scholarly journals Appearance of Mink Cell Focus-Inducing Recombinants during In Vivo Infection by Moloney Murine Leukemia Virus (M-MuLV) or the Mo+PyF101 M-MuLV Enhancer Variant: Implications for Sites of Generation and Roles in Leukemogenesis

1999 ◽  
Vol 73 (7) ◽  
pp. 5671-5680 ◽  
Author(s):  
Jeffrey K. Lander ◽  
Bruce Chesebro ◽  
Hung Fan
Keyword(s):  
Bone Marrow ◽  
Murine Leukemia Virus ◽  
Time Course ◽  
Leukemia Virus ◽  
The Other ◽  
Other Hand ◽  
Disease Induction ◽  
Mink Cell ◽  
Murine Leukemia

ABSTRACT One hallmark of murine leukemia virus (MuLV) leukemogenesis in mice is the appearance of env gene recombinants known as mink cell focus-inducing (MCF) viruses. The site(s) of MCF recombinant generation in the animal during Moloney MuLV (M-MuLV) infection is unknown, and the exact roles of MCF viruses in disease induction remain unclear. Previous comparative studies between M-MuLV and an enhancer variant, Mo+PyF101 MuLV, suggested that MCF generation or early propagation might take place in the bone marrow under conditions of efficient leukemogenesis. Moreover, M-MuLV induces disease efficiently following both intraperitoneal (i.p.) and subcutaneous (s.c.) inoculation but leukemogenicity by Mo+PyF101 M-MuLV is efficient following i.p. inoculation but attenuated upon s.c. inoculation. Time course studies of MCF recombinant appearance in the bone marrow, spleen, and thymus of wild-type and Mo+PyF101 M-MuLV i.p.- and s.c.-inoculated mice were carried out by performing focal immunofluorescence assays. Both the route of inoculation and the presence of the PyF101 enhancer sequences affected the patterns of MCF generation or early propagation. The bone marrow was a likely site of MCF recombinant generation and/or early propagation following i.p. inoculation of M-MuLV. On the other hand, when the same virus was inoculated s.c., the primary site of MCF generation appeared to be the thymus. Also, when Mo+PyF101 M-MuLV was inoculated i.p., MCF generation appeared to occur primarily in the thymus. The time course studies indicated that MCF recombinants are not involved in preleukemic changes such as splenic hyperplasia. On the other hand, MCFs were detected in tumors from Mo+PyF101 M-MuLV s.c.-inoculated mice even though they were largely undetectable at preleukemic times. These results support a role for MCF recombinants late in disease induction.

scholarly journals SERINC5 Potently Restricts Retrovirus Infection In Vivo

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Uddhav Timilsina ◽  
Supawadee Umthong ◽  
Brian Lynch ◽  
Aimee Stablewski ◽  
Spyridon Stavrou
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Viral Envelope ◽  
The Other ◽  
Immunodeficiency Virus ◽  
Retrovirus Infection ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACT The serine incorporator (SERINC) proteins are multipass transmembrane proteins that affect sphingolipid and phosphatidylserine synthesis. Human SERINC5 and SERINC3 were recently shown to possess antiretroviral activity for a number of retroviruses, including human immunodeficiency virus (HIV), murine leukemia virus (MLV), and equine infectious anemia virus (EIAV). In the case of MLV, the glycosylated Gag (glyco-Gag) protein was shown to counteract SERINC5-mediated restriction in in vitro experiments and the viral envelope was found to determine virion sensitivity or resistance to SERINC5. However, nothing is known about the in vivo function of SERINC5. Antiretroviral function of a host factor in vitro is not always associated with antiretroviral function in vivo. Using SERINC5−/− mice that we had generated, we showed that mouse SERINC5 (mSERINC5) restriction of MLV infection in vivo is influenced not only by glyco-Gag but also by the retroviral envelope. Finally, we also examined the in vivo function of the other SERINC gene with known antiretroviral functions, SERINC3. By using SERINC3−/− mice, we found that the murine homologue, mSERINC3, had no antiretroviral role either in vivo or in vitro. To our knowledge, this report provides the first data showing that SERINC5 restricts retrovirus infection in vivo and that restriction of retrovirus infectivity in vivo is dependent on the presence of both glyco-Gag and the viral envelope. IMPORTANCE This study examined for the first time the in vivo function of the serine incorporator (SERINC) proteins during retrovirus infection. SERINC3 and SERINC5 (SERINC3/5) restrict a number of retroviruses, including human immunodeficiency virus 1 (HIV-1) and murine leukemia virus (MLV), by blocking their entry into cells. Nevertheless, HIV-1 and MLV encode factors, Nef and glycosylated Gag, respectively, that counteract SERINC3/5 in vitro. We recently developed SERINC3 and SERINC5 knockout mice to examine the in vivo function of these genes. We found that SERINC5 restriction is dependent on the absence of glycosylated Gag and the expression of a specific viral envelope glycoprotein. On the other hand, SERINC3 had no antiviral function. Our findings have implications for the development of therapeutics that target SERINC5 during retrovirus infection.

