In the past five years, a large number of new chemokines and chemokine receptors have been identified. Alarming progress in the areas of bioinformatics and expressed sequence tag (EST) databases attributed to this development. Recent discoveries provide compelling evidences supporting the roles of these messengers and their receptors in the control of viral infection as well as in aiding virus survival. Chemokines in Viral Infections is the first to provide a comprehensive write up on the various evidences available to date on the interactions between host chemokine system and viral chemokines. This book intends to unravel the chemokine constellation in the context of viral infections, a versatility that was not fully understood five years ago. This book is excellent reading material and will be of interest to research scientists, clinicians and postgraduate students.

Chemokines represent a family of over 40 small proteins that, for the most part, are secreted into the environment and function by binding to G protein-coupled receptors (GPCRs) that are expressed on numerous different cell types. When initially identified close to 30 years ago, these molecules were associated with various human inflammatory diseases and it was recognized that expression may be integral in leukocyte recruitment to inflamed tissue. Within a relatively short period of time, early participants within the field determined that these proteins displayed distinct and conserved structural features and exerted potent chemotactic effects on defined lymphocyte subsets. There are now four sub-families of chemokines identified based on defined structural criteria relating to the positional location of conserved cysteine residues within the amino-terminus of the protein. Chemokines are now recognized as important in numerous biological processes ranging from maintaining the organizational integrity of secondary lymphoid tissue to participating in various aspects of both innate and adaptive immune responses following microbial infection.

A comprehensive review of what is known about the role of cytokines and chemokines in a variety of human infectious diseases, including gram-negative and -positive infections, listeriosis, mycobacterial infections, lyme arthritis, pneumonia, fungal infections, HIV, leishmaniasis, and sepsis. The authors demonstrate the different cytokine and chemokine production profiles in response to a wide variety of pathogens and the importance of host genetic factors in determining the type and magnitude of responses to a given microorganism. They also critically evaluate the use of cytokines and anticytokines in the treatment of infectious diseases and show how knowledge of cytokine pleiotropic effects, redundancy, and the complexity of the cytokine network has led to better design and better outcomes in cytokine-based therapies for specific infections.

Sexual transmission of HIV-1 is often established by one genetic variant, the transmitted/founder (T/F) virus. T/F HIV-1 may have specific phenotypic properties that are selected for during transmission. To date, the most consistent phenotypic property associated with T/F viruses is use of the chemokine receptor CCR5 as a coreceptor for entry. Small molecule CCR5 antagonists, such as Maraviroc (MVC), inhibit HIV-1 entry by functioning as allosteric inhibitors. These molecules bind within the transmembrane helices of CCR5, inducing a conformational change that prevents the HIV-CCR5 interaction. As with most drugs, HIV-1 has developed strategies to overcome this inhibition. Some viruses develop mutations in the envelope (Env) glycoprotein that enable the use of antagonist-bound CCR5. In Chapter Two, we evaluate 87 CCR5-using viruses to address differences between T/F viruses and viruses isolated from chronically infected individuals (chronic controls-CC) in their ability to mediate entry via varying amounts of CCR5 in the presence of MVC. We demonstrate that CC viruses exhibit partial resistance (PR) to MVC more frequently than T/F viruses, suggesting that T/F and CC HIV-1 differentially utilize CCR5 in a manner that may be biologically important in the context of transmission. Following the discovery of the chemokine receptors CXCR4 and CCR5 as cofactors for HIV-1 entry, it was revealed that their cognate chemokine ligands could inhibit HIV-1 infection in vitro. Multiple cell types have been implicated in secreting chemokines that function to modulate HIV-1 infection. Recently the platelet-derived chemokine PF4 was shown to inhibit HIV-1. However, despite plasma and local concentrations of PF4 being within the range used in these studies, HIV-1 is still able to propagate in vivo. In Chapter Four, we sought to understand the mechanism of action of PF4 and determine it's in vivo relevance. I confirmed and extended previous studies showing that PF4 inhibits infection by HIV-1 and other viruses. However, the inhibitory capacity of PF4 is limited to a defined concentration range, after which inhibition wanes and viral infection is ultimately enhanced at higher chemokine concentrations that are commonly found in vivo. Thus, rather than being a potential anti-viral agent as previously suggested, PF4 may contribute to the hematologic abnormalities commonly seen in HIV-infected individuals by enhancing virus infection in the bone marrow.