Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses

Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus originally identified in human prostate cancers (33). Small numbers of XMRV-infected cells have been observed in prostatic stromal cells but not in prostate carcinoma (33). Another study identified XMRV proviral DNA in 6 and 23% of prostate tumors when analyzed by real-time PCR and immunostaining, respectively (27). While initial studies associated XMRV almost exclusively in men who were homozygous for a variant of RNase L (R462Q), which is known to have reduced antiviral activity (33), more recent work failed to link XMRV infection and RNase L mutation (4). XMRV has also been reported in patients with chronic fatigue syndrome (CFS) (17). A total of 67% of CFS patients were positive for XMRV proviral DNA, whereas only 3.7% of healthy subjects were positive for XMRV. Subsequent testing by several other groups found no evidence of infection with XMRV in CFS patients or in healthy controls (30). In Europe, no XMRV was detected in 139 prostate cancer patients in an Irish cohort (4), while no or very few XMRV-specific DNA, RNA, or antibodies were detected in Germany or the United Kingdom cohort of CFS (7, 10, 34).These conflicting data make it unclear to what degree XMRV infects humans and whether it plays a role in human diseases. If an etiological link is confirmed, detection and prevention of XMRV would provide novel intervention strategies for early diagnosis and treatment of both diseases. Moreover, since XMRV or XMRV-specific antibodies were detected in apparently healthy subjects, it would be critical to monitor XMRV contamination in clinical products for transfusion and transplantation.For a better understanding of XMRV transmission, tissue tropism, and pathogenicity, studies of XMRV infection in animal models are crucial. Laboratory mice have provided important small animal model systems for many human diseases, due to their availability, size, low cost, ease of handling, and fast reproduction rate, and extensive studies have been carried out in mice to study the pathogenesis of closely related murine leukemia viruses (MLVs) (5,11,20,23,32). However, studies of XMRV pathogenesis in a mouse model have been hampered by the lack of functional receptor for XMRV in standard laboratory mice derived from Mus musculus species.XMRV is closely related to xenotropic MLVs (X-MLVs) (33). The X-MLVs and polytropic MLVs (P-MLV) use Xpr1 as a receptor for cell entry (1, 31, 37), and so does XMRV (6, 13, 36). Xpr1 has four known variant receptor alleles in mice, Xpr1 n , Xpr1 sxv , Xpr1 c , and Xpr1 p , and each has a different susceptibility for P-MLV and/or X-MLV (35). P-MLV uses Xpr1 n as receptor and most cells from Mus musculus laboratory mice express this receptor (35). Wild mice of the Eurasian genus Mus, such as Mus dunni, express the Xpr1 sxv allele and are susceptible to both P-MLV and X-MLV, whereas the Asian mouse species Mus castaneus expresses Xpr1 c and is susceptible only to X-MLV (19). Mus pahari is another Asian wild mouse species. T...

Section: Discussionmentioning

confidence: 90%

Early Events in Retrovirus XMRV Infection of the Wild-Derived MouseMus pahari

Sakuma

Tonne

Squillace

et al. 2011

“…A 17-amino-acid-long immunosuppressive domain of EBOV is highly similar to the domain in the p15E envelope proteins of nononcogenic retroviruses (23,24). The biological effects of the immunosuppressive domain of retroviruses have been studied extensively and include disabling the activity of protein kinase C, which is involved in T cell activation, suppression of cell-mediated immunity, and the induction of an imbalance between Th1 and Th2 responses (25). The peptides corresponding to the immunosuppressive domain of EBOV showed strong suppression of activation and strong apoptosis of human CD4 ϩ and CD8 ϩ T cells (24).…”

mentioning

confidence: 99%

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

Lubaki

Ilinykh

Pietzsch

et al. 2013

127

dEbola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the "immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs.

“…By comparison, retroviruses of the Lentivirus genus lack this third, C-terminal cysteine, further supporting its role as the mediator of the intersubunit disulfide bond. Second, those retroviruses with covalently bonded subunits also encode an immunosuppressive domain (ISD), lacking in lentiviruses, that has been shown to inhibit lymphocyte proliferation (40) and allow escape from immune effectors of the innate and adaptive arms of the host immune system in a mouse model (41)(42)(43)(44). Third, the membrane proximal external region (MPER)-a stretch of 30 residues immediately upstream of the transmembrane region that is thought to be important for Env protein incorporation into virions, as well as membrane disruption during fusion (45-47)-is longer in lentiviruses by 25 to 30 amino acids (48).…”

Section: Betaretroviral and Lentiviral Tms Share Sequence Features Imentioning

confidence: 99%

Betaretroviral Envelope Subunits Are Noncovalently Associated and Restricted to the Mammalian Class

Henzy

Coffin

2013

The structure of the transmembrane subunit (TM) of the retroviral envelope glycoprotein (Env) is highly conserved among most retrovirus genera and includes a pair of cysteines that forms an intramolecular disulfide loop within the ectodomain. Alpha-, gamma-, and deltaretroviruses have a third cysteine, adjacent to the loop, which forms a disulfide bond between TM and the surface subunit (SU) of Env, while lentiviruses, which have noncovalently associated subunits, lack this third cysteine. The Betaretrovirus genus includes Jaagsiekte sheep retrovirus (JSRV) and mouse mammary tumor virus (MMTV), as well as many endogenous retroviruses. Envelope subunit association had not been characterized in the betaretroviruses, but lack of a third cysteine in the TM ectodomain suggested noncovalently associated subunits. We tested the Env proteins of JSRV and MMTV, as well as human endogenous retrovirus K (HERV-K)108 -a betaretrovirus-like human endogenous retrovirus-for intersubunit bonding and found that, as in the lentiviruses, the Env subunits lack an intersubunit disulfide bond. Since these results suggest that the number of cysteines in the TM loop region readily distinguishes between covalent and noncovalent structure, we surveyed endogenous retroviral TM sequences in the genomes of vertebrates represented in public databases and found that (i) retroviruses with noncovalently associated subunits have been present during all of anthropoid evolution and (ii) the noncovalent env motif is limited to mammals, while the covalent type is found among five vertebrate classes. We discuss implications of these findings for retroviral evolution, cross-species transmissions, and recombination events involving the env gene. R etrovirus infection is mediated by the envelope (Env) glycoprotein, which is a class I viral fusion protein (VFP) in all of the orthoretroviral genera except the epsilonretroviruses. Class I VFPs are synthesized as precursors that trimerize in the endoplasmic reticulum and are cleaved by cellular furin in the late Golgi apparatus to generate two subunits: a surface subunit (SU), which interacts with the receptor on target cells, and a transmembrane subunit (TM), which mediates fusion and is anchored in the viral envelope near its C terminus. After cleavage, SU and TM remain associated either noncovalently or via an intersubunit disulfide bond (1-3, 82, 83), resulting in trimers of heterodimers that traffic to the cell's plasma membrane to become part of the viral envelope when newly synthesized particles bud from the cell (4).During infection, the fusion subunits of class I VFPs go through a series of conformational changes that lead from a metastable to a stable state. The first conformational change, which occurs upon binding of SU to the receptor, exposes a hydrophobic region at the N terminus of TM-the fusion peptide-which inserts into the plasma membrane of the target cell. This step then triggers the formation by TM of a highly stable six-helix bundle, a trimeric hairpin structure built around alpha-helic...