Journal of Clinical Virology 37 Suppl. 1 (2006) S4–S10 www.elsevier.com/locate/jcv > HHV-6 and the immune system: mechanisms of immunomodulation and viral escape Paolo Lusso* Unit of Human Virology, Department of Biological and Technical Research (DIBIT), San Rafaele Scientific Institute, Milano, Italy Abstract Clinical and experimental evidence indicates that human herpesvirus 6 (HHV-6) can interfere with the function of the host immune system through a variety of mechanisms. Both HHV-6A and B can infect, either productively or nonproductively, several types of immune cells. The primary target for HHV-6 replication, both in vitro and in vivo, is the CD4 + T lymphocyte, a pivotal cell in the generation of humoral and cell-mediated adaptive immune responses. HHV-6A, but not B, also replicates in various cytotoxic effector cells, such as CD8 + T cells, gd T cells and natural killer cells. In professional antigen-presenting cells like macrophages and dendritic cells, HHV-6 infection is typically nonproductive; yet, it induces dramatic functional abnormalities, including a selective suppression of IL-12, a critical cytokine in the generation of Th1-polarized antiviral immune responses. This and other immunomodulatory effects seem to be mediated by the engagement of the primary HHV-6 receptor, CD46. Moreover, HHV-6 infection results in a generalized loss of CD46 expression in lymphoid tissue, which may lead to an aberrant activation of autologous complement. Additional mechanisms of immunomodulation by HHV-6 include alterations in cell surface receptor expression and cytokine/chemokine production. HHV-6 can also modulate influence responses through the expression of virally-encoded homologs of chemokines and chemokine receptors. By modulating specific antiviral immune responses, HHV-6 can facilitate its own spread and persistence in vivo, as well as enhance the pathogenic effects of other agents, such as human immunodeficiency virus. © 2006 Elsevier B.V. All rights reserved. 1. Introduction Although twenty years have elapsed since the discovery of human herpesvirus 6 (HHV-6) (Salahuddin et al., 1986), the pathogenic mechanisms and the clinical consequences of infection with this virus are still only partially elucidated. Besides the lack of standardized diagnostic methods, a major complicating factor is the existence of two viral variants (or subgroups), defined HHV-6A and B, which exhibit different epidemiological and biological features, as well as, possibly, disease associations (Ablashi et al., 1991). Both HHV-6 variants, however, possess a distinct tropism for immune cells, particularly for the CD4 + T lymphocyte, a pivotal cell in the generation and orchestration of cognate, antigen-specific immune responses. Productive infection of CD4 + T cells almost invariably results in cytopathic effects and cell destruction. However, HHV-6 may also cause important phenotypic and functional alterations when it establishes a nonproductive infection, as seen with professional antigen-presenting cells (APC), or indirectly through the induction of aberrant cytokine and chemokine production. These experimental observations are corrobo- rated by a series of clinical reports suggesting that HHV-6 * Correspondence address: Tel.: +39 02 2643 2821; Fax: +39 02 2643 4905. E-mail address: paolo.lusso@hsr.it (P. Lusso). infection may be associated with immunosuppression in the absence of human immunodeficiency virus (HIV) or other concurrent infections. For example, thymic atrophy and progressive immunodeficiency have been etiologically linked with disseminated HHV-6A and B coinfection in a child who showed no evidence of HIV-1 coinfection (Knox et al., 1995). Similar findings were later reported in an adult case (Yoshikawa et al., 2002). In patients who received allogenic bone marrow transplantation, active HHV-6 infection, as revealed by the presence of plasma viremia, was associated with lymphocytopenia and detective T-cell proliferation to recall antigens (Wang et al., 2002). The interactions between HHV-6 and the immune system have been extensively characterized using in vitro and ex vivo models, while in vivo studies are still limited, also due to the lack of suitable and easily accessible animal model systems. This review summarizes the current knowledge on the complex interplay between HHV-6 and the immune system. 2. Mechanisms of immunomodulation by HHV-6 Modulation of the host immune responses represents an important mechanism whereby viruses create a favorable 1590-8658/ $ – see front matter © 2006 Elsevier B.V. All rights reserved.