Porcine Endogenous Retrovirus Transmission Characteristics of Galactose α1-3 Galactose-Deficient Pig Cells

Quinn, Gary; Wood, James C. S.; Ryan, David; Suling, Kristen M.; Moran, Kathleen; Kolber-Simonds, Donna; Greenstein, Julia L.; Schuurman, Henk‐Jan; Hawley, Robert J.; Patience, Clive

doi:10.1128/jvi.78.11.5805-5811.2004

Cited by 25 publications

(17 citation statements)

References 33 publications

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“…For some viruses, including porcine endogenous retrovirus, pseudorabies virus, and lymphocytic choriomeningitis virus, neutralization by nonimmune human serum is triggered by natural antibodies binding to Gal␣1-3Gal epitopes on virus (21,37,43,47,50). However, we previously reported that naturally occurring antibodies to Gal␣1-3Gal are not involved in neutralizing HSV-1 virus (12).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

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Lubinski

Jiang

et al. 2006

J Virol

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Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) binds complement component C3b and protects virus from complement-mediated neutralization. Differences in complement interacting domains exist between gC of HSV-1 (gC1) and HSV-2 (gC2), since the amino terminus of gC1 blocks complement C5 from binding to C3b, while gC2 fails to interfere with this activity. We previously reported that neutralization of HSV-1 gC-null virus by HSV antibody-negative human serum requires activation of C5 but not of downstream components of the classical complement pathway. In this report, we evaluated whether activation of C5 is sufficient to neutralize HSV-2 gC-null virus, or whether formation of the membrane attack complex by C6 to C9 is required for neutralization. We found that activation of the classical complement pathway up to C5 was sufficient to neutralize HSV-2 gC-null virus by HSV antibody-negative human serum. We evaluated the mechanisms by which complement activation occurred in seronegative human serum. Interestingly, natural immunoglobulin M antibodies bound to virus, which triggered activation of C1q and the classical complement pathway. HSV antibody-negative sera obtained from four individuals differed over an approximately 10-fold range in their potency for complement-mediated virus neutralization. These findings indicate that humans differ in the ability of their innate immune systems to neutralize HSV-1 or HSV-2 gC-null virus and that a critical function of gC1 and gC2 is to prevent C5 activation.Viruses employ a variety of mechanisms to evade both innate and adaptive immunity. Herpes simplex virus type 1 (HSV-1) establishes latency within the sensory ganglia of the peripheral nervous system, and interferes with the induction of interferon and immunity mediated by antibody and complement (5, 35, 39). HSV-1 also blocks cytotoxic T-lymphocyte activation by preventing antigen presentation by the major histocompatibility complex class I (15, 22, 51). HSV-1 encodes the immediate-early protein ICP47, which prevents the transport of antigenic peptides into the endoplasmic reticulum and subsequent loading onto major histocompatibility complex class I molecules.HSV-1 glycoproteins E (gE) and I (gI) together form a high-affinity Fc receptor (2,4,6,10,25,26). This receptor binds the Fc region of HSV-specific immunoglobulin G (IgG) antibodies in a process called antibody bipolar bridging (10). Antibody bipolar bridging blocks functions mediated by IgG, including antibody-dependent complement neutralization, antibody-dependent cellular cytotoxicity, and phagocytosis (7,10,40,49). In a murine flank model of infection, antibody is significantly more effective at protecting animals against disease caused by an HSV-1 mutant deficient in Fc receptor activity than by wild-type virus (40).HSV-1 glycoprotein C binds complement component C3b and inhibits the interaction of C5 and properdin (P) with C3b, blocking activation of both the classical and alternative complement pathways (11,23,32). HSV-1 gC prevent...

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Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

Hook

Lubinski

Jiang

et al. 2006

J Virol

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“…However, when retroviruses bud from the surfaces of cells from transgenic pigs expressing human complement regulator proteins, the viruses acquire numerous cellular proteins, including these human complement regulatory proteins. Expression of these proteins on the virus surface will also prevent the human immune system from eliminating the virus (235,260,316), increasing the risk of transmission. Without the human complement regulator genes on the surface of PERV, antiGal-alpha-1,3-Gal antibodies prevent virus infection (207,208).…”

