BETA March 1997.
by Mark Bowers
Chemokines -- proteins that act as chemical messengers between cells of the immune system -- have been studied intently by immunologists since 1986. To date, more than 40 different chemokines have been isolated and characterized. Chemokines were first identified in 1987. A capsule history of chemokine research follows.
Jay Levy proposes that a soluble cell antiviral factor (CAF) made by CD8 cells inhibits HIV replication in infected cells and accounts for long-term non-progressors' high CD4 cell counts and failure to develop opportunistic infections. Efforts to isolate CAF begin.
Yoshimura, Matsushima and Tanaka report purification of the first identified chemokine: "human monocyte-derived neutrophil chemotactic factor," or interleukin 8 (IL-8).
At the 3rd International Symposium on Chemotactic Cytokines at Baden, Germany, the term "chemokines" is coined. Two groups - alpha and beta -- are identified.
Mario Clerici and Gene Shearer of he U.S. National Cancer Institute propose that a shift in cytokine patterns from Th1 (cellular immunity) to Th2 (humoral immunity) explains HIV disease progression. Th1 type cells produce IL-2 and interferon gamma that help the body eliminate infected cells, while Th2-type cells produce IL-4, IL-10 and other cytokines that activate antibody production.
At the 1st International Symposium on HIV and Cytokines, Reims, France, 15-27 March 1995, IL-12 levels are reported to be low in HIV-infected individuals. Phase II clinical studies of IL-12 begin in Europe and the U.S.
Researchers at the Tumor Cell Biology Laboratory of the NCI isolate RANTES, MIP-1a and MIP1-b, and announce that Levy's elusive CAF has been identified. b chemokines are reported to be the major suppressors of M-tropic HIV.
Michael Baier and colleagues at Paul-Ehrlich-Institut in Germany report that IL-16, a chemoattractant cytokine, suppresses the replication of HIV and simian immuno-deficiency virus (SIV).
Richard Koup and William Paxton at Aaron Diamond AIDS Research Center report that relative resistance to HIV is associated with the activity of the b chemokines RANTES, MIP-1a and MIP1-b.
Nathaniel Landau at Aaron Diamond AIDS Research Center and colleagues identify CCR-5, the receptor for RANTES, MIP-1a and MIP1-b, as the major co-receptor for HIV-1.
At the 11th International Conference on AIDS in Vancouver, British Columbia, Jay Levy and Robert Gallo debate the identity of CAF. Levy and Otto Yang at Massachusetts General Hospital each report that CAF is intact even when antibodies directed to RANTES, MIP-1a and MIP1-b are present. What goes into CAF, however, is still not known.
Nathaniel Landau and Richard Koup at Aaron Diamond find genetic mutations in the CCR-5 gene in 2 people who were repeatedly exposed to HIV without becoming infected.
Marc Parmentier at the Université Libre de Bruxelles in Belgium publishes data on 723 HIV-infected Caucasians, none of whom have mutations for the CCR-5 gene.
Stephen O'Brien of the National Cancer Institute reports that of 1,955 people studied, 11% of Caucasians and 1.7% of African Americans have 2 copies (one from each parent) of a mutant gene for CCR-5 and are therefore highly resistant to HIV infection.
Fernando Arenzano-Seisdedos and colleagues at the Pasteur Institute in France report that synthetic RANTES blocks HIV-1 infection.
Cheryl Lapham and colleagues at Food and Drug Administration report evidence for a physical association among CD4, gp120 and CXCR-4 on the surface of cell membranes.
Fiorenza Cocchi and colleagues at the Institute of Human Virology in Maryland and the San Raffaele Scientific Institute in Milan, Italy, report that the binding region of gp120 to CCR-5 is within the third variable (V3) loop of the HIV envelope.
Leandros Arvanitakis and collegues at Cornell University in New York describe a virally encoded chemokine receptor, Kaposi's sarcoma-associated herpesvirus (KSHV) GPCR, that was pirated from a cellular gene by the virus. They propose that this receptor allows KSHV to access IL-8 to create a new blood supply for tumors (angiogenesis).
Immune Response Corp suggests that Remune, a therapeutic vaccine candidate, increases cellular production of chemokines. Research to confirm the suggestion will be performed within the context of current clinical trials.
Robert Gallo publically speculates that vaccines based on chemokines will be more successful than those based on parts (subunits) of HIV.
This information is designed to support, not replace, the relationship that exists between you and your doctor.