Activation of Vav by the Gammaherpesvirus M2 Protein Contributes to the Establishment of Viral Latency in B Lymphocytes

Abstract

Gammaherpesviruses subvert eukaryotic signaling pathways to favor latent infections in their cellular reservoirs. To this end, they express proteins that regulate or replace functionally specific signaling proteins of eukaryotic cells. Here we describe a new type of such viral-host interaction that is established through M2, a protein encoded by murine gammaherpesvirus 68. M2 associates with Vav proteins, a family of phosphorylation-dependent Rho/Rac exchange factors that play critical roles in lymphocyte signaling. M2 expression leads to Vav1 hyperphosphorylation and to the subsequent stimulation of its exchange activity towards Rac1, a process mediated by the formation of a trimolecular complex with Src kinases. This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2. Infection of Vavdeficient mice with gammaherpesvirus 68 results in increased long-term levels of latency in germinal center B lymphocytes, corroborating the importance of the M2/Vav cross talk in the process of viral latency. These results reveal a novel strategy used by the murine gammaherpesvirus family to subvert the lymphocyte signaling machinery to its own benefit.The persistence of herpesvirus in the infected organism is dictated by the establishment of latency in particular cell types within the host. In the case of gammaherpesviruses, such as the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), latency occurs by maintenance of the viral genome in the nuclei of infected B lymphocytes. To favor such a process, these viruses have developed a number of strategies aimed at interfering with different aspects of the host cell signaling machinery. For instance, the EBV genome encodes two proteins, latent membrane protein 1 (LMP1) and LMP2, which contribute to the activation of naïve B cells by mimicking the function of two important B-cell surface receptors, the CD40 molecule and the B-cell receptor, respectively (9). The spurious activation of the downstream pathways of those receptors by LMP1 and LMP2 contributes to B-cell activation, differentiation, and the rescue of infected germinal center (GC) B-cell blasts into the memory B-cell pool (36). Similarly, the K1 and K15 proteins encoded by KSHV can alter B-cell signaling by promoting the activation of the NF-B and the nuclear factor of activated T cells. In addition, they interfere with the function of tyrosine kinases and tumor necrosis factor receptor-associated factors (9). It is likely that the viral machinery devoted to the manipulation of the signaling pathways of host cells is not restricted to these examples. Indeed, the genomes of most gammaherpesviruses contain a large number of genes that are not directly linked to viral entry, replication, or morphogenesis (10,15,27,31). The identification of additional herpesvirus proteins controlling the activation, differentiation, and survival of latently infected cells is of particular interest as these proteins constitute key components of ga...

Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade

“…40,50). Finally, we detected induction of genes for M6 and M9, unique MHV68 genes whose functions are unknown.…”

Rho’ing in and out of cells

“…In vivo studies showed that the interaction of M2 with Vav proteins is important for the establishment of a latent infection of MHV-68 in B cells. 109,110 Retroviruses like HIV also may establish latency. In a transcriptome study in cell lines latently infected with HIV, Cdc42 expression was found to be downregulated, which perhaps may be involved in cellular maintenance of latency.…”

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

“…35,36 Depending on the endocytic uptake routes engaged during the initial interaction of the herpesviruses with the host, specific Rho GTPase signaling is triggered and significant actin cytoskeleton rearrangements are induced, [37][38][39][40] creating an optimal microenvironment for viral replication, persistence and dissemination. It is of interest that apart from lytic infection, the interactions between gamma-herpeviruses and Rho GTPase signaling remain active even during non-productive infection, facilitating either the establishment of latency 41 or affecting cell motility and invasion and promoting the oncogenic properties of these viruses. 36,42 Less information is available for b-herpesviruses.…”