Four vaccines are recommended by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices for adolescents. Parental attitudes may play a key role in vaccination uptake in this age group. In 2011, we conducted a cross-sectional survey among parents of adolescents in one county in Georgia to identify parental attitudes toward adolescent vaccination, reasons for vaccine acceptance or refusal, and impact of a physician recommendation for vaccination. Physician recommendation was reported as one of the top reasons for receipt or intent to receive any of the vaccines. Physician recommendation of any of the four vaccines was associated with receipt of Tdap (p<0.001), MCV4 (p<0.001), and HPV (p = 0.03) and intent to receive Tdap (p = 0.05), MCV4 (p = 0.005), and HPV (p = 0.05). Compared with parents who did not intend to have their adolescent vaccinated with any of the vaccines, parents who did intend reported higher perceived susceptibility (3.12 vs. 2.63, p = 0.03) and severity of disease (3.89 vs. 3.70, p = 0.02) and higher perceived benefit of vaccination (8.48 vs. 7.74, p = 0.02). These findings suggest that future vaccination efforts geared toward parents may benefit from addressing the advantages of vaccination and enhancing social norms. Physicians can play a key role by providing information on the benefits of adolescent vaccination.

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Murine gammaherpesvirus 68 (MHV68) shares genomic colinearity with Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, although it is more closely related to Kaposi's sarcoma-associated herpesvirus and herpesvirus saimiri (42,44). It is capable of infecting inbred and outbred stains of laboratory mice and therefore provides a tractable small-animal model with which to study gammaherpesvirus pathogenesis (7,15,34,39,(47)(48)(49). Hallmarks of MHV68 infection include acute viremia that is cleared approximately 2 weeks postinfection in wild-type mice and is accompanied by a massive expansion of immune cells (52). Acute infection leads to the establishment of long-term latency in the memory B-cell compartment, although other cell types, such as naïve B cells, macrophages, and dendritic cells (DCs), have been shown to harbor latent virus at early times postinfection (16,17,52). Like the other gammaherpesviruses, MHV68 has been shown to be associated with lymphoproliferative disease, and longterm infections can lead to the development of lymphomas (35,47). MHV68 facilitates an understanding of viral and host determinants of gammaherpesvirus pathogenesis in vivo.Toll-like receptors (TLRs), a type of pattern recognition receptor, are an important part of the innate immune system. TLRs recognize pathogens by detecting pathogen-associated molecular patterns (37, 51). There are 12 known mammalian TLRs, and with the exception of TLR3, engagement through their ligands activates the MyD88-interleukin-1 (IL-1)-associated receptor kinase-tumor necrosis factor receptor-associated factor 6 (MyD88-IRAK-TRAF6) signaling pathway, which then leads to activation of several transcription factors, such as NF-B, mitogen-activated protein kinase, and interferon regulating factors. Engagement of TLRs expressed on antigen-presenting cells, including DCs and macrophages, with their ligand(s) results in chemokine and cytokine production, increased antigen presentation, and the expression of costimulatory molecules (2, 27). These events can initiate an inflammatory response through chemokine secretion and cellular recruitment (1,2,27). TLR engagement mediates the maturation and migration of DCs to lymph nodes, which facilitates interaction with T lymphocytes (27,29). TLR ligands such as lipopolysaccharide and double-stranded RNA are known to act as adjuvants, enhancing the adaptive immune response (25). DC interactions with naïve T cells differentiate them into TH1 and TH2 or T regulatory lymphocytes (32).There are several TLRs whose ligands are viral pathogenassociated molecular patterns. TLR3 recognizes doublestranded RNA (3), TLR7 and -8 recognize single-stranded RNA (13,22,23), and TLR9 recognizes CpG DNA (24). These TLRs induce an antiviral host defense response, especially secretion of alpha/beta interferon. TLRs have been shown to be important in activating the innate immune response to control virus replication during virus infections. MyD88 signaling is important to control lymphocytic choriomeningitis virus infection and ...