scholarly journals Diminished Potential for B-Lymphoid Differentiation after Murine Leukemia Virus Infection In Vivo and in EML Hematopoietic Progenitor Cells

2007 ◽  
Vol 81 (13) ◽  
pp. 7274-7279 ◽  
Author(s):  
Samantha L. Finstad ◽  
Naomi Rosenberg ◽  
Laura S. Levy
Keyword(s):  
Bone Marrow ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Selective Advantage ◽  
Moloney Murine Leukemia Virus ◽  
Vitro Model ◽  
B Lymphoid ◽  
Murine Leukemia

ABSTRACT Infection with a recombinant murine-feline gammaretrovirus, MoFe2, or with the parent virus, Moloney murine leukemia virus, caused significant reduction in B-lymphoid differentiation of bone marrow at 2 to 8 weeks postinfection. The suppression was selective, in that myeloid potential was significantly increased by infection. Analysis of cell surface markers and immunoglobulin H gene rearrangements in an in vitro model demonstrated normal B-lymphoid differentiation after infection but significantly reduced viability of differentiating cells. This reduction in viability may confer a selective advantage on undifferentiated lymphoid progenitors in the bone marrow of gammaretrovirus-infected animals and thereby contribute to the establishment of a premalignant state.

scholarly journals Tissue Distribution and Timing of Appearance of Polytropic Envelope Recombinants during Infection with SL3-3 Murine Leukemia Virus or Its Weakly Pathogenic SL3ΔMyb5 Mutant

2001 ◽  
Vol 75 (1) ◽  
pp. 522-526 ◽  
Author(s):  
Karen Rulli ◽  
Patricia A. Lobelle-Rich ◽  
Alla Trubetskoy ◽  
Jack Lenz ◽  
Laura S. Levy
Keyword(s):  
Bone Marrow ◽  
Murine Leukemia Virus ◽  
Recombinant Virus ◽  
Time Course ◽  
Leukemia Virus ◽  
Transplantable Tumor ◽  
Tumor Induction ◽  
Recombinant Viruses ◽  
Nih Swiss ◽  
Murine Leukemia

ABSTRACT A time course analysis was performed to identify the sites of formation and timing of appearance of polytropic recombinant viruses following infection of NIH/Swiss mice with the murine retrovirus SL3-3 murine leukemia virus (SL3) or with a weakly pathogenic mutant termed SL3ΔMyb5. The results indicated that (i) polytropic recombinant viruses occur initially in the thymus of SL3-infected animals, (ii) the timing of appearance of polytropic recombinants in bone marrow is not consistent with their participation in the previously reported formation of transplantable tumor-forming cells at 3 to 4 week postinoculation, and (iii) the efficient generation of recombinant virus is correlated with efficient tumor induction.

scholarly journals SERINC5 potently restricts retrovirus infection in vivo

2020 ◽  
Author(s):  
Uddhav Timilsina ◽  
Supawadee Umthong ◽  
Brian Lynch ◽  
Aimee Stablewski ◽  
Spyridon Stavrou
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Viral Envelope ◽  
The Other ◽  
Immunodeficiency Virus ◽  
Retrovirus Infection ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACTThe Serine Incorporator (SERINC) proteins are multipass transmembrane proteins that affect sphingolipid and phosphatidylserine synthesis. Human SERINC5 and SERINC3 were recently shown to possess antiretroviral activity to a number of retroviruses including human immunodeficiency virus (HIV), murine leukemia virus (MLV) and equine infectious anemia virus (EIAV). In the case of MLV, the glycosylated Gag (glyco-Gag) protein was found to counteract SERINC5-mediated restriction in in vitro experiments and that the viral envelope determines virion sensitivity or resistance to SERINC5. However, nothing is known about the in vivo function of SERINC5. Antiretroviral function of a host factor in vitro is not always associated with antiretroviral function in vivo. Using SERINC5-/- mice we generated, we show that mouse SERINC5 (mSERINC5) restriction of MLV infection in vivo is dependent not only on glyco-Gag, but also on the retroviral envelope. Finally, we also examined the in vivo function of the other SERINC gene with known antiretroviral functions, SERINC3. By using SERINC3-/- mice, we found that the murine homologue, mSERINC3, had no antiretroviral role both in vivo and in vitro. This report provides the first data showing that SERINC5 restricts retrovirus infection in vivo and that restriction of retrovirus infectivity in vivo is dependent on both the presence of glyco-Gag and the viral envelope.IMPORTANCEThis study examines for the first time the in vivo function of the Serine Incorporator (SERINC) proteins during retrovirus infection. SERINC3/5 restrict a number of retroviruses including human immunodeficiency virus 1 (HIV-1) and murine leukemia virus (MLV) by blocking their entry into cells. Nevertheless, HIV-1 and MLV encode factors, Nef and glycosylated Gag respectively, that counteract SERINC3/5 in vitro. We recently developed SERINC3 and SERINC5 knockout mice to examine the in vivo function of these genes. We found that SERINC5 potently restricted retrovirus infection in a glycosylated Gag and envelope dependent manner. On the other hand, SERINC3 had no antiviral function. Our findings have implication in the development of therapeutics that target SERINC5 during retrovirus infection.

