Chemokines in Human Immunodeficiency Virus (HIV) Infection (Commentary) (Report‪)‬

In 1986, just about two years after the identification of HIV-1 as the causative agent of AIDS, a research team led by J.A. Levy demonstrated that [CD8.sup.+] T cells are capable to prevent in vitro HIV-1 infection of susceptible cells by secreting soluble factors (1). However, the exact nature of these factors remained unknown until a research team led by P. Lusso demonstrated that three inflammatory CC chemokines, RANTES (CCchemokine ligand 5 or CCL5), macrophage inflammatory protein 1[alpha] (MIP-1 [alpha] or CCL3) and MIP 1 [beta] (CCL4) were the major components of the HIV-suppressive factor(s) released by [CD8.sup.+] T cells (2). Joon Feng and colleagues identified CXCR4, a receptor for the CXC chemokine stronal cell-derived factor 1 (SDF1), as the long sought coreceptor for T-tropic HIV-1 strains (3). It is well known that the expression of human CD4, the high-affinity receptor for HIV-1, was necessary but not sufficient for viral entry (4) and a species-specific cofactor was required (5). These discoveries led within a few months to another milestone of the HIV research, i.e., the identification of CCR5, a receptor for CC chemokines, as the main coreceptor for primary Mtropic HIV-1 strains (6). Although other chemokine receptors have been identified that can facilitate HIV infection in vitro (7), it is now well recognized that only CCR5 and CXCR4 are the critical coreceptors for HIV infection in vivo. Chemokines are small proteins in the cytokine family that bind to chemokine receptors promoting a large number of functions among which, more importantly, the development and homeostasis of the immune system, the cellular movement by chemotaxis, the stem cell survival, the angiogenesis. They are divided into four subfamilies based on structure and primary amino acid sequence: CXC, CC, C, and CX3C (8). To date, approximately 50 human chemokines and 20 receptors have been discovered. In addition to HIV infection, chemokines and their receptors are found associated with many pathologies including transplant rejection, cancer, autoimmune, pulmonary and vascular diseases (for a comprehensive review see (9)).