In vitro studies Th1 to Th2 switch

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HHV-6 replicates especially efficiently in CD4+ cells, the primary cells that orchestrate the immune response through complex direct cell to cell interactions as well as the secretion of multiple cytokines with both autocrine and paracrine effects (Gosselin et al., 1992). In vitro, HHV-6 has been shown to influence the immune balance between pro-inflammatory (Th1) and anti-inflammatory (Th2) cytokines. Interleukin 12 (IL-12) produced by macrophages is the predominant stimulator of Th1 activity, whereas IL-4 stimulates Th2. Human measles virus has been described to selectively suppress IL-12 (Karp, 1999), which drives the immune balance toward a Th2 response. Similarly, Arena et al. (1999) have described in vitro downregulation of IL-12 in peripheral blood monocytes as well as upregulation by HHV-6 of IL-10, a known suppressor of Th1 cells. These studies are consistent with those of Smith et al. (2003, 2004) in which HHV-6-induced suppression of IL-12 in macrophages following stimulation with interferon a and LPS. In addition, Smith et al. (2003, 2004) observed that even UV-inactivated HHV-6 downregulated IL-12, similar to observations with UV-irradiated measles virus. The fact that inactivated virus can inhibit IL-12 suggests that receptor blockade was made by the mechanism of inhibition, rather than a requirement for active replication. Over 10 years before, Flamand et al. (1991) had demonstrated that HHV-6 induced the secretion in peripheral blood cells of IL-1-beta, interferon-a, and tumor necrosis factor-a, also a known suppressor of IL-12. Flamand et al. (1995) later reported that HHV-6

decreased the production of IL-2, a product of Th1 cells, when using CD3 or phytohemagglutinin (PHA) as a stimulant. All of these in vitro observations confirm that HHV-6 is pivotal in shifting immune activity from a Th1 to a Th2 response, which is less likely to neutralize viral activity.

While specific immunity is undoubtedly involved in protection against the clinical consequences of HHV-6 infection, innate immunity, including NK cells may provide the first line of defense. Flamand et al. (1996) showed that HHV-6 actually stimulated PBMC in vitro to produce IL-15 that had an enhancing effect on NK-cell activity. This is also consistent with increases in NK-cell activity during the febrile phase of exanthema subitum. 0n the other hand, Lusso et al. (1993) had shown earlier than HHV-6 could induce CD4 expression on NK cells, postulating that it increased their susceptibility to infection with HIV-1. Collectively, these observations have led others to postulate that NK defect increases in susceptibility of individuals to the clinical sequelae associated with HHV-6 infection.

Another mechanism for susceptibility may involve CD46, widely represented on the surface of most nucleated cells, which has been suggested as a possible receptor for the HHV-6. This cell surface molecule has been implicated as a regulator of complement activation and may also be a receptor for the measles virus (Greenstone et al., 2002), Neisseria, and Group Strep A. It has been suggested by Lusso et al. (1991, 1993, 1995) that CD46 can act as a bridge between the innate and adaptive immune responses via regulation of IL-12. Fusion induced by CD46 may be the mechanism by which the cytopathic effect of the HHV-6 is expressed in heart transplant recipients as pancreatitis and gastroduodenitis (Mori et al., 2002).

Although in vitro studies can be valuable in forming hypotheses about the interactions of viruses with immune cells, the most compelling evidence of immunosuppression induced by HHV-6 is derived from clinical observations in pharmacologically suppressed patients undergoing transplant.

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How To Bolster Your Immune System

How To Bolster Your Immune System

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