No Retroviremia or Pathology in Long-Term Follow-Up of Monkeys Exposed to a Murine Amphotropic Retrovirus

Cornetta, Kenneth; Ra, Morgan; Gillio, Alfred P.; Sturm, Sabine; Baltrucki, Leon; O’Reilly, Richard J.; Anderson, W. French

doi:10.1089/hum.1991.2.3-215

Cited by 78 publications

(31 citation statements)

References 12 publications

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“…The results of XMRV studies in macaques seem similar to those with a replication-competent, recombinant amphotropic murine retrovirus generated from a Moloney MLV (MoMLV)-based gene therapy packaging cell line, where large amounts of virus established only transient infection and were "cleared" from the peripheral blood after intravenous injection in normal, immunocompetent animals or a moderately immune-suppressed monkey (49,50). However, injection of highly immunosuppressed monkeys with a similar recombinant murine retrovirus containing amphotropic env sequences resulted in high retrovirus replication and T cell lymphomas in 3 animals after retrovirus-mediated gene transfer (39).…”

Section: Discussionmentioning

confidence: 75%

“…XMRV production in the cells was visualized by TEM (Fig. 1), the amount of virus in the stock was quantified for the total number of particles by using an STF-PERT assay, and infectious particles were determined as TCID 50 in LNCaP cells and Mv1Lu cells. The total number of RT-containing particles determined by the STF-PERT assay was 5.5 ϫ 10 6 particles per ml; the infectious particles were determined by virus titration using the STF-PERT assay for readout (10 5.5 TCID 50 per ml in Mv1Lu cells and 10 4.5 TCID 50 per ml in LNCaP cells) or focus formation in S ϩ L Ϫ mink cells (1.04 ϫ 10 4 FFU per ml).…”

Section: Xmrv Infection In Rhesus Macaquesmentioning

confidence: 99%

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No Evidence of Xenotropic Murine Leukemia Virus-Related Virus Transmission by Blood Transfusion from Infected Rhesus Macaques

Williams

Galvin²,

Gao

et al. 2013

J Virol

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The discovery of xenotropic murine leukemia virus-related virus (XMRV) in human tissue samples has been shown to be due to virus contamination with a recombinant murine retrovirus. However, due to the unknown pathogenicity of this novel retrovirus and its broad host range, including human cell lines, it is important to understand the modes of virus transmission and develop mitigation and management strategies to reduce the risk of human exposure and infection. XMRV transmission was evaluated by whole-blood transfusion in rhesus macaques. Monkeys were infected with XMRV to serve as donor monkeys for blood transfers at weeks 1, 2, and 3 into naïve animals. The donor and recipient monkeys were evaluated for XMRV infection by nested PCR assays with nucleotide sequence confirmation, Western blot assays for development of virus-specific antibodies, and coculture of monkey peripheral blood mononuclear cells (PBMCs) with a sensitive target cell line for virus isolation. XMRV infection was demonstrated in the virus-injected donor monkeys, but there was no evidence of virus transmission by whole-blood transfusion to naïve monkeys based upon PCR analysis of PBMCs using XMRV-specific gag and env primers, Western blot analysis of monkey plasma up to 31 to 32 weeks after transfusion, and coculture studies using monkey PBMCs from various times after transfusion. The study demonstrates the lack of XMRV transmission by whole-blood transfusion during the acute phase of infection. Furthermore, analysis of PBMC viral DNA showed extensive APOBEC-mediated G-to-A hypermutation in a donor animal at week 9, corroborating previous results using macaques and supporting the possible restriction of XMRV replication in humans by a similar mechanism.

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Section: Discussionmentioning

confidence: 75%

Section: Xmrv Infection In Rhesus Macaquesmentioning

confidence: 99%

No Evidence of Xenotropic Murine Leukemia Virus-Related Virus Transmission by Blood Transfusion from Infected Rhesus Macaques

Williams

Galvin²,

Gao

et al. 2013

J Virol

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“…In light of the immune response to FCS, we used Western blot analysis 15,24 to study patient serum samples for the presence of antibodies to the Moloney murine leukemia virus p30 antigen contained in the envelope of the LASN vector. A study of 53 healthy human sera demonstrated no immune reactivity to MMLV p30.…”

