Immune modulation

The broad immunotropism of HHV-6, particularly of variant A (Table 1), may dramatically affect, directly or indirectly, the function of the cellular and humoral arms of the immune system. As discussed above, both variants have a primary tropism for CD4+ T cells, which are pivotal in the orchestration of the immune responses. Variant A also efficiently infects different types of cytotoxic effector cells such as CD8+ T lymphocytes, NK cells, and gd T lymphocytes. Moreover, both mononuclear phagocytic cells and DC can be infected, albeit usually in a nonproductive fashion, and the infection results in dramatic phenotypic and functional alterations.

In accordance with the above observations, multiple lines of clinical and experimental evidence suggest that HHV-6 may be an immunosuppressive agent in its own right. One such hint comes from the SCID-hu Thy/Liv mouse model in which infection with either HHV-6 subgroup A or B results in a rapid destruction of the thymic grafts with dramatic thymocyte depletion affecting all major intrathymic cell populations (Gobbi et al., 1999). Consistent with these experimental observations, disseminated coinfection with HHV-6A and -6B has been etiologically linked with thymic atrophy and progressive immunodeficiency in a child who showed no evidence of HIV-1 infection (Knox et al., 1995). Similar findings were recently reported in an adult case (Yoshikawa et al., 2002b). While this evidence is suggestive, the full extent of HHV-6-induced immunosuppression in vivo needs to be further investigated.

The emerging hypothesis that HHV-6 may directly affect the function of the immune system is supported by a series of in vitro data. HHV-6 was shown to render CD4+ T cells more susceptible to apoptosis both in vivo and in vitro (Yasukawa et al., 1998). Terminally infected T cells fail to express the T-cell receptor (TCR) complex (the TCR ap heterodimer associated with the CD3 antigen complex) on their surface membrane (Lusso et al., 1988), as a consequence of the ability of HHV-6 to transcriptionally downregulate the expression of several CD3 chains in the course of its lytic infection (Lusso et al., 1991b). This effect is induced by both HHV-6A and -6B strains (P. Lusso, unpublished observation). Because of the critical role played by the TCR complex in T-cell activation, downregulation of CD3 likely has an immunosuppressive effect. Another unexpected phenotypic feature observed in infected T lymphocytes is that a variable proportion of them coexpresses both CD4 and CD8 (Lusso et al., 1988). This phenomenon is related to the unique ability of HHV-6 to activate transcriptionally the expression of CD4 in cells that physiologically do not express it, such as mature CD8+ cells (Lusso et al., 1991a). This effect seems to be mediated by early gene products of HHV-6, as indicated by experiments with the viral DNA polymerase inhibitor phosphonofor-mic acid (PFA) (Lusso et al., 1991a). Direct activation of the CD4 promoter by HHV-6 has been suggested (Flamand et al., 1998). Similar observations were subsequently made in NK cells and y8 T cells (Lusso et al., 1993, 1995). Owing to the inefficient growth of subgroup-B isolates in CD4-negative cells, de novo CD4 induction was hitherto documented only with HHV-6A. Nonetheless, increased levels of CD4 expression were observed upon infection with different HHV-6B strains in Jurkat, a CD4low neoplastic T-cell line (P. Lusso, unpublished observation).

Modulation of the host immune responses represents an important mechanism exploited by viruses in order to create a favorable environment for their survival (Vossen et al., 2002). This is particularly important for herpesviruses, which usually persist in their host throughout life. HHV-6 has been shown to significantly modulate the expression of various cytokines and chemokines that play essential roles in the generation of the immune responses. HHV-6-infected peripheral blood mono-nuclear cells (PBMC) or enriched T-cell cultures were shown to produce 50% less IL-2 after stimulation, and this was accompanied by diminished cellular proliferation (Flamand et al., 1995). Besides downregulating IL-2, HHV-6 infection of PBMC was also shown to increase the production of interferon (IFN)-a, tumor necrosis factor (TNF)-a, IL-1p, IL-8, IL-10, and IL-15 (Kikuta et al., 1990; Flamand et al., 1991, 1996; Inagi et al., 1996; Arena et al., 1999), while inhibiting the production of IFN-g (Arena et al., 1999). However, the latter effect was not observed in a continuous CD4+ T-cell line, SupT1 (Mayne et al., 2001). HHV-6 infection also induces the expression of the G protein-coupled receptor EBI-1, which is typically induced by EBV infection (Hasegawa et al., 1994). In addition, dramatic effects on chemokine production were documented in HHV-6-infected lymphoid tissue ex vivo (see below).

