HIV Coreceptors and Chemokines as Therapeutic Targets Against HIV/AIDS

The Human Immunodeficiency Virus (HIV) is a marvel in its capacity to evade anti-viral countermeasures. This virus is able to employ a wide variety of mechanisms to sustain infection, including a high genomic mutation rate that enables gradual escape from host immune responses as well as the effects of therapeutic drugs. Consequently, clinical benefit in the treatment of HIV infection currently requires combinations of drugs that inhibit two distinct steps in the virus life cycle, genomic replication and the maturation of viral precursor proteins. Although such strategies are complex, expensive and to some extent toxic, they nevertheless prove that HIV infection can be controlled by chemotherapeutic agents. Given this foundation, the current goals for anti-HIV chemotherapy are to identify other steps in the virus life cycle, and the molecules involved in these processes, that may be targets for simplified, safer and more cost effective therapies. Strategies to inhibit the earliest steps in the virus life cycle are particularly attractive, as they would stop the spread of integrated proviruses which are impossible to eradicate without destruction of the host cell. Fortunately, entirely new possibilities for antiviral therapy have been introduced by recent discoveries concerning the nature of virus-cell interactions in HIV infection. During the past few years, it has been established that the ability of HIV to enter its host cell is entirely dependent on an array of 7 transmembrane spanning, G protein coupled receptors (GCR) now also called HIV coreceptors. More important, we have learned that the natural ligands for these receptors, chemokines, disrupt the viral entry process and effectively block viral replication. Consequently, the process of HIV entry has become a major target for therapeutic strategies that capitalize on these discoveries. This review will address the relationships between HIV infection and chemokine systems and how they may be exploited for the development of such strategies.