Endogenous CD317/Tetherin Limits Replication of HIV-1 and Murine Leukemia Virus in Rodent Cells and Is Resistant to Antagonists from Primate Viruses

Abstract

Human CD317 (BST-2/tetherin) is an intrinsic immunity factor that blocks the release of retroviruses, filoviruses, herpesviruses, and arenaviruses. It is unclear whether CD317 expressed endogenously in rodent cells has the capacity to interfere with the replication of the retroviral rodent pathogen murine leukemia virus (MLV) or, in the context of small-animal model development, contributes to the well-established late-phase restriction of human immunodeficiency virus type 1 (HIV-1). Here, we show that small interfering RNA (siRNA)-mediated knockdown of CD317 relieved a virion release restriction and markedly enhanced the egress of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) in rat cells, including primary macrophages. Moreover, rodent CD317 potently inhibited MLV release, and siRNA-mediated depletion of CD317 in a mouse T-cell line resulted in the accelerated spread of MLV. Several virus-encoded antagonists have recently been reported to overcome the restriction imposed by human or monkey CD317, including HIV-1 Vpu, envelope glycoproteins of HIV-2 and Ebola virus, Kaposi's sarcoma-associated herpesvirus K5, and SIV Nef. In contrast, both rat and mouse CD317 showed a high degree of resistance to these viral antagonists. These data suggest that CD317 is a broadly acting and conserved mediator of innate control of retroviral infection and pathogenesis that restricts the release of retroviruses and lentiviruses in rodents. The high degree of resistance of the rodent CD317 restriction factors to antagonists from primate viruses has implications for HIV-1 smallanimal model development and may guide the design of novel antiviral interventions.

APOBEC3G Complexes Decrease Human Immunodeficiency Virus Type 1 Production

“…The concentration of p24 antigen in the pellet of the ultracentrifuged culture supernatant was divided by the sum of the amount of p24 antigen reactivity in the cell lysate and in the pellet of the ultracentri- fuged culture supernatant to yield the percent p24 antigen produced. The percentage of p24 antigen produced from HeLa cells cotransfected with HIV-1 and a control empty (A3G-negative expression) vector was comparable to that in similar experiments reported by others (13,16,47). Cells cotransfected with the control plasmid not expressing A3G, as well as cells cotransfected with the plasmid expressing C97A A3G-HA that did not form detectable A3G complexes at 24 h, each produced significantly more pseudovirions at 24 h than did cells cotransfected with WT A3G-HA or Y124A A3G-HA (Fig.…”

Molecular Determinants of Hepatitis B and D Virus Entry Restriction in Mouse Sodium Taurocholate Cotransporting Polypeptide

“…Tissue or cell type tropism of viral infection is sometimes restricted by cell-based antiviral defense mechanisms, for example, species specificity of primate lentiviruses imposed by the cytoplasmic body component TRIM5␣ (38) and the cytidine deaminase APOBEC3G (39), which blocks cross-species infection by targeting incoming viral capsid and deoxycytidines in reversetranscribed viral cDNAs, respectively. Moreover, retroviral infection could also be restrained by molecules such as CD317, also known as tetherin (40,41), which targets the progeny viral particle budding process. In fact, productive infection of HBV of human hepatocytes critically depends on some liver-specific transcription factors, e.g., HNF4A and HLF (42).…”

Feline Tetherin Efficiently Restricts Release of Feline Immunodeficiency Virus but Not Spreading of Infection

“…IFN-inducible factors restricting viral replication include the cytidine deaminase APOBEC3G (40,60) and the E3 ubiquitin ligase TRIM5 (1), both of which target replication primarily during the process of viral entry. A third IFN-inducible activity, tetherin (BST-2/ CD317/HM1.24), acts to restrict viral release (13,35,36,41,62). The importance of these factors in controlling viral replication is underlined by the requirement for lentiviral genomes to encode trans-acting countermeasures; lentiviral Vif proteins (33,54,55) and spumaviral Bet proteins (28,42,51) counteract APOBECs whereas HIV-1 Vpu, HIV-2 Nef, and HIV-2 and simian immunodeficiency virus (SIV) Envs may counteract tetherins (15,18,26,35,36,62,65).…”