Another important mechanism by which HHV-6 may modulate the host immune system is suggested by the presence of both chemokine and chemokine-receptor homologs in the viral genome. HHV-6 encodes two putative chemokines (U22 and U83) and two putative chemokine receptors (U12 and U51) (Isegawa et al., 1998; French et al., 1999; Milne et al., 2000). U83 encodes a highly selective and effective CCL2 agonist, which is able to induce transient calcium mobilization and chemotaxis in THP-1 cells, a monocytoid cell line (Zou et al., 1999; Luttichau et al., 2003). HHV-6-infected cells will thereby attract CCR2-expressing cells, for example, monocytes, thus enhancing the chances to spread the infection and establish latency in these cells. U12 and U51 encode two G protein-coupled receptors similar to chemokine receptors: U12, which is expressed in the late stage of HHV-6 infection in cord blood mononuclear cells and monocytes/macrophages, is a functional p-chemokine receptor, related to CCR-1, -3, and -5; this receptor is activated by regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP-1) a and -1p, and MCP-1, but not by IL-8, suggesting that the chemokine selectivity of the U12 product is distinct from that of the known mammalian chemokine receptors (Isegawa et al., 1998; Kondo et al., 2002a). Unlike U12, U51 is transcribed early post infection. When expressed in epithelial cells, U51 has been shown to specifically bind RANTES, but not to transduce intracellular signals following binding (Milne et al., 2000). In epithelial cells, U51 expression resulted in specific transcriptional downregulation of RAN-TES expression, and this correlated with reduced secretion of RANTES protein into the culture supernatants (Milne et al., 2000). U51 has also recently been suggested to act as a positive regulator of virus replication in vitro (Zhen et al., 2005).

One study has suggested that HHV-6 could induce a shift from a Th1 to a Th2 profile in in vitro--infected PBMC by downregulating IL-12 and upregulating IL-10 (Arena et al., 1999). On the other hand, others have reported that infection of T-cell lines with HHV-6 resulted in the downregulation of IL-10, IL-10 receptor, and IL-14 (Mayne et al., 2001). More recently, exposure of human macrophages to HHV-6 was shown to profoundly and selectively impair their ability to produce IL-12 upon stimulation with IFN-g and lipopolysaccharides (LPS), without affecting the production of TNF-a, RANTES, and MIP-1 p (Smith et al., 2003). IL-12 production was affected at the post-transcriptional level and was independently of viral replication, as the effect was not abrogated by UV-inactivation of the viral inoculum. Similar observations were made in DC, in which pre-exposure to HHV-6 impaired the maturation of DC driven by IFN-g and LPS, as documented by a reduced expression of MHC class I, HLA-DR, CD40, and CD80 (Smith et al., 2005). As seen in macrophages, HHV-6 dramatically suppresses the secretion of IL-12 in DC cultures, while the production of other cytokines, including two cytokines that influence DC maturation (i.e. IL-10 and TNF-a) was not significantly modified. Functionally, DC previously treated with HHV-6 were impaired in their ability to stimulate allogeneic T-cell proliferation. HHV-6 has also been shown to induce transcriptional downregulation of DC-SIGN in infected immature DC (Niiya et al., 2004). The alteration of the expression of DC-SIGN, which is involved in DC rolling and transmigration into periphery and T-lymphocyte activation, may affect their ability to initiate and sustain specific immune responses. Altogether, these data suggest that the interference with the functional maturation of DC is a potential mechanism of HHV-6-mediated immunosuppression.

Another intriguing mechanism that might be exploited by HHV-6 to evade the immune system has been recently proposed (Kemper et al., 2003), although these results have not yet been reproduced in other studies. Coengagement of CD3 and the HHV-6 receptor CD46 in the presence of IL-2 was shown to induce a T-regulatory 1(Tr1)-specific cytokine phenotype in human CD4+ T cells (Kemper et al., 2003). These CD3/CD46 stimulated IL-10-producing CD4+ T cells proliferate strongly, suppress activation of bystander T cells, and acquire a memory phenotype. If confirmed, the CD46-mediated induction of Tr1 cells may provide a further explanation for the choice of CD46 as a cellular receptor by many microbial agents.

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