Murine gammaherpesvirus 68 (MHV68) establishes a lifelong infection in mice and is used as a model pathogen to study the role of viral and host factors in chronic infection. The maintenance of chronic MHV68 infection, at least in some latency reservoirs, appears to be dependent on the capacity of the virus to reactivate from latency in vivo. However, the signals that lead to MHV68 reactivation in vivo are not well characterized. Toll-like receptors (TLRs), by recognizing the specific patterns of microbial components, play an essential role in the activation of innate immunity. In the present study, we investigated the capacity of TLR ligands to induce MHV68 reactivation, both in vitro and in vivo. The stimulation of latently infected B cell lines with ligands for TLRs 3, 4, 5, and 9 enhanced MHV68 reactivation; the ex vivo stimulation of latently infected primary splenocytes, recovered from infected mice, with poly(I:C), lipopolysaccharide, flagellin, or CpG DNA led to early B-cell activation, B-cell proliferation, and a significant increase in the frequency of latently infected cells reactivating the virus. In vivo TLR stimulation also induced B-cell activation and MHV68 reactivation, resulting in heightened levels of virus replication in the lungs which correlated with an increase in MHV68-specific CD8؉ T-cell responses. Importantly, TLR stimulation also led to an increase in MHV68 latency, as evidenced by an increase in viral genome-positive cells 2 weeks post-in vivo stimulation by specific TLR ligands. Thus, these data demonstrate that TLR stimulation can drive MHV68 reactivation from latency and suggests that periodic pathogen exposure may contribute to the homeostatic maintenance of chronic gammaherpesvirus infection through stimulating virus reactivation and reseeding latency reservoirs.Gammaherpesviruses are characterized by their capacity to establish lifelong latent infection within host lymphocytes. Virus reactivation is thought to be necessary for transmission of the virus to new hosts and may also be required to maintain reservoirs of latently infected cells in the chronically infected host (8,19,30,52,53). The switch between latency and the lytic cycle for the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) has been extensively characterized in established latently infected cell lines in vitro (18,45,61). The initiation of the EBV lytic cycle can be stimulated by several different reagents, including anti-immunoglobulin (anti-Ig), calcium ionophore, sodium butyrate, and tetradecanoyl phorbol acetate (TPA) (45). KSHV reactivation can also be induced by stimulation with phorbol esters and sodium butyrate (9, 37).Toll-like receptors (TLRs) are important pattern recognition receptors in innate immunity. Following TLR engagement by ligands of microbial origin, dendritic cells undergo maturation, which in turn activates the adaptive immune response. Pathogen-associated molecular patterns (PAMPs) recognized by TLRs can come from bacteria, fungi, protoz...

NF-B signaling is critical to the survival and transformation of cells infected by the human gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here we have examined how elimination of the NF-B transcription factor p50 from mice affects the life cycle of murine gammaherpesvirus 68 (MHV68). Notably, mice lacking p50 in every cell type were unable to establish a sufficiently robust immune response to control MHV68 infection, leading to high levels of latently infected B cells detected in the spleen and persistent virus replication in the lungs. The latter correlated with very low levels of virus-specific immunoglobulin G (IgG) in the infected p50 ؊/؊ mice at day 48 postinfection. Because the confounding impact of the loss of p50 on the host response to MHV68 infection prevented a direct analysis of the role of this NF-B family member on MHV68 latency in B cells, we generated and infected mixed p50 ؉/؉ /p50 ؊/؊ bone marrow chimeric mice. We show that the chimeric mice were able to control acute virus replication and exhibited normal levels of virus-specific IgG at 3 months postinfection, indicating the induction of a normal host immune response to MHV68 infection. However, in p50 ؉/؉ /p50 ؊/؊ chimeric mice the p50 ؊/؊ B cells exhibited a significant defect compared to p50 ؉/؉ B cells in supporting MHV68 latency. In addition to identifying a role for p50 in the establishment of latency, we determined that the absence of p50 in a subset of the hematopoietic compartment led to persistent virus replication in the lungs of the chimeric mice, providing evidence that p50 is required for controlling virus reactivation. Taken together, these data demonstrate that p50 is required for immune control by the host and has distinct tissue-dependent roles in the regulation of murine gammaherpesvirus latency during chronic infection.Murine gammaherpesvirus 68 (MHV68) is a natural pathogen of rodents and shares many biologic properties with the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As a gammaherpesvirus, MHV68 is lymphotropic and is associated with pathologies and neoplasia that increase upon loss of host immune control (21,56,75). Chronic infection with MHV68 initiates with an acute productive phase of infection and dissemination to secondary lymphoid tissues, leading to the establishment of a quiescent latent virus program in B cells and ultimately memory B cells, with intermittent reactivation events that are controlled by the immune system (27,56,87). The genetic tractability of MHV68 and the murine host permit a molecular dissection of key factors and signaling pathways required for chronic infection by the virus, in addition to those processes utilized for immune control by the host (29). NF-B signaling is one host pathway that is utilized by gammaherpesviruses to promote latency and cell survival (8,18,40,65).Gammaherpesviruses encode numerous gene products that hijack NF-B signaling by distinct mechanisms to regulate virus and host gene ex...