Potential Role for CD63 in CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection of Macrophages

Abstract

Macrophages and CD4؉ lymphocytes are the principal target cells for human immunodeficiency virus type 1 (HIV-1) infection, but the molecular details of infection may differ between these cell types. During studies to identify cellular molecules that could be involved in macrophage infection, we observed inhibition of HIV-1 infection of macrophages by monoclonal antibody (MAb) to the tetraspan transmembrane glycoprotein CD63. Pretreatment of primary macrophages with anti-CD63 MAb, but not MAbs to other macrophage cell surface tetraspanins (CD9, CD81, and CD82), was shown to inhibit infection by several R5 and dualtropic strains, but not by X4 isolates. The block to productive infection was postfusion, as assessed by macrophage cell-cell fusion assays, but was prior to reverse transcription, as determined by quantitative PCR assay for new viral DNA formation. The inhibitory effects of anti-CD63 in primary macrophages could not be explained by changes in the levels of CD4, CCR5, or ␤-chemokines. Infections of peripheral blood lymphocytes and certain cell lines were unaffected by treatment with anti-CD63, suggesting that the role of CD63 in HIV-1 infection may be specific for macrophages.

Tetraspanins CD9 and CD81 Modulate HIV-1-Induced Membrane Fusion

“…Given that viruses depend on their host cells to replicate and spread, surface protein distribution and intracellular activation state of target cells may affect the efficiency of infection. Tetraspanins are proteins involved in a wide range of cellular and viral processes, particularly fusion events (21)(22)(23)(24)(25)(26)(27)(28)45). Tetraspanins may also regulate preliminary steps of viral cycle due to their function as molecular organizers of cellular membrane protein microdomains (13).…”

“…Tetraspanins are also involved in membrane fusion events such as sperm-oocyte fusion (20), myotube formation (21), and fusion of mononuclear phagocytes (22). In addition, these molecules are implicated in viral processes such as CD63 in HIV infection (23,24), CD81 in hepatitis C virus infection (25), CD82 in cell-to-cell human T cell leukemia virus type I (HTLV-1) spreading (26), and CD9 in feline immunodeficiency virus (FIV) and canine distemper virus spreading (27,28).…”

Macrophages and HIV-1: dangerous liaisons

“…The differential inclusion of cellular proteins in viral particles may be relevant for virus transmission and replication. The CD63 molecule may be involved in R5 HIV-1 infection of macrophages but not of T cells (von Lindern et al, 2003). In macrophages, budding into endosomes may render the virus inaccessible to antiviral inhibitors, including RNAi, and enable the virus to persist in macrophages, which function as viral reservoirs.…”

Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to CD81-dependent infection by malaria sporozoites

“…For instance, infection by some viruses can be specifically blocked by antibodies to certain tetraspanins, including human T cell leukemia virus 1 by anti-CD81 and anti-CD82 antibodies (Imai and Yoshie, 1993), canine distemper virus and feline immunodeficiency virus by anti-CD9 antibodies (Loffler et al, 1997;Willett et al, 1997), and human immunodeficiency virus 1 by anti-CD63 antibodies (von Lindern et al, 2003). Additionally, the tetraspanin CD81 is required for infection of hepatocytes by hepatitis C virus (HCV), and functions as a receptor for HCV envelope glycoprotein E2, at least for certain viral strains (Bartosch et al, 2003;Pileri et al, 1998;Zhang et al, 2004).…”