Immunomodulation and immunosuppression by human herpesvirus 6A and 6B

Like other members of the Herpesviridae family, human herpesvirus (HHV)-6A and HHV-6B have developed a wide variety of strategies to modulate or suppress host immune responses and, thereby, facilitate their own spread and persistence in vivo. Long considered two variants of the same virus, HHV-6A and HHV-6B have recently been reclassified as distinct viral species, although the established nomenclature has been maintained. In this review, we summarize the distinctive profiles of interaction of these two viruses with the human immune system. Both HHV-6A and HHV-6B display a tropism for CD4⁺ T lymphocytes, but they can also infect, in a productive or nonproductive fashion, other cells of the immune system. However, there are important differences regarding the ability of each virus to infect cytotoxic effector cells, as HHV-6A has been shown to productively infect several of these cells, whereas HHV-6B infects them inefficiently at best. In addition to direct cytopathic effects, both HHV-6A and HHV-6B can interfere with immunologic functions to varying degrees via cytokine modulation, including blockade of IL-12 production by professional antigen-presenting cells, modulation of cell-surface molecules essential for T-cell activation, and expression of viral chemokines and chemokine receptors. Some of these effects are related to signaling through and downregulation of the viral receptor, CD46, a key molecule linking innate and adaptive immune responses. Increasing attention has recently been focused on the importance of viral interactions with dendritic cells, which may serve both as targets of virus-mediated immunosuppression and as vehicles for viral transfer to CD4⁺ T cells. Our deepening knowledge of the mechanisms developed by HHV-6A and HHV-6B to evade immunologic control may lead to new strategies for the prevention and treatment of the diseases associated with these viruses. Moreover, elucidation of these viral mechanisms may uncover new avenues to therapeutically manipulate or modulate the immune system in immunologically mediated human diseases.