Tetherin (BST2) is the host cell factor that blocks the particle

Tetherin (BST2) is the host cell factor that blocks the particle release of some enveloped viruses. While cBST2504 failed to restrict wild-type feline immunodeficiency virus (FIV) egress FIV mutants bearing a frameshift at the level of the envelope-encoding region were potently blocked. The transient expression Cinnamic acid of the FIV envelope glycoprotein was able to rescue mutant particle release from feline tetherin-positive cells but did not antagonize human BST2 activity. Moreover cBST2504 was capable of specifically immunoprecipitating the FIV envelope glycoprotein. Finally cBST2504 also exerted its function on HIV-2 ROD10 and on the simian immunodeficiency virus SIVmac239. Taken together Cinnamic acid these results show that feline tetherin does indeed have a short N-terminal region and that the FIV envelope glycoprotein is the predominant factor counteracting tetherin restriction. INTRODUCTION All the viruses belonging to the family are characterized by specific properties such as the ability to infect macrophages and nondividing cells and a slow disease progression. In addition to these common features feline immunodeficiency virus (FIV) shares additional relevant similarities (14) with human immunodeficiency virus (HIV) the most important human pathogen belonging to this viral genus. Indeed while in nondomestic felids FIV is minimally pathogenic (6 8 27 62 63 Cinnamic acid as is the simian immunodeficiency virus (SIV) SIVagm and other naturally occurring SIVs in their natural hosts (66) the relatively recent jump to a new host species i.e. (42 64 has led to high immune virulence and to a severe immunodeficiency syndrome similar to the one caused by HIV-1 in humans. HIV-1 and HIV-2 similarly resulted from cross-species transmissions from chimpanzees/gorillas and sooty mangabeys respectively to humans (9 15 18 25 66 Thus FIV is the only nonprimate lentivirus that causes an AIDS-like disease in its natural Cinnamic acid host the domestic cat (3 43 44 72 In addition FIV enters target cells via CD134 (57) a T cell-costimulatory protein and CXCR4 (48 69 70 a coreceptor and its genome encodes a factor called Vif as is the corresponding one in HIV-1 that is required for the production of fully infectious virions (61). Given the close similarity Cinnamic acid of HIV and FIV in terms of genome structure mechanism of transmission course of infection as well as pathogenicity the domestic cat is considered the smallest available natural animal model for the study of AIDS in humans Cinnamic acid and for the development of potential therapeutic strategies (62 69 70 In addition to conventional innate and acquired immune responses humans and other mammals have evolved different antiviral factors to defend themselves from retroviral infection. Among these the so-called “host restriction factors” are host cellular proteins constitutively expressed or induced by interferon (IFN) in response to viral infection. Host restriction factors represent a crucial aspect of innate immunity defined as intrinsic immunity (4 19 The properties that mainly characterize these proteins and have contributed to their discovery are their species and virus specificities (28 52 53 The species-specific expression and activity of restriction factors limit viral host tropism and constitute a barrier to cross-species transmission events (64). In order to efficiently replicate retroviruses need to overcome restriction factors and have thus evolved countermeasures or strategies to antagonize ADAM17 them. In the case of HIV and SIV different counteracting factors have been identified among accessory and structural proteins including Vif Vpu Nef and the envelope glycoprotein (32). To date three major types of restriction factors acting at specific steps of the retroviral life cycle have been discovered: APOBEC3G (52 55 56 which targets reverse transcription; TRIM5α (59) which interferes with the uncoating of incoming capsids; and more recently tetherin/BST2 (40 65 which blocks the release of viral particles. Tetherin is constitutively expressed in human cell lines such as HeLa cells (22) several cancer cell lines (41) B cells T cells monocytes macrophages and plasmacytoid dendritic cells (5 36 67 and its expression can be induced by type I and type II interferon treatment (36 38 65 Tetherin also causes the retention of fully formed mature virions on the surface of cells infected with Vpu-deficient HIV-1 (40). The HIV-1 Vpu protein antagonizes tetherin by causing its degradation and sequestration into a perinuclear compartment.