Section: Use Of Transgenic Pigs To Overcome Immunological Rejectionmentioning

confidence: 99%

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

2012

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SUMMARY Xenotransplantation may be a solution to overcome the shortage of organs for the treatment of patients with organ failure, but it may be associated with the transmission of porcine microorganisms and the development of xenozoonoses. Whereas most microorganisms may be eliminated by pathogen-free breeding of the donor animals, porcine endogenous retroviruses (PERVs) cannot be eliminated, since these are integrated into the genomes of all pigs. Human-tropic PERV-A and -B are present in all pigs and are able to infect human cells. Infection of ecotropic PERV-C is limited to pig cells. PERVs may adapt to host cells by varying the number of LTR-binding transcription factor binding sites. Like all retroviruses, they may induce tumors and/or immunodeficiencies. To date, all experimental, preclinical, and clinical xenotransplantations using pig cells, tissues, and organs have not shown transmission of PERV. Highly sensitive and specific methods have been developed to analyze the PERV status of donor pigs and to monitor recipients for PERV infection. Strategies have been developed to prevent PERV transmission, including selection of PERV-C-negative, low-producer pigs, generation of an effective vaccine, selection of effective antiretrovirals, and generation of animals transgenic for a PERV-specific short hairpin RNA inhibiting PERV expression by RNA interference.

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“…Complement sensitivity of VSV harvested from pig cells with or without ␣-Gal epitope. To confirm that virus inactivation by human serum is mainly mediated by ␣-Gal epitope and anti-␣-Gal natural antibodies, we employed the porcine testis cell line ST-IOWA and its derivative (ST-IOWA Gal-null) lacking the ␣-galactosyl transferase gene (GGTA1) (37). While Galnull cells have been shown to produce PERV resistant to human serum (37), VSV passaged through these cells was tested in this study.…”

Section: Fig 2 Demonstration Of Hcd55 Incorporation On Vsv Particlesmentioning

confidence: 99%

“…To confirm that virus inactivation by human serum is mainly mediated by ␣-Gal epitope and anti-␣-Gal natural antibodies, we employed the porcine testis cell line ST-IOWA and its derivative (ST-IOWA Gal-null) lacking the ␣-galactosyl transferase gene (GGTA1) (37). While Galnull cells have been shown to produce PERV resistant to human serum (37), VSV passaged through these cells was tested in this study. ST-IOWA Gal-null cells produced VSV resistant to complement-mediated inactivation, although at the highest serum concentration (50%) there was some degree of inactivation, implying that although ␣-Gal is the major xenoreactive epitope, there are other minor xenoreactive epitopes (9).…”

Section: Fig 2 Demonstration Of Hcd55 Incorporation On Vsv Particlesmentioning

confidence: 99%

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-α(1-3) Galactosyl Epitope

Magre

Takeuchi

Langford

et al. 2004

J Virol

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Complement activation mediated by the major xenogeneic epitope in the pig, galactosyl-␣(1-3) galactosyl sugar structure (␣-Gal), and human natural antibodies could cause hyperacute rejection (HAR) in pig-tohuman xenotransplantation. The same reaction on viruses bearing ␣-Gal may serve as a barrier to zoonotic infection. Expressing human complement regulatory proteins or knocking out ␣-Gal epitopes in pig in order to overcome HAR may therefore pose an increased risk in xenotransplantation with regard to zoonosis. We investigated whether amphotropic murine leukemia virus, porcine endogenous retrovirus, and vesicular stomatitis virus (VSV) budding from primary transgenic pig aortic endothelial (TgPAE) cells expressing human CD55 (hCD55 or hDAF) was protected from human-complement-mediated inactivation. VSV propagated through the ST-IOWA pig cell line, in which ␣-galactosyl-transferase genes were disrupted (Gal null), was also tested for sensitivity to human complement. The TgPAE cells were positive for hCD55, and all pig cells except the Gal-null ST-IOWA expressed ␣-Gal epitopes. Through antibody binding, we were able to demonstrate the incorporation of hCD55 onto VSV particles. Viruses harvested from TgPAE cells were relatively resistant to complement-mediated inactivation by the three sources of human sera tested. Additionally, VSV from Gal-null pig cells was resistant to human complement inactivation. Such protection of enveloped viruses may increase the risk of zoonosis from pigs genetically modified for pig-to-human xenotransplantation.

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Porcine Endogenous Retrovirus Transmission Characteristics of Galactose α1-3 Galactose-Deficient Pig Cells

Cited by 25 publications

References 33 publications

Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-α(1-3) Galactosyl Epitope

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