In Vivo Function of a Gammaherpesvirus Virion Glycoprotein: Influence on B-Cell Infection and Mononucleosis

Section: Discussionmentioning

confidence: 64%

Persistent Gammaherpesvirus Replication and Dynamic Interaction with the Host In Vivo

Hwang¹,

Wu²,

Tong³

et al. 2008

“…However, we have found no evidence for this by reverse transcription-PCR from MHV-68-infected epithelial cells, fibroblasts, or macrophages (data not shown). (39). They also found less B-cell binding by a gp150 knockout recovered from mouse lungs.…”

Section: Discussionmentioning

confidence: 91%

Evidence for a Multiprotein Gamma-2 Herpesvirus Entry Complex

Gillet¹,

Stevenson

2007

Herpesviruses use multiple virion glycoproteins to enter cells. How these work together is not well understood: some may act separately or they may form a single complex. Murine gammaherpesvirus 68 (MHV-68) gB, gH, gL, and gp150 all participate in entry. gB and gL are involved in binding, gB and gH are conserved fusion proteins, and gp150 inhibits cell binding until glycosaminoglycans are engaged. Here we show that a gH-specific antibody coprecipitates gB and thus that gH and gB are associated in the virion membrane. A gH/gL-specific antibody also coprecipitated gB, implying a tripartite complex of gL/gH/gB, although the gH/gB association did not require gL. The association was also independent of gp150, and gp150 was not demonstrably bound to gB or gH. However, gp150 incorporation into virions was partly gL dependent, suggesting that it too contributes to a single entry complex. gp150؊ and gL ؊ gp150 ؊ mutants bound better than the wild type to B cells and readily colonized B cells in vivo. Thus, gp150 and gL appear to be epithelial cell-adapted accessories of a core gB/gH entry complex. The cell binding revealed by gp150 disruption did not require gL and therefore seemed most likely to involve gB.

“…gM and gN are also widely conserved in herpesviruses, and gM is an essential protein of 21), but the gM/gN heterodimer functions mainly in virion assembly and egress (7,17). ORF4 encodes a complement-binding protein (15), and gp150 promotes virion release (10,30). In addition to these glycoproteins, the predicted multiple membrane-spanning protein encoded by ORF58 may play a role in virion attachment to polarized cells (33).…”

mentioning

confidence: 99%

The Murine Gammaherpesvirus 68 ORF27 Gene Product Contributes to Intercellular Viral Spread

May

Walker

Colaco

et al. 2005

Herpesviruses remain predominantly cell associated within their hosts, implying that they spread between cells by a mechanism distinct from free virion release. We previously identified the efficient release of murine gammaherpesvirus 68 (MHV-68) virions as a function of the viral gp150 protein. Here we show that the MHV-68 ORF27 gene product, gp48, contributes to the direct spread of viruses from lytically infected to uninfected cells. Monoclonal antibodies to gp48 identified it on infected cell surfaces and in virions. gp48-deficient viruses showed no obvious deficit in virion cell binding, single-cycle replication, or virion release but had reduced lytic propagation between cells. After intranasal infection of mice, ORF27-deficient viruses were impaired predominantly in lytic replication in the lungs. There was a small deficit in latency establishment, but long-term latency appeared normal. Since ORF27 has homologs in both Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, it is likely part of a conserved mechanism employed by gammaherpesviruses to disseminate lytically in their hosts.Epidemic viruses generally rely on high infectivities to transmit infection before immune responses become effective. In contrast, persistent viruses use immune evasion to establish a state of chronic, low-level infectivity. In keeping with this strategy of stealth, persistent viruses generally release virions only in very specific settings and otherwise spread via cell-cell contact.Herpesviruses are archetypal persistent pathogens. Acute infections are not associated with a detectable viremia, consistent with a predominance of direct, cell-to-cell virus transfer. In herpes simplex virus, this is a function of gE and gI, which are dispensable for lytic replication in vitro but contribute to dissemination in vivo (11). Glycoprotein D of pseudorabies virus, which binds virions to cells, illustrates the converse: it is important for growth in vitro but dispensable for growth in vivo (22). Thus, spread by virion release and spread by cell-cell contact, though clearly overlapping in their requirements for membrane fusion, appear to be separable processes involving distinct attachment proteins. Any therapeutic intervention must therefore encompass these two separate modes of viral spread.We are interested in the molecular processes that underlie the dissemination of gammaherpesviruses. These viruses lack genetic homologs of alphaherpesvirus gE and gI. The virusdriven proliferation of latently infected lymphocytes plays a central role in host colonization by gammaherpesviruses (8), but lytic replication must still be required for entry into and exit from hosts as well as for viral transit between different cell types. Cell-binding virion proteins have been identified for Epstein-Barr virus (EBV) (6, 32) and Kaposi's sarcoma-associated herpesvirus (KSHV) (2), but the processes by which gammaherpesviruses spread between cells in vivo remain unknown. Moreover, the strict species tropisms of EBV and KSHV make it difficult to u...