PERSPECTIVE
Promiscuous Chemokine Receptors and Their Redundant Ligands Play an Enigmatic Role during HIV-1 Infection

Steven L. Kunkel

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

There is little doubt that basic biomedical research efforts in the last fifty years have provided great mechanistic insight into disease processes. While these advances are likely to take a prominent place in historic archives, they barely appear on the radar screen when compared to the history-altering impact of past and present global infectious diseases. The plague(s), malaria, yellow fever, schistosomiasis, influenza, small pox, polio, and human immunodeficiency virus (HIV) have all exacted a heavy toll on humanity and have truly altered the course of history during the past millennium. Although significant strides recently have been made to halt some of these disease-causing agents, mainly via vaccine development, therapeutic advances to treat and cure others have been painfully slow. A number of reasons may account for this slow progress toward therapeutic development, ranging from lack of significant interest by modern countries' funding agencies, regarding parasite research, for example, to the uncanny ability of certain infectious agents to elude mechanistic scrutiny. The best recent example of this latter scenario is the multitude of difficulties associated with the biology, pathogenesis, treatment, and prevention of HIV infection. While heavy emphasis is currently directed toward HIV vaccine development, this preventive approach has a variety of hurdles to clear, including a better understanding of the basic biology of HIV infection. To underscore the complexities associated with the basic biology of HIV, only recently have years of basic research efforts begun to pay dividends and shed some light on mechanisms of viral entry into specific leukocyte subpopulations (1).

The studies by Park and coworkers, presented in this issue of the Red Journal, begin to address some of the complexities of HIV infection in lung inflammatory cells (4). Their investigations suggest that macrophage-tropic or dual-tropic HIV-1 entry into alveolar macrophages preferentially utilize CD4 and the chemokine receptor CCR5. Additional interesting data show that despite the expression of the chemokine receptor CXCR4 by alveolar macrophages, which should allow entry of T-tropic HIV-1, this viral strain did not efficiently enter alveolar macrophages. Park and colleagues supply information that supports the concept that HIV-1 entry into alveolar macrophages is viral-strain specific, even though these cells express CD4 and the chemokine receptor which should allow entry of other viral strains. Thus, the mechanism(s) involved in HIV entry is truly more complex than the simultaneous expression of CD4 and a chemokine receptor, and may require additional, as yet undetermined, cofactors.

The studies of Park and associates are only one of many that support a fundamental enigma associated with the field of chemokine biology. What are the true biologic roles of the 50-plus chemokine ligands and the 14 to 15 different chemokine receptors during the initiation, maintenance, and resolution of human disease? This question is further confounded by the established promiscuity found in the ligand:receptor interactions that may occur between the multiple members of the chemokine family (5). As shown in Table 1, chemokines are a large family of multiple proteins that may bind to various ligands. Therefore, it may not be too surprising that different HIV strains may possess some degree of chemokine-receptor promiscuity as the virus searches for a CD4⁺ chemokine-receptor positive cell (6, 7). However, the possibility exists that chemokine-receptor expression may not convey the final specificity for viral entry, as the data regarding alveolar macrophages imply in the Park article.

Expression of specific chemokine receptors by CD4⁺ leukocytes is clearly a programmed response of these cells, directed toward sampling their local environment for the presence of an appropriate activating/chemotactic factor (chemokine ligand). A number of studies have demonstrated that specific chemokine-receptor expression is associated with the activation of a specific subpopulation of leukocytes and the subsequent development of a particular type of immune response (8, 9). For example, there is increasing evidence to support the notion that type-1 immune responses, dictated by the production of interferon- and interleukin (IL)-12, involve the expression of CXCR3 and CCR5 (10), whereas type-2 responses, dictated by the production of IL-4 and IL-13, involve the expression of CCR3 and CCR8 (11, 12). The expression of specific chemokine receptors in conjunction with an appropriate production pattern of adhesion molecules likely insures the response-specific recruitment and activation of effector cells. This process is the consequence of an established cytokine/chemokine cascade, whose primary purpose is to mount an appropriate response to an immunologic challenge, rather than render leukocytes susceptible to viral entry.

The programmed induction of chemokine receptor expression on CD4⁺ leukocytes is of clear benefit to the host in mounting an appropriate immune response, although the subsequent use of these receptors by HIV is likely the result of evolution and a millennium of genetic pressures. Apparently, these genetic pressures push both ways, as the 32 base-pair deletion in the CCR5 receptor gene (32-CCR5) on human leukocytes has allowed for some resistance to infection without impairing the host's immune response (13). The data based on chemokine-receptor usage and HIV biology have risen exponentially in the past few years; however, this knowledge has not directly transferred into a silver therapeutic bullet to treat acquired immunodeficiency syndrome, which necessitates a more complete understanding of host-HIV interactions.

	Footnotes

Address correspondence to: Steven L. Kunkel, Ph.D., Dept. of Pathology, 1301 Catherine Rd., The University of Michigan Medical School, Ann Arbor, MI 48109-0602.

(Received in original form March 8, 1999).

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