Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues

Wirtz, Nikolaus; Schader, Sina I.; Holtappels, Rafaela; Simon, Christian O.; Lemmermann, Niels A. W.; Reddehase, Matthias J.; Podlech, Jürgen

doi:10.1007/s00430-008-0095-0

Cited by 33 publications

(27 citation statements)

References 24 publications

(36 reference statements)

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“…The role of neutralizing antibodies in vivo remains unclear in this context. A number of studies have documented an inverse correlation between neutralization titers and intrauterine transmission (74)(75)(76)(77), and virus-specific antibodies have been shown to confer a degree of protection in animal models (78,79) and human kidney transplant recipients (80). In contrast, the administration of polyclonal human IgG containing high titers of neutralizing antibodies failed to prevent congenital infection in a randomized clinical trial (37), and a correlation between anti-gB antibody titers and protection in vaccinated transplant recipients was found to be independent of neutralization activity (81).…”

Section: Discussionmentioning

confidence: 99%

The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

Murrell

Bedford

Ladell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell-cell transmission. This process of cell-cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128-131A complex, a feature of WT but not passaged strains of HCMV.virology | immune evasion | herpesvirus | HCMV | cell-cell spread H uman cytomegalovirus (HCMV) is a major cause of morbidity and mortality in the immunocompromised and the leading infectious cause of congenital malformation. As a result, a vaccine has been designated as a priority. However, basic studies of clinically relevant isolates that inform our understanding of the disease process are limited due to the rapid accumulation of genetic mutations during in vitro passage of HCMV. The same three genetic sites are reproducibly affected: the RL13 gene; the UL128 locus (UL128L), which comprises UL128, UL30, and UL131A; and the ∼15-kb U L /b′ gene region (1). Deletions in the U L /b′ region can affect tropism [UL148 (2)], latency [UL136 and UL138 (3-7)], and resistance to NK cells [UL141 (8-10), UL142 (11, 12), and UL135 (13)]. Disabling mutations in RL13 and UL128L independently contribute to the release of high-titer cell-free virus, whereas loss of UL128L restricts virus entry to fibroblasts alone by preventing assembly of a pentameric glycoprotein complex (gH/gL/pUL128/ pUL130/pUL131A) in the virion envelope (1,14,15).The rapid selection of mutations is a major obstacle to the propagation of genetically intact "clinical" strains of HCMV, which in turn has led to significant gaps in our understanding of the affiliated disease processes (16). In particular, HCMV is largely cell-associated in vivo (17), and clinical isolates exhibit a similar phenotype in vitro (17, 18), yet most studies in the field are based on laboratory strains that produce high titers of cell-free virus (19). As a consequence, little is known about the fundamental processes involved in the infectious spread of cell-associated HCMV.In this study, we used a system tha...

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Section: Discussionmentioning

confidence: 99%

The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

Murrell

Bedford

Ladell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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“…It should be noted that we transferred 200 l of serum from donor to recipient mice, which is actually an underestimation of the protective capacity. Whether these protective effects are mediated via neutralizing antibodies that limit cell-to-cell spread (39) and viral dissemination (35) or via nonneutralizing MCMV-binding antibodies is unclear. Neutralizing CMV-specific antibodies were detectable rather late in infection and the titers of these neutralizing antibodies were low, which is consistent with other low-cytopathogenicity viruses (40).…”

