U. Med. Ctr., NY; Aaron Diamond AIDS Res. Ctr., Rockefeller U., NY; Stanford U. Med. Ctr., CA; U. Louisville Sch. Med., KY; DNAX Res. Inst., Palo Alto, CA] *UR979	60	10
4	T. Dragic, et al., "HIV-1 entry into CD4⁺ cells is mediated by the chemokine receptor CC-CKR-5," Nature, 381(6584):667-73, 20 June 1996. [Aaron Diamond AIDS Res. Ctr., Rockefeller U., NY; Progenics Pharmaceuticals, Inc., Tarrytown, NY] *UR979	55	†
5	M. Muzio, et al., "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex," Cell, 85(6):817-27, 14 June 1996. [U. Michigan Med. Sch., Ann Arbor; German Cancer Res. Ctr., Heidelberg; European Molec. Bio. Lab., Heidelberg; Human Genome Sci., Rockville, MD] *UR604	51	5
6	F. Cocchi, et al., "Identification of RANTES, MIP-1a and MIP-1b as the major HIV-suppressive factors produced by CD8⁺ T cells," Science, 270(5243):1811-5, 15 December 1995. [NCI, Bethesda, MD; Advanced BioScience Labs, Kensington, MD; Inst. Human Virology, Baltimore, MD] *TK476	49	†
7	G. Alkhatib, et al., "CC CKR5: A RANTES, MIP-1a, MIP-1b receptor as a fusion cofactor for macrophage-tropic HIV-1," Science, 272(5270):1955-8, 28 June 1996. [NIH, NIAID, Bethesda, MD] *UV294	47	†
8	C.M. Fraser, et al., "The minimal gene complement of Mycoplasma genitalium," Science, 270(5235):397-403, 20 October 1995. [Inst. Genom. Res., Rockville, MD; SUNY Buffalo, NY; Johns Hopkins Sch. Med., Baltimore, MD; U. North Carolina Sch. Med., Chapel Hill] *TA374	45	†
9	M.P. Boldin, et al., "Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death," Cell, 85(6):803-15, 14 June 1996. [Weizmann Inst. Science, Rehovot, Israel] *UR604	45	†
10	B.J. Doranz, et al., "A dual-tropic primary HIV-1 isolate that uses fusin and the b-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors," Cell, 85(7):1149-58, 28 June 1996. [U. Pennsylvania, Philadelphia; Free U. Brussels, Belgium; U. Louisville, KY] *UV484	45	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

Earlier this year, this column focused on three of the hottest papers of 1996. Between them they identified one of the holy grails of AIDS researchers for the past 10 years: the cofactors that human immunodeficiency virus (HIV) needs to infect cells. At that time (Science Watch, 8[3]:7, May/June 1997) the three papers were sitting just below the Top Ten. They are now safely ensconced at #1, #3, and #4; what is gratifying is that the research that inspired them is on the list at #6, while two papers that take the cofactor findings further are at #7 and #10.

Robert Gallo, Director of the Institute of Human Virology at the University of Maryland in Baltimore, and his colleagues, published a report in December of 1995 in Science that showed that three chemokines-molecules involved in the inflammatory responses of the immune system-were able to suppress infection by HIV (paper #6). The three, known as RANTES, MIP-1a and MIP-1b, pointed researchers at a receptor called CKR-5, because it was the one chemokine receptor that was known to bind all three HIV suppressants. Thus it was that first fusin (#1), and, within a couple of weeks, CKR-5 (#3 and #4), were positively identified as the coreceptors that HIV needs (in addition to CD4) to fuse with host cells.

The fusin paper by National Institutes of Health researcher Edward A. Berger and colleagues was sent to Science in March of 1996; by the time it was published in May his group had also identified CKR-5 as another cofactor (though not in time to win that race too). That is the paper currently at #7. At #10 is work from Robert Doms's group in the Department of Pathology and Laboratory Medicine, University of Pennsylvania. This helps to make sense of changes shown by HIV as the infection proceeds.

Viruses isolated shortly after an individual becomes positive for HIV tend to infect macrophages, rather than T cells, and do not cause cells to fuse into a multinucleated syncytium. They are said to be M-tropic. Later in the infection, isolates infect T cells and do induce the formation of syncytia, and the emergence of this type of T-tropic HIV is accompanied by a decline in CD4⁺ lymphocytes and the development of AIDS. An important question, especially for therapy, is whether M-tropic viruses turn into T-tropic viruses, or whether the T-tropic strains are there all along, but either in very small numbers or suppressed. Some researchers have described dual-tropic isolates, which not only induce syncytia but also remain capable of infecting and multiplying within macrophages. These, it was conjectured, might be an intermediate step in the evolution of HIV during an infection.

The different tropisms are the result of differences in the env protein of HIV. Doms's group created human cells that expressed either T-tropic or M-tropic env proteins. They mixed these with other cells expressing CD4 and either fusin or CKR-5. Bingo! T-tropic env fused only with fusin while M-tropic env would fuse only with CKR-5. What of dual-tropic strains?

The env protein from one such isolate, called 89.6, was duly expressed in a cell, which proved able to fuse with both fusin and CKR-5 (in the presence of CD4, of course). (It also fused with two other b-chemokines, CKR-3 and CKR-2b, which neither purely T-tropic nor purely M-tropic env proteins responded to.) This is interesting because the extra-cellular domains of fusin and CKR-5 are not very similar (only 21% homology), while 89.6 env protein is around 90% homologous to well-characterized env proteins from T-tropic and M-tropic isolates, and no closer to either. This suggests that relatively subtle changes in the env protein underly the different tropisms; it also adds additional weight to the idea that M-tropic strains evolve into T-tropic ones as a result of changes to the env protein.

As Gallo observed drily in the paper that set these particular hares running, "These data may have relevance for the prevention and therapy of AIDS." Of course, publishing in the penultimate issue of the year, Gallo had no chance to be seen as among the hottest papers of 1995. Had he delayed two weeks he would have been way ahead of the pack in 1996. But that's probably a poor reason to procrastinat.

Science writer Dr. Jeremy Cherfas
works with the Biotechnology and Biological Sciences
Research Council of the U.K., Swindon.