Feline immunodeficiency virus targets activated CD4 ⁺ T cells by using CD134 as a binding receptor

Abstract

The major surface glycoprotein of feline immunodeficiency virus (FIV) specifically binds to a 43-kDa glycoprotein expressed on the surface of a subset of T cells in peripheral blood mononuclear cells and IL-2-dependent T cell lines. Binding to this molecule, in conjunction with CXC chemokine receptor (CXCR) 4, is required for productive infection of these cells by primary isolates of FIV. Here, we demonstrate that the 43-kDa molecule is CD134, a receptor for FIV recently identified independently [Shimojima, M., et al. (2004) Science 303, 1192-1195]. Furthermore, we show that CD134 is specifically up-regulated on CD4 + T cells that have been activated by treatment with IL-2 and Con A. CD8 + T cells remained negative for CD134 expression regardless of the activation state. Binding of the FIV major surface glycoprotein on activated CD4 + T cells was observed through direct interaction with CD134 whereas, on activated CD8 + T cells, the binding was CD134-independent and mediated by CXCR4 and, to a lesser extent, heparan sulfate proteoglycans. However, this CD134-independent interaction was not sufficient to render CD8 + T cells permissive to FIV infection, as FIV replicated primarily in activated CD4 + T cells and not in cells negative for CD134 expression. Altogether, our results substantiate that CD134 acts as a primary binding receptor for FIV and explain the specific targeting and depletion of the CD4 + T cell population observed during the course of infection independent of the use of CD4 as a binding receptor/coreceptor.

Effect of Bovine Lactoferrin on Functions of Activated Feline Peripheral Blood Mononuclear Cells During Chronic Feline Immunodeficiency Virus Infection

“…Persistent immune activation in HIV and FIV infection results in progression to AIDS [6,8,23]. Recent studies reported that FIV targets activated CD4+ cells using its primary receptor upregulated by stimuli and cytokines, indicating the infection is propagated in activated and proliferating T cells preferentially [4,14,22]. Additionally, lasting activation of immune cells leads to an anergic state of the cells and a lack of sensitivity to immune response including failures of cytokine production, antigen recognition and transmission of signaling pathways [12,16].…”

Binding of equine infectious anemia virus to the equine lentivirus receptor-1 is mediated by complex discontinuous sequences in the viral envelope gp90 protein

“…Interestingly, ELR1 is a member of the TNFR protein family, and TNFR-like proteins have been identified as receptors for certain avian oncoviruses and as a co-receptor component (CD134) for FIV (Brojatsch et al, 1996;Adkins et al, 1997Adkins et al, , 2000de Parseval et al, 2004;Shimojima et al, 2004;Zhang et al, 2005;Barnard et al, 2006). Taken together, these observations suggest that EIAV may represent a critical transitional link between the simple oncoviruses and the more complex immunodeficiency lentiviruses in terms of genetic composition and receptor usage.…”

“…The SU protein is bound at the virion surface through interaction with the TM protein and is responsible for the initial binding to receptor proteins on the target cell surface. Studies of the specificity of functional receptors for various retroviruses have indicated a general pattern of single receptor protein use by oncoviruses (such as murine and avian leukemia viruses) that is in distinct contrast to the dual co-receptor usage observed with the lentiviruses human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) (Eiden et al, 1993;de Parseval et al, 2004;Douglas et al, 1997;Barnard et al, 2006). Whilst the general assumption has been that all lentiviruses may use dual co-receptors for infection of target cells, the recent identification of a single functional receptor for equine infectious anemia virus (EIAV) has revealed an unexpected diversity in lentivirus receptor specificity and interactions .…”

“…The receptor-binding domain has been located in the Nterminal third of the subunit, and two variable regions, VRA and VRB, have been shown to contribute to receptor recognition for the amphotropic and ecotropic MuLVs (Heard & Danos, 1991;Battini et al, 1992;Ott & Rein, 1992; Morgan et al, 1993;Battini et al, 1995). In contrast to MuLV receptor usage, HIV, SIV and FIV have been shown to recognize the CD4 (HIV-1, HIV-2 and SIV) or CD134 (FIV) proteins as a primary binding receptor, with either CXCR4 or CCR5 chemokine receptor as a secondary co-receptor for infection of target cells (Douglas et al, 1997;de Parseval et al, 2004de Parseval et al, , 2005Shimojima et al, 2004;Gomez & Hope, 2005). The detailed structural characterizations of HIV-1 gp120 and its co-receptors provide the prototypic model for the functional binding of lentivirus SU proteins to dual co-receptors, distinct from that of MuLV (Fass et al, 1997;Poignard et al, 2001).…”

Genetically Divergent Strains of Feline Immunodeficiency Virus from the Domestic Cat ( Felis catus ) and the African Lion ( Panthera leo ) Share Usage of CD134 and CXCR4 as Entry Receptors

“…There have been conflicting reports regarding the pathogenicity of lentiviruses in nondomestic felids, and the observation that two distinct biological phenotypes can be discerned between subtypes B and E of FIV Ple may indicate distinct pathogenicities in vivo. The virus-receptor interaction is a critical determinant of viral cell tropism and cytopathicity, and FIV Fca targets activated CD4 ϩ T cells primarily due to the restricted expression of the primary receptor CD134 and coreceptor CXCR4 in this T-cell compartment (12,34,49). Accordingly, a decline in circulating CD4 ϩ T lymphocytes is associated with FIV infection of the domestic cat (1).…”