Section: Discussionmentioning

confidence: 99%

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Welten

Redeker

Toes

et al. 2016

J Virol

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Antibodies are implicated in long-term immunity against numerous pathogens, and because of this property, antibody induction is the basis for many vaccines. Little is known about the influence of viral persistence on the evolving antibody response. Here, we examined the characteristics of antibody responses to persistent infection by employing the prototypic betaherpesvirus family member cytomegalovirus (CMV) in experimental mouse models. During the course of infection, mouse CMV (MCMV)-specific IgM and IgG responses are elicited; however, IgG levels gradually inflate in the persistent phase of infection while IgM levels are stably maintained. Whereas CD27-CD70 interactions are dispensable, the CD28/B7 costimulatory pathway is critical for the class switching of MCMV-specific IgM-to-IgG B cell responses, which corresponds to the CD28/B7-dependent formation of CD4 ؉ T follicular helper cells (T FH ) and germinal center (GC) B cells. Furthermore, the initial viral inoculum dose dictates the height of the antibody levels during IgG antibody inflation and relates to the induction of long-lived plasma cells and memory B cells. Antibody avidity nonetheless is not altered after the establishment of viral persistence and occurs independently of the inoculum doses. However, repetitive challenge with intact viral particles, accompanied by increased GC reactivity, promotes the development of high-avidity IgG responses with neutralizing capacity. These insights can be used for the rational design of CMV-based vaccines aimed at inducing antibody responses. IMPORTANCE Antibodies provide long-term protection to different pathogens. However, how antibody responses develop during persistent virus infection is not entirely clear.Here, we characterize factors that influence the virus-specific antibody response to persistent CMV. This study describes that during persistent infection, CMV-specific IgM antibody levels are stably maintained while IgG2b and IgG2c levels gradually inflate over time. In contrast, the IgG avidity remains similar after the establishment of viral persistence. The induction of T follicular helper cells and GC B cells requires CD4 ؉ T cell help and CD28/B7 costimulation signals and is essential for the development of CMV-specific IgG antibody responses. Furthermore, neutralizing CMV-specific antibodies appear to develop late after infection, yet the neutralizing capacity can be improved upon repetitive viral challenge that is associated with increased GC reactivity. The results described here could inform the use of CMV-based vaccines and may help to understand how our immune system copes with this persistent virus.T he maintenance of long-lived humoral responses after infection and vaccination is attributed to both long-lived plasma cells that continuously produce antibodies and to memory B cells that are able to form antibody-secreting cells after reexposure (1, 2). Antibodies can protect against numerous pathogens by direct neutralization and/or by supporting effector functions of immune cells (1, ...

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“…This could be because the times of virus infection are not synchronous in this model and/or because levels of maternal antibodies (and whether they are neutralizing or nonneutralizing) differ between latent mothers. It is known that virus-specific antibodies are not necessary for resolution of acute infection in adult mice, although they do restrict cell-to-cell spread during primary infection (25,70). Passive treatment of infected neonatal pups with MCMV-immune sera or virus-specific antibodies exhibits a protective effect against the virus, significantly reducing viral titers and disease pathology in the brain (8).…”

Section: Discussionmentioning

confidence: 99%

Transmission of Murine Cytomegalovirus in Breast Milk: a Model of Natural Infection in Neonates

Paveglio

Lingenheld

et al. 2011

J Virol

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Vertical transmission of viruses in breast milk can expose neonates to infectious pathogens at a time when the capacity of their immune system to control infections is limited. We developed a mouse model to study the outcomes of acquisition of murine cytomegalovirus (MCMV) when neonates are breastfed by mothers with acute or latent infection. Breast milk leukocytes collected from lactating mice were examined for the presence of MCMV IE-1 mRNA by reverse transcription-PCR (RT-PCR) with Southern analysis. As determined by this criterion, breast milk leukocytes from both acute and latent mothers were positive for MCMV. This mimics the outcome seen in humans with latent cytomegalovirus infection, where reactivation of virus occurs specifically in the lactating mammary gland. Interestingly, intraperitoneal injection of breast milk collected from mothers with latent infection was sufficient to transfer MCMV to neonatal mice, demonstrating that breast milk was a source of virus. Furthermore, we found that MCMV was transmitted from infected mothers to breastfed neonates, with MCMV IE-1 mRNA or infectious virus present in multiple organs, including the brain. In fact, 1 day of nursing was sufficient to transmit MCMV from latent mothers to breastfed neonatal mice. Together, these data validate this mouse model of vertical transmission of MCMV from mothers with acute or latent MCMV infection to breastfed neonates. Its relevance to human disease should prove useful in future studies designed to elucidate the immunological and pathological ramifications of neonatal infection acquired via this natural route.

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Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues

Cited by 33 publications

References 24 publications

The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Transmission of Murine Cytomegalovirus in Breast Milk: a Model of Natural Infection in Neonates

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