I've worked in HIV/AIDS research since 1988, studying the HIV envelope glycoproteins, their roles as mediators of virus entry and as targets for neutralizing antibodies. What's more important, I think, than trying to understand how these proteins look like and function is to try to find out how to stop them working—because doing that would keep the virus out of the cells it infects and therefore harmless. Two ways to do this are by inducing neutralizing antibodies by immunization with the envelope glycoproteins, and by using drugs that target the virus-cell fusion process. My lab, and many, many others have projects aimed at both areas of research.

“What's more important, I think, than trying to understand how these proteins look like and function is to try to find out how to stop them working—because doing that would keep the virus out of the cells it infects and therefore harmless.” ~John P. Moore

The 1996 Nature paper by Tanya Dragic et al. was one of five papers that were published within the same week by five different groups, all identifying CCR5 as being the entry coreceptor for the most commonly transmitted, dominant HIV-1 variants. The existence of such a coreceptor had been strongly suspected since 1986, but it wasn't until two studies by Bob Gallo's and Ed Berger's groups in late 1995 and early 1996 that it became obvious how to identify the missing receptor—sufficiently obvious that five groups, including Ed's, all found it at the same time.

Our own paper was derived from two separate manuscripts submitted to Nature by my group (Dragic et al.) and a colleague's (Rick Koup's; Bill Paxton et al.) that were on overlapping themes. For reasons best known to one reviewer, Nature asked us to amalgamate the two manuscripts into a single paper. So the two original first authors (both, at that time, highly talented post-docs who have since earned faculty positions) became the first and last authors. Somehow a credible paper was assembled from the existing information and additional data on CCR5 that Tanya had obtained during the review period.

All five papers on CCR5 have since been very highly cited, I think for two reasons: firstly, the HIV/AIDS field is very large, and there are a correspondingly large number of papers on any one topic; secondly, there was, and has remained, a lot of general interest in how HIV enters cells and how this can be stopped.

The CCR5 field remains very active. Drug candidates that bind to CCR5 and prevent HIV entry into cells are now in Phase III clinical trials and doing well (i.e., they are able to reduce HIV viral load quite efficiently), although there are some immunology-related safety issues still to be resolved before they’re licensed. We're studying how HIV develops resistance to these drugs in cell culture, and we've previously looked at how they bind to CCR5. We're also testing a CCR5 inhibitor in animal models as a device to prevent HIV transmission, by applying it vaginally or rectally as a microbicidal gel. So, a lot's going on, triggered by those five papers and the ones that made them possible. In HIV/AIDS research, nobody works in a vacuum.

John P. Moore, Ph.D.
Joan and Sanford I. Weill Medical College
Cornell University
New York, NY, USA