HIV and the 7-Transmembrane Domain Receptors

Abstract

The recent discovery of a chemokine receptor, fusin (fusin/CXCR-4), as the long-sought human immunodeficiency virus type 1 (HIV-1) coreceptor opened an entirely new field of aquired immunodeficiency syndrome (AIDS) research on mechanisms of viral entry, tropism and pathogenesis. It was soon followed by the identification of the chemokine receptor CCR-5 as the major macrophage-tropic (M-tropic) HIV-1 coreceptor and the demonstration that other chemokine receptors, CCR-3 and CCR-2b, also may serve as coreceptors, albeit at somewhat lower efficiency. Very recently it was demonstrated that the mechanism of the coreceptor function involves the formation of a complex on the cell surface between the HIV-1 envelope, the primary receptor CD4 and the coreceptor. Thus the prevention of the HIV-1 envelope glycoprotein-mediated fusion by the chemokines RANTES, macrophage inflammatory protein-1α (MlP-1α) and MlP-1β, as well as by the recently identified fusin/CXCR-4 ligand, stromal cell-derived factor-1 (SDF-1) could be explained by disruption of that complex. Interestingly, the identification of the HIV-1 coreceptor CCR-5 not only provided new insights into the mechanisms of viral entry and tropism, but also may help in explaining why some people with genetic alterations in CCR-5 are protected from HIV-1 infection.

Coreceptor Competition for Association with CD4 May Change the Susceptibility of Human Cells to Infection with T-Tropic and Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1

“…Together, these findings suggested that in certain cells with low CD4 densities, the relative levels of CCR5 and CXCR4 expression and their ability to associate with CD4 may influence the susceptibility of the cells to infection with X4 and R5 viruses, as was previously speculated (5). In the present study, we provide evidence that CCR5 and CXCR4, when expressed in the same cell, interfere with each other's function during HIV-1 envelope-mediated cell fusion and viral cell entry.…”

N-Linked Glycosylation of CXCR4 Masks Coreceptor Function for CCR5-Dependent Human Immunodeficiency Virus Type 1 Isolates

“…Although some 15 related coreceptor molecules have been shown by one or more laboratories to function in the fusion or entry of at least one HIV isolate, it is now well recognized that the principal HIV-1 coreceptors remain the initially discovered CXC chemokine receptor CXCR4 and the CC-chemokine receptor CCR5 (7,21). Previously, it was hypothesized that the very first step in HIV-1 entry involves the formation of a trimolecular complex between the viral Env, CD4, and a coreceptor molecule (18,33,52), and both functional and biochemical evidence to support this hypothesis has been reported (35,59,84,88,90). Defining the elements of the coreceptor molecules involved in these interactions is of critical importance for our understanding of the virus entry mechanism.…”

Human Uterine Natural Killer Cells but Not Blood Natural Killer Cells Inhibit Human Immunodeficiency Virus Type 1 Infection by Secretion of CXCL12

“…This is either directly, through antibody-dependent cell-mediated cytotoxicity (2,18,38,43), or indirectly, through the production of chemokines; CC-chemokine ligand 3 (CCL3; also called MIP-1␣), CCL4 (MIP1-␤), and CCL5 (RANTES), which are natural ligands of CCR5 (10) and which block viruses that utilize the CCR5 coreceptor for entry (5,6,9,13,16,26). NK cells also produce cytokines, including gamma interferon (IFN-␥), granulocyte/ macrophage colony-stimulating factor, and tumor necrosis factor alpha which can suppress HIV replication by recruiting other effector cells (16).…”