Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodeficiency viruses

Abstract

Human immunodeficiency virus type 1 (HIV-1) requires both CD4 and a coreceptor to infect cells. Macrophage-tropic (M-tropic) HIV-1 strains utilize the chemokine receptor CCR5 in conjunction with CD4 to infect cells, while T-cell-tropic (T-tropic) strains generally utilize CXCR4 as a coreceptor. Some viruses can use both CCR5 and CXCR4 for virus entry (i.e., are dual-tropic), while other chemokine receptors can be used by a subset of virus strains. Due to the genetic diversity of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) and the potential for chemokine receptors other than CCR5 or CXCR4 to influence viral pathogenesis, we tested a panel of 28 HIV-1, HIV-2, and SIV envelope (Env) proteins for the ability to utilize chemokine receptors, orphan receptors, and herpesvirus-encoded chemokine receptor homologs by membrane fusion and virus infection assays. While all Env proteins used either CCR5 or CXCR4 or both, several also used CCR3. Use of CCR3 was strongly dependent on its surface expression levels, with a larger number of viral Env proteins being able to utilize this coreceptor at the higher levels of surface expression. ChemR1, an orphan receptor recently shown to bind the CC chemokine I309 (and therefore renamed CCR8), was expressed in monocyte and lymphocyte cell populations and functioned as a coreceptor for diverse HIV-1, HIV-2, and SIV Env proteins. Use of ChemR1/CCR8 by SIV strains was dependent in part on V3 loop sequences. The orphan receptor V28 supported Env-mediated cell-cell fusion by four T-or dual-tropic HIV-1 and HIV-2 strains. Three additional orphan receptors failed to function for any of the 28 Env proteins tested. Likewise, five of six seven-transmembrane-domain receptors encoded by herpesviruses did not support Env-mediated membrane fusion. However, the chemokine receptor US28, encoded by cytomegalovirus, did support inefficient infection by two HIV-1 strains. These findings indicate that additional chemokine receptors can function as HIV and SIV coreceptors and that surface expression levels can strongly influence coreceptor use.

Human chemokine receptors CCR5, CCR3 and CCR2B share common polarity motif in the first extracellular loop with other human G‐protein coupled receptors

“…Taken together, these results confirm the role of CCR5 as the major coreceptor for M-tropic HIV-1 [17,41,42] and also the importance of GPR-CY6 as another coreceptor for M-tropic strains [43,44]. In addition, we show that BRB2, well known to play an important role in regulation of blood pressure and heart rate [45], can also act as coreceptor for the entry of M-tropic HIV-1 strains.…”

CCR7, CCR8, CCR9 and CCR10 in the mouse hippocampal CA1 area and the dentate gyrus during and after pilocarpine‐induced status epilepticus

“…It has been known that chemokines play some roles in multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD) and acquired immunodeficiency syndrome (AIDS; Cocchi et al 1995;Feng et al 1996;Berger 1997;Rucker et al 1997). In the immune system, chemokines promote cell survival, whereas in the CNS neuronal chemokine receptors may serve as trophic and protective factors to enhance the survival of neurons (Araujo and Cotman 1993;Horuk et al 1997;Limatola et al 2000;Olimpia et al 2000;Eugenin et al 2003;Watson and Fan 2005).…”

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

“…Along with strong expression on monocytes (Geissmann et al, 2003) and NK cells (Imai et al, 1997b), CX3CR1 is present on lymphocytes, microglial cells (Nishiyori et al, 1998), and neurons (Meucci et al, 2000). CX3CR1 has HIV coreceptor activity (Reeves et al, 1997;Rucker et al, 1997), and its interaction with gp120 is blocked specifically by CX3CL1 . However, the pattern of HIV strains that can use CX3CR1 is restricted, suggesting that this receptor may not play a key role in HIV.…”