Chemoattractants attract HIV researchers

I n this issue of the Journal of ExperimentaI Medicine, Loetscher et al. show that receptors for ~-chemokines are upregulated when T lymphocytes are activated by interleukin-2 (1). This paper will be of considerable interest not just to those who have worked for some years to identify conditions whereby chemokines could attract T ceils, but also to HIV researchers and conceivably to retrovirologists in general. It is not often that two seemingly unrelated fields, chemotaxis and retroviral infection, meld to create an entire new area of research, but that is exactly what has happened over the past six months. For several years, it has been known that CD8 § T ceils secrete factors that suppress HIV-1 replication in CD4 + T cells (2-4). The nature of these factors remained elusive, however, until December of last year when Cocchi et al. showed that the [3-chemokines MIP-lci, MIP-I[3, and RANTES contributed to the CD8+-cell suppressive effect (5). It is probable that these ~-chemokines are not the only components of CD8 + cell conditioned medium that have an anti-viral effect against HIV-1, but it is certain that they are important components of the cocktail. It has also been known, for over a decade in this case, that HIV-1 needs a species-specific (but not cell lineagespecific) accessory fusion factor (second receptor) to enter CD4 + cells (6-8). The expression of CD4 is necessary, but not sufficient, for efficient HIV-1 replication. In the absence of the second receptor, HIV-1 can bind to its target cells (via CD4), but the fusion process is not initiated (6). The identity of the second receptor remained unknown despite much searching by many research groups. The logjam in this field was finally broken in April of this year by the publication of a paper from Ed Berger's group at the National Institutes of Health showing that the second receptor for at least some strains of HIV-1 was LESTR (fusin), a member of the same receptor superfamily as the ~-chemokine receptors (9). The inhibitory effects ofMIP-lot, MIP-I~, and RANTES are largely restricted to primary, NSI strains of HIV-1 (5, 10). However, LESTR was clearly shown to be the second receptor for strains of HIV-1 adapted to growth in permanent cell lines (TCLA strains) and primary viruses of the more aggressive, SI phenotype (9). Furthermore, LESTR is not known to be a ~-chemokine receptor; indeed, its physiological ligand is presently unknown (9, 11). These discrepancies notwithstanding, the potential connection between Berger's paper and that ofCocchi et al. did not go unappreciated by many research groups (5, 9). The [3-chemokine receptors are from the seven transmembrane-spanning, G-protein-coupled superfamily (1216). Dozens of these receptors are encoded by the human genome, and they bind a range of ligands, including peptide hormones, neuropeptides and the etand ~-chemokines. Other members of the receptor superfamily are involved in vision, taste, and smell perception. As the superfamily name suggests, the receptors span the plasma membrane seven times, so that about half of the protein is buried in the membrane. The extracellular domains, especially the N H 2 terminus, are involved in ligand binding, the intraceilular regions in coupling to the effector systems of signal transduction pathways, via G-proteins (12-16). Several groups commenced a search for a ~3-chemokine receptor that could serve as the second receptor for primary, NSI strains of HIV-1. It did not take long for the recently published CKR-5 receptor (17) to be identified as an HIV-1 second receptor (18, 19). CKR-5 appears to be the counterpart of LESTR for NSI primary viruses, and its second receptor functions are inhibited by ~-chemokines. Thus, [3-chemokines inhibit HIV-1 replication by blocking the fusion of the virus with its target cell, perhaps by a competitive interaction with the receptor (18). In addition, it has been shown that CD4 + T cells from some persons who have been multiply exposed to HIV-1 yet remain uninfected (EU individuals) are incompetent at fusing with NSI HIV-1 strains (18). The defect in the EU cells may lie at the level of the CKR=5 receptor, either because this is nonfunctional for HIV-1 entry or because it is ligated endogenously by the ~-chemokines that are over-secreted from the EU T cells. Many questions on the relationship between the ~-chemokines and HIV-1 replication in vitro and in vivo remain unanswered, but the present paper of Loetscher et al. addresses a significant issue (1). The principal finding in the paper is that CKR-1 and CKR-2 are upregulated in response to IL-2 stimulation. IL-4, IL-10, and IL-12 are partial activators, whereas several other cytokines are ineffective. Triggering of the cells via CD3 or CD28 (or non-specifically by PHA) does not upregulate CKR.-1 and CKR-2; indeed, anti-CD3 or anti-CD28 activation of CKR.-1and CKR.-2-expressing cells actually downregulates receptor expression (1). CKR-1, like CKR-5, is a MIP-lcx and RANTES receptor (unlike CKR-5, CKR-1 does not bind MIP-113 avidly) (12, 13), and it can function, albeit to a very limited extent, as an HIV-1 second receptor (18). CKR-2 is a receptor for MCP-1 and MCP-3, ~-chemo-