scholarly journals Moloney Murine Leukemia Virus Infects Cells of the Developing Hair Follicle after Neonatal Subcutaneous Inoculation in Mice

1999 ◽  
Vol 73 (3) ◽  
pp. 2509-2516 ◽  
Author(s):  
Michael A. Okimoto ◽  
Hung Fan
Keyword(s):  
Bone Marrow ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Hair Follicles ◽  
Moloney Murine Leukemia Virus ◽  
Wild Type ◽  
Outer Root Sheath ◽  
Murine Leukemia

ABSTRACT The nature of Moloney murine leukemia virus (M-MuLV) infection after a subcutaneous (s.c.) inoculation was studied. We have previously shown that an enhancer variant of M-MuLV, Mo+PyF101 M-MuLV, is poorly leukemogenic when used to inoculate mice s.c., but not when inoculated intraperitoneally. This attenuation of leukemogenesis correlated with an inability of Mo+PyF101 M-MuLV to establish infection in the bone marrow of mice at early times postinfection. These results suggested that a cell type(s) is infected in the skin by wild-type but not Mo+PyF101 M-MuLV after s.c. inoculation and that this infection is important for the delivery of infection to the bone marrow, as well as for efficient leukemogenesis. To determine the nature of the cell types infected by M-MuLV and Mo+PyF101 M-MuLV in the skin after a s.c. inoculation, immunohistochemistry with an anti-M-MuLV CA antibody was performed. Cells of developing hair follicles, specifically cells of the outer root sheath (ORS), were extensively infected by M-MuLV after s.c. inoculation. The Mo+PyF101 M-MuLV variant also infected cells of the ORS but the level of infection was lower. By Western blot analysis, the level of infection in skin by Mo+PyF101 M-MuLV was approximately 4- to 10-fold less than that of wild-type M-MuLV. Similar results were seen when a mouse keratinocyte line was infected in vitro with both viruses. Cells of the ORS are a primary target of infection in vivo, since a replication defective M-MuLV-based vector expressing β-galactosidase also infected these cells after a s.c. inoculation.

scholarly journals Disruption of Hematopoiesis and Thymopoiesis in the Early Premalignant Stages of Infection with SL3-3 Murine Leukemia Virus

2002 ◽  
Vol 76 (5) ◽  
pp. 2363-2374 ◽  
Author(s):  
Karen Rulli ◽  
Jack Lenz ◽  
Laura S. Levy
Keyword(s):  
Bone Marrow ◽  
Murine Leukemia Virus ◽  
Time Course ◽  
Infected Animal ◽  
Leukemia Virus ◽  
Long Terminal Repeats ◽  
Early Stages ◽  
Tumor Outgrowth ◽  
Nih Swiss ◽  
Murine Leukemia

ABSTRACT A time course analysis of SL3-3 murine leukemia virus (SL3) infection in thymus and bone marrow of NIH/Swiss mice was performed to assess changes that occur during the early stages of progression to lymphoma. Virus was detectable in thymocytes, bone marrow, and spleen as early as 1 to 2 weeks postinoculation (p.i.). In bone marrow, virus infection was detected predominantly in immature myeloid or granulocytic cells. Flow cytometry revealed significant reductions of the Ter-119+ and Mac-1+ populations, and significant expansions of the Gr-1+ and CD34+ populations, between 2 and 4 weeks p.i. Analysis of colony-forming potential confirmed these findings. In the thymus, SL3 replication was associated with significant disruption in thymocyte subpopulation distribution between 4 and 7 weeks p.i. A significant thymic regression was observed just prior to the clonal outgrowth of tumor cells. Proviral long terminal repeats (LTRs) with increasing numbers of enhancer repeats were observed to accumulate exclusively in the thymus during the first 8 weeks p.i. Observations were compared to the early stages of infection with a virtually nonpathogenic SL3 mutant, termed SL3ΔMyb5, which was shown by real-time PCR to be replication competent. Comparison of SL3 with SL3ΔMyb5 implicated certain premalignant changes in tumorigenesis, including (i) increased proportions of Gr-1+ and CD34+ bone marrow progenitors, (ii) a significant increase in the proportion of CD4− CD8− thymocytes, (iii) thymic regression prior to tumor outgrowth, and (iv) accumulation of LTR enhancer variants. A model in which disrupted bone marrow hematopoiesis and thymopoiesis contribute to the development of lymphoma in the SL3-infected animal is discussed.

