The excitement over chemokines and their receptors has been snowballing since the International AIDS Conference in 1996. Virtually overnight, the new field of chemokine research was born and basic research of these molecules is progressing at a frenetic pace. Study of these molecules may provide new insight into the mechanisms of HIV infection and pathogenicity. Why the furor over chemokines? In addition to protease inhibitors and drugs like AZT, chemokine-based therapies would be directed against a different point in the life cycle of HIV. These new therapies may actually prevent the virus from infecting cells and limit the transmission of HIV.

First, what are chemokines and what do they do? Chemokines are soluble proteins that attract white blood cells to an inflamed area or site of infection within the body. They are made and secreted by a variety of cells in the immune system. Each chemokine binds to a specific receptor on the surface of white blood cells such as monocytes, lymphocytes, basophils, and eosinophils. This interaction is extremely precise, meaning the chemokine will only dock to a chemokine receptor of a specific shape. This exact match-up of chemokine and receptor triggers a cascade of events within the cell leading to chemotaxis, the mobilization of immune cells to an area of the body where they are needed.

For many years the conundrum in AIDS research has been that HIV gains entry into a human cell by binding to CD4 receptors on the surface of immune cells; however, animals with CD4 receptors on their cells are not infected by HIV. Intuitively this suggests that HIV probably recruits an additional molecule or co-receptor to aid its entry into human cells, but identification of this co-receptor has eluded researchers, until recently. In December, 1996 Robert Gallo and his group at the Institute of Human Virology, in Baltimore, found 3 chemokines, MIP1a, MIP 1b, and RANTES that inhibit HIV replication. On the heels of this discovery, five research groups published evidence demonstrating chemokine receptor involvement in HIV's ability to infect cells. In essence, the virus must simultaneously bind both the chemokine receptor, for instance cysteine-cysteine chemokine receptor 5 (CCR-5), and CD4 on the cell surface to gain entry into the cell and initiate infection. This profound discovery has brought a new focus to the field of HIV research.

Exactly how are chemokine receptors involved in the AIDS disease process? Macrophage tropic HIV-1 strains are implicated in approximately 90% of sexually transmitted HIV, and it is CCR-5 that is the major co-receptor for this type of virus. These strains of HIV-1 are also known as non-synctitial inducing virus (NSI), which are associated with less severe disease. After the initial infection, the HIV-1 virus replicates and continually mutates, giving rise to new strains. Eventually, as the infection progresses, synctium inducing (SI) HIV-1 virus strains begin to predominate. These SI strains of HIV-1 use different chemokine receptors to specifically invade CD4+ T-cells and are known as T-cell lymphocyte (TCL) tropic. For example, SI strains invade T-cells by using the CXCR-4, or fusin, chemokine receptor, in conjunction with the CD4 receptor. Unfortunately, it is these SI virus strains that are especially virulent and responsible for rapid disease progression and the poor clinical outcome seen in many people with AIDS.

HIV-1 does not kill every individual that it infects, in fact, a few individuals seem entirely resistant to the virus, despite repeated exposure. Also, a small number of individuals experience a much slower disease progression. Studies focusing on the differences between these individuals and the larger number of individuals who acquire the disease more rapidly, yielded little information. Recently, it has been determined that chemokine receptors are probably responsible for this phenomenon of natural resistance in some of these individuals. Nathaniel Landau and Richard Koup's group at the Aaron Diamond AIDS Research Center , and several other research groups, have characterized this resistance to HIV-1 infection associated with changes in the CCR-5 chemokine receptor gene. Humans normally contain two copies of the CCR-5 gene. In some individuals this gene is missing 32 nucleotide base pairs and encodes a shortened, mutant protein incapable of being used as an HIV coreceptor. Approximately 10-15% of the Caucasian population have one normal CCR-5 gene and one mutant CCR-5 gene (heterozygous individuals) and only 1% have two mutant, non-functional genes (homozygous individuals). All individuals studied to date with two mutant CCR-5 genes were HIV-1 negative. Individuals with one mutant gene and one normal gene exhibited much slower disease progression and are called Longterm Non-Progressors (LTNPs). Homozygous individuals lacking the functional CCR-5 co-receptor are apparently healthy, which suggests that blocking these receptors might prevent HIV infection without adverse effects on the patient. Many naturally HIV-resistant individual possess two normal CCR-5 genes, perhaps other defective chemokine receptors are involved. Clearly more research needs to be done in this area.

The major question surrounding chemokine research is: How will chemokines and their receptors impact future treatments for HIV and AIDS? First of all, hope for any new therapies should be tempered with caution; attempts to block the CD4 co-receptor, with soluble CD4, were unsuccessful. Soluble CD4 was able to block infection by laboratory strains of HIV-1 but unable to block infection by many primary HIV-1 strains from HIV-infected individuals. With this in mind, two different strategies for chemotherapies might be envisioned. The first is to develop agents that raise natural levels of chemokines in the body which may help cells resist HIV infection. Limiting the accompanying effects of generalized inflammation and continuous white blood cell activation will be an important consideration with this and any chemokine-based approach. A second, more promising avenue might be the development of modified chemokines; in theory they would occupy the chemokine-HIV coreceptor without initiating the potential negative effects associated with chemokine binding and activation. British Biotech has developed a modified version of MIP-1a chemokine as a possible anti-HIV drug; clinical studies are planned for HIV-positive individuals. Fernando Arenzo-Seisodos, along with colleagues at the Pasteur Institute, and Swiss and Canadian researchers identified a RANTES derivative that does not induce chemotaxis. Researchers at the Geneva Biomedical Research Institute and their colleagues have also recently demonstrated that a derivative of RANTES was able to inhibit HIV-1 infection in macrophages and lymphocytes, in the laboratory. Many research groups with numerous collaborations are pursuing this type of drug discovery -identifying agents that block chemokine co-receptors without triggering inflammation.

On the vaccine front, vaccines that induce and increase the natural level of chemokines might be used to block infection of cells by HIV. Since the lack of CCR-5 chemokine receptor affords natural resistance to HIV it might also be possible to develop vaccines that cause the elimination of, or blocking of the co-receptor. At this point, the role of other chemokine receptors in natural HIV resistance is unclear. But it is plausible to think that the CXCR-4/fusin receptor, a target of synctium inducing (SI) virus in late disease, or other chemokine receptors may also be good candidates for vaccines. However, such approaches would also have to wait until the function of the co-receptors is more fully understood. Studies of other HIV-resistant individuals, but who have functional CCR-5 receptors, may clarify the potential role of other chemokine receptors in natural HIV resistance. These studies are currently underway.

HIV/AIDS infected individuals demand results from the research and clinical communities. The first practical application of chemokine research may be the development of a diagnostic test, for HIV-positive individuals, to determine presence of a mutated, non-functional CCR-5 co-receptor. Such diagnostic information may be predictive of disease progression and a consideration for clinical treatment strategies. It is clear that many questions remain for chemokine and HIV researchers to answer. Fortunately, current drug therapies are enjoying a certain amount of success in slowing HIV replication and the resulting immune collapse for a number of HIV positive individuals. Nevertheless, mutability of the virus necessitates the development of new therapies that further stymie AIDS progression, with the goal of making AIDS a manageable illness, much like diabetes is today. Chemokine research has marked a tremendous turning point in understanding HIV pathogenesis and natural resistance. The breakneck pace of current research offers the hope of new and better treatments in the battle against AIDS.

Steve is a microbiologist and member of STEP's Scientific Review Committee.

References

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