Section: Immune Response To Retroviral Vectormentioning

confidence: 99%

Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial

Muul

Tuschong

Soenen

et al. 2002

Blood

195

109

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“…Of late, therefore, the use of replication-competent retroviral (RCR) vectors has been advocated, and it has been demonstrated by various groups that these are much more efficacious than their RDR counterparts (15, 23, 26-29, 40-42, 45). Mitotic cells, of course, are not unique to tumors, and although it may be expected that RCR vectors would not replicate efficiently outside of the immune-privileged environment of a solid tumor in a healthy individual, the possibility of spread occurring in dividing cells outside of the tumor mass must nevertheless be considered (7,33,35). Moreover, not least due to recent events demonstrating that retroviral vectors are capable, albeit in rare circumstances, of inducing oncogenesis in humans (19,30), safety is a primary concern in retroviral vector design (46).…”

mentioning

confidence: 99%

Tissue- and Tumor-Specific Targeting of Murine Leukemia Virus-Based Replication-Competent Retroviral Vectors

Metzl

Mischek

Salmons

et al. 2006

J Virol

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Replication-competent retrovirus vectors based on murine leukemia virus (MLV) have been shown to effectively transfer therapeutic genes over multiple serial infections in cell culture and through solid tumors in vivo with a high degree of genomic stability. While simple retroviruses possess a natural tumor selectivity in that they can transduce only actively dividing cells, additional tumor-targeting strategies would nevertheless be advantageous, since tumor cells are not the only actively dividing cells. In this study, we used the promiscuous murine cytomegalovirus promoter, a chimeric regulatory sequence consisting of the hepatitis B virus enhancer II and the human ␣1-antitrypsin (EII-Pa1AT) promoter, and a synthetic regulatory sequence consisting of a series of T-cell factor binding sites named the CTP4 promoter to generate replicating MLV vectors, whereby the last two are transcriptionally restricted to liver-and ␤-catenin/T-cell factor-deregulated cells, respectively. When the heterologous promoters were used to replace almost the entire MLV U3 region, including the MLV TATA box, vector replication was inefficient since nascent virus particle production from infected cells was greatly decreased. Fusion of the heterologous promoters lacking the TATA box to the MLV TATA box, however, generated vectors which replicated with almost-wild-type kinetics throughout permissive cells while exhibiting low or negligible spread in nonpermissive cells. The genomic stability of the vectors was shown to be comparable to that of a similar vector containing wild-type MLV long terminal repeats, and tropism analysis over repeated infection cycles showed that the targeted vectors retained their original specificity.Because simple retroviruses can transduce only actively dividing cells (3,26,36,44), their use in cancer gene therapy has been extensively investigated, and over the last decade, numerous preclinical in vivo studies and clinical trials have been carried out using replication-defective retroviral (RDR) vectors (13). Although promising results have been obtained with animal models, therapeutic benefit in clinical settings has remained elusive, especially for cancer gene therapy, since the infection efficiency of solid tumors is too low (34). Of late, therefore, the use of replication-competent retroviral (RCR) vectors has been advocated, and it has been demonstrated by various groups that these are much more efficacious than their RDR counterparts (15, 23, 26-29, 40-42, 45). Mitotic cells, of course, are not unique to tumors, and although it may be expected that RCR vectors would not replicate efficiently outside of the immune-privileged environment of a solid tumor in a healthy individual, the possibility of spread occurring in dividing cells outside of the tumor mass must nevertheless be considered (7,33,35). Moreover, not least due to recent events demonstrating that retroviral vectors are capable, albeit in rare circumstances, of inducing oncogenesis in humans (19,30), safety is a primary concern in retroviral vect...

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No Retroviremia or Pathology in Long-Term Follow-Up of Monkeys Exposed to a Murine Amphotropic Retrovirus

Cited by 78 publications

References 12 publications

No Evidence of Xenotropic Murine Leukemia Virus-Related Virus Transmission by Blood Transfusion from Infected Rhesus Macaques

No Evidence of Xenotropic Murine Leukemia Virus-Related Virus Transmission by Blood Transfusion from Infected Rhesus Macaques

Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial

Tissue- and Tumor-Specific Targeting of Murine Leukemia Virus-Based Replication-Competent Retroviral Vectors

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