scholarly journals The endogenous mink cell focus-forming (MCF) gp70 linked to the Rmcf gene restricts MCF virus replication in vivo and provides partial resistance to erythroleukemia induced by Friend murine leukemia virus.

1988 ◽  
Vol 167 (5) ◽  
pp. 1535-1546 ◽  
Author(s):  
R S Buller ◽  
M Sitbon ◽  
J L Portis
Keyword(s):  
Cell Cultures ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Backcross Progeny ◽  
Genetic Studies ◽  
Mink Cell ◽  
Current Report ◽  
Murine Leukemia

The Rmcf locus restricts the in vitro replication of mink cell focus-forming (MCF) viruses in cell cultures derived from mice carrying the resistance allele. Previously we reported that in cell cultures from first backcross progeny, this Rmcf-linked restriction segregates with the expression of an endogenous retroviral gp70 serologically related to that of MCF viruses. The current report details the results of genetic studies designed to examine the possible association of this endogenous gp70 with resistance of mice to Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. This env gene segregates as a single dominant trait in (DBA/2 X IRW) X IRW progeny, in which the expression of the gene can be detected by serological techniques. Results indicated that the gp70- progeny developed leukemia at the same rate as the susceptible IRW parent, whereas the tempo of disease among the gp70+ progeny was significantly slower. However, the resistance mediated by this gene was only partial, since most of the gp70+ offspring eventually developed erythroleukemia when followed for 6 mo. This endogenous gp70 also segregated with a restriction to the expression of recombinant MCF viruses after infection with F-MuLV. Since in this study all unlinked genes segregated independently, this is direct evidence that MCF viruses participate in the induction of erythroleukemia.

scholarly journals Differential disease restriction of Moloney and Friend murine leukemia viruses by the mouse Rmcf gene is governed by the viral long terminal repeat.

1991 ◽  
Vol 174 (2) ◽  
pp. 389-396 ◽  
Author(s):  
B K Brightman ◽  
Q X Li ◽  
D J Trepp ◽  
H Fan
Keyword(s):  
Long Terminal Repeat ◽  
Murine Leukemia Virus ◽  
Time Course ◽  
Leukemia Virus ◽  
Terminal Repeat ◽  
Moloney Murine Leukemia Virus ◽  
Erythroid Progenitors ◽  
Equivalent Time ◽  
Induced Tumors ◽  
Murine Leukemia

Neonatal CxD2 (Rmcfr) and Balb/c (Rmcfs) mice inoculated with Moloney murine leukemia virus (M-MuLV) exhibited approximately equivalent time course and pathology for disease. CxD2 mice showed only slightly reduced presence of Moloney mink cell focus-forming virus (M-MCF) provirus as seen by Southern blot analysis compared to Balb/c mice. This lack of restriction for disease and spread of MCF was in sharp contrast to that seen for CxD2 mice inoculated with Friend murine leukemia virus (F-MuLV), where incidence of disease and propagation of MCFs were severely restricted, as previously reported. Inoculation of CxD2 mice with FM-MuLV, a recombinant F-MuLV virus containing M-MuLV LTR sequences (U3 and R), resulted in T cell disease of time course equal to that seen in Balb/c mice; there also was little restriction for propagation of MCFs. This indicated that presence of the M-MuLV long terminal repeat (LTR) was sufficient for propagation of MCFs in CxD2 mice. Differing restriction for F-MuLV vs. M-MuLV in CxD2 mice was explained on the basis of different "MCF propagator cells" for the two viruses. It was suggested that cells propagating F-MCF (e.g., erythroid progenitors) are blocked by endogenous MCF-like gp70env protein, whereas cells propagating M-MCF (e.g., lymphoid) do not express this protein on their surface. F-MuLV disease in CxD2 mice was greatly accelerated when neonates were inoculated with a F-MuLV/F-MCF pseudotypic mixture. However, F-MCF provirus was not detectable or only barely detectable in F-MuLV/F-MCF-induced tumors, suggesting that F-MCF acted indirectly in induction of these tumors.

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