Antiviral function and efficacy of polyvalent immunoglobulin products against CMV isolates in different human cell lines

Frenzel, Katrin; Ganepola, Susanne; Michel, Detlef; Thiel, Eckhard; Krüger, Detlev H.; Uharek, Lutz; Hofmann, Jörg

doi:10.1007/s00430-012-0229-2

Cited by 19 publications

(11 citation statements)

References 39 publications

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“…Our findings that cell-cell spread into epithelial cells is resistant to neutralizing antibodies is in direct contrast with a large number of studies in which focus formation in epithelial cells was found to be highly sensitive to neutralizing antibodies (28,30,(32)(33)(34)39). To resolve this discrepancy, we performed focus expansion assays using the TB40-BAC4 strain of HCMV.…”

Section: -E)mentioning

confidence: 39%

“…Many current vaccine strategies are designed to induce a neutralizing antibody response (21)(22)(23)(24)(25)(26)(27). However, it is unclear whether the transmission of HCMV is sensitive or resistant to neutralization, potentially because many studies have used viruses that spread efficiently via the cellfree route (19,(28)(29)(30)(31)(32)(33)(34)(35)(36). To determine the neutralization sensitivity of Merlin, we tested a panel of antibody preparations.…”

Section: Significancementioning

confidence: 99%

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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: -E)mentioning

confidence: 39%

Section: Significancementioning

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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“…The reported results of HCMV antibody treatment in patients differ very much between different studies. This might be explained by an inefficiency of HCMV antibody to block cell-tocell virus transmission in fibroblasts, different IgG preparations (38), and by differences between NK cells from different donors to mediate an ADCC effect (39). We demonstrated that NK92-CD16-158V cells had an enhanced effect on the control of HCMV transmission through ADCC.…”

Section: Discussionmentioning

confidence: 85%

Natural Killer Cells Can Inhibit the Transmission of Human Cytomegalovirus in Cell Culture by Using Mechanisms from Innate and Adaptive Immune Responses

Wu¹,

Sinzger²,

Reichel

et al. 2015

J Virol

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Human cytomegalovirus (HCMV) transmission within the host is important Human cytomegalovirus (HCMV) is an enveloped virus that belongs to the family Herpesviridae. HCMV remains the most important viral pathogen in severely immunocompromised individuals, with substantial morbidity and mortality. It is also the major cause of congenital infections that lead to developmental abnormalities and fetal death (1).Following initial infection, HCMV transmission can occur in cell cultures either by cell-free virus through the supernatant or by cell-to-cell transmission involving direct cell contact (2). In clinical practice, HCMV detection by isolation in cell cultures, pp65 antigenemia, and detection of viral DNA from blood (DNAemia) are used to diagnose an active systemic HCMV infection. From in vitro data, it can be concluded that antigenemia requires cell-tocell contact between infected cells and polymorphonuclear leukocytes (PMN), which allows PMNs to load with viral antigens, mainly pp65 (3). Although the mechanisms of HCMV cell-to-cell transmission are not fully clear, many authors hypothesized that this mode is more important in vivo. This is also supported by the fact that most clinical HCMV isolates spread strictly from cell to cell in fibroblast cultures at low passage numbers (4).During infection, HCMV encounters the host immune defense mechanisms, including intrinsic, innate, and adaptive immunity. The clinical outcome of HCMV infection mainly depends on the antiviral immunity. As effectors of the innate immunity, NK cells provide a rapid response to virus-infected cells (5). The most prominent functions of NK cells are their ability to produce antiviral cytokines and lyse virus-infected cells. NK cells can be activated by HCMV-infected cells (6, 7), and they are supposed to be important for the protection against HCMV infections in vivo. A case report indicated that NK cell deficiency was associated with severe herpesvirus infections, including active HCMV infection confirmed by virus isolation (8). Another case report showed that NK cell expansion was correlated with the control of an HCMV infection in the absence of T cells in a T Ϫ B Ϫ NK ϩ SCID patient (9). Furthermore, HCMV is the only virus known that can shape the human NK cell's receptor repertoire (10, 11). These clues highly suggest a role of NK cells in the defense against HCMV infection; however, direct proof of NK cells in controlling HCMV infection is absent.By using an improved focus expansion assay (4, 12), we used a systematic approach to investigate the contribution of NK cells to

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“…Although IVIG usually has significant neutralizing antibody titers, we infer that during cyclic treatment IVIG suppresses intracellular HSV1 replication by an unknown mechanism(s) because HSV1 spreads exclusively via axonal transport in the PNS and CNS [35]. This is not without precedent as IVIG has been reported to inhibit HSV1 and HCMV plaque formation in monolayer cultures when added after virus is internalized [36,37]. Additionally, a pool of non-neutralizing monoclonal antibodies was shown to suppress growth of HSV1 in acutely infected Tgs cultured in vitro [38].…”

Section: Discussionmentioning

confidence: 99%

Establishment of HSV1 Latency in Immunodeficient Mice Facilitates Efficient In Vivo Reactivation

et al. 2015

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The establishment of latent infections in sensory neurons is a remarkably effective immune evasion strategy that accounts for the widespread dissemination of life long Herpes Simplex Virus type 1 (HSV1) infections in humans. Periodic reactivation of latent virus results in asymptomatic shedding and transmission of HSV1 or recurrent disease that is usually mild but can be severe. An in-depth understanding of the mechanisms regulating the maintenance of latency and reactivation are essential for developing new approaches to block reactivation. However, the lack of a reliable mouse model that supports efficient in vivo reactivation (IVR) resulting in production of infectious HSV1 and/or disease has hampered progress. Since HSV1 reactivation is enhanced in immunosuppressed hosts, we exploited the antiviral and immunomodulatory activities of IVIG (intravenous immunoglobulins) to promote survival of latently infected immunodeficient Rag mice. Latently infected Rag mice derived by high dose (HD), but not low dose (LD), HSV1 inoculation exhibited spontaneous reactivation. Following hyperthermia stress (HS), the majority of HD inoculated mice developed HSV1 encephalitis (HSE) rapidly and synchronously, whereas for LD inoculated mice reactivated HSV1 persisted only transiently in trigeminal ganglia (Tg). T cells, but not B cells, were required to suppress spontaneous reactivation in HD inoculated latently infected mice. Transfer of HSV1 memory but not OVA specific or naïve T cells prior to HS blocked IVR, revealing the utility of this powerful Rag latency model for studying immune mechanisms involved in control of reactivation. Crossing Rag mice to various knockout strains and infecting them with wild type or mutant HSV1 strains is expected to provide novel insights into the role of specific cellular and viral genes in reactivation, thereby facilitating identification of new targets with the potential to block reactivation.

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Antiviral function and efficacy of polyvalent immunoglobulin products against CMV isolates in different human cell lines

Cited by 19 publications

References 39 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

Natural Killer Cells Can Inhibit the Transmission of Human Cytomegalovirus in Cell Culture by Using Mechanisms from Innate and Adaptive Immune Responses

Establishment of HSV1 Latency in Immunodeficient Mice Facilitates Efficient In Vivo Reactivation

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