Host Pathogenesis

The roseola viruses induce acute lytic infection, latency, and some features of cell transformation. The cell receptor for HHV-6 is CD46, a ubiquitous type-1 glycoprotein that regulates complement activation. CD46 binds to gH via a gH-gL-gQ complex.[10] As CD46 is widely expressed, this explains the broad cell tropism noted. CD4+ T-lymphocytes are preferentially infected, but CD8+ T-lymphocytes, y8 T-lymphocytes, natural killer (NK) cells, macrophages, dendritic cells, bone marrow progenitors, fibroblasts, epithelial cells, and fetal astrocytes can also support viral replication. Some differences in infection of transformed lymphocytes have been noted between HHV-6A and HHV-6B, while HHV-6A has greater neurotropism. Other coreceptors for infection may exist. HHV-7 requires cell surface CD4 association with gB which is necessary but not sufficient for viral internalization. Cell surface heparin-like glycoproteins are also required for viral entry. HHV-7 tropism is mainly for CD4+ T-lymphocytes. However, HHV-7 can be identified in diverse tissue samples suggesting that HHV-7 cell tropism may be broader. In particular, HHV-7 antigens have been identified in salivary epithelial cells. HHV-7 replication has also been identified in macrophages and CD34+ hematopoietic progenitor cells.

Viral replication involves production of DNA-contain-ing capsids in the nucleus, acquisition of tegument in the cytoplasm, and addition of a secondary envelope containing glycoproteins acquired from the annulate lamellae. Virions transit through the Golgi where glycosylation further modifies the envelope glycoproteins before release of mature virions. Infected host cells can die by apoptosis or necrotic lysis. Polypoid giant cells have been described with in vitro HHV-7 infection and result from cell cycle dysregulation. After primary infection, the virus is maintained in a latent state with low levels of gene transcription. Intermittent bouts of lytic replication allow persistence. Interestingly, specific T-lymphocyte activation stimuli can induce HHV-7 but not HHV-6B reactivation in vitro. HHV-7 replication produces HHV-6B transactivation suggesting that in vivo, there may be a sequence to viral reactivation.

The host response to infection involves production of neutralizing antibody and cell-mediated immunity. T-lymphocyte IFN-g responses are detected against type-specific antigens. NK cells also contribute to host immunity via IL-15 production. HHV-6A and HHV-6B induce immunomodulation by depletion of CD4 T-lymphocytes via destruction of thymic progenitors and, as with HHV-7, via peripheral induction of apoptosis. The majority of apoptotic cells are uninfected and apoptosis can involve Fas ligand, TNF-a, or p53. CD4+ T-lymphocytes directly infected with HHV-7 up-regulate the antiapoptotic molecule bcl-2 and down-regulate the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) R1 receptor to prevent apoptosis and maintain viral replication, but up-regulate TRAIL to induce apoptosis in immune effector cells. HHV-6A also depletes CD4 T-lymphocytes by formation of syncytia. A further mechanism of immune evasion described for HHV-7 is blockade of viral antigen presentation to cytotoxic T-lymphocytes by the binding of the U21-encoded glycoprotein to major histocompatibility complex (MHC) class 1 molecules that diverts the MHC molecules to lysosomes.

T-lymphocyte proliferation is inhibited by down-regulation of IL-2 and function inhibited by down-modulation of CD3, CD4, and the chemokine receptor CXCR4. Type-1 response cytokines up-regulated in T-lymphocytes include TNF-a, IFN-g, and IL-18. TGF-p is also up-regulated. IL-8 and adhesion molecule induction enhances inflammatory injury, as may production of reactive oxygen species and PGE2 by monocytes. HHV-6 encodes a unique chemokine analog, vCCL4, that binds to the chemokine receptor CCR2 expressed on cells including macrophages. HHV-7 also up-regulates the lymphocyte-specific G-protein-coupled receptor EB 1 which aids recruitment of infected lymphocytes to areas in which they can propagate infection.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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