HHV-6 & Immune Suppression/Autoimmunity

Recent evidence demonstrates that HHV-6 (especially HHV-6A) can cause selective immunosuppression in otherwise immunocompetent adults. HHV-6A was shown to dramatically accelerate progression from HIV to full blown AIDS in macaques by causing an early depletion in both CD4+ and CD8+ cells (Lusso 2007), and HHV-6A may cause more destruction of lymphoid tissue and apoptosis of immune cells than HIV. Bob Gallo spoke on this subject in 2006 at the 5th International Conference on HHV-6 & -7 in Barcelona, telling the group that HHV-6A is an important progression factor in AIDS and has been wrongly ignored. Of note, HIV cannot invade CD8 cells until HHV-6A has first infected the cell to induce the CD4+ receptor (Lusso 1991). HHV-6A induces de novo expression of CD4 messenger RNA and protein in normal mature CD8+ T lymphocytes, rendering them susceptible to infection with HIV. For additional information on the role of HHV-6 in AIDS, please visit our webpage on HHV-6 & HIV/AIDS Progression.

HHV-6 infection can result in the following mechanisms associated with immune suppression/autoimmunity:

Depletion of CD4+ T lymphocytes via direct infection and induction of apoptosis (Grivel 2003, Lusso 1988)
Lytic infection of cytotoxic effector cells – CD8+, NK cells (Lusso 1991A, Lusso 1995)
Functional impairment and delay in maturation of dendritic cells and macrophages (Kakimoto 2002, Smith 2005)
Suppression of the ability of macrophages and dendritic cells to produce IL-12p70 upon stimulation with interferon gamma (Smith 2003, 2005)
Suppression of IL-2 secretion (Flamand 1995)
Disturbance of key immune activation pathways and cytokine networks, including an upregulation of TNF alpha, TNF- alpha, RANTES, IL-1beta and IL-10 (Flamand 1991,Arena 1999, Grivel 2000)
Downregulation of complement activity through the CD46 receptor and downregulation of IL-2. (Russell 2004)
Modification of monocytes that favor immune evasion, including reduced levels of CD14, CD64 and HLA-DR antigen on their surface while CD32 expression is unaffected (Janelle 2006)
Dysregulation of monocyte-mediated antifungal defenses (Cermelli 2006)
HHV-6 specific IL-10 producing CD4+ T cells and CD4+ Th1 responses in HHV-6 infected individuals are selectively impaired. (Wang 2006)
Generalized loss of CD46 expression in lymphoid tissue (Lusso 2006)
Delayed immune response after acute HHV-6 infection (Kumagai 2006)
Downmodulation of the CD3/T-cell receptor complex (Lusso 1991, Sullivan 2008)
Suppression of IFN-beta gene induction by IE proteins from HHV-6, interfering with innate antiviral response (Jaworska 2007)

Key Papers: HHV-6 & Immune Suppression/Autoimmunity

Li	2011	Human Herpesvirus 6 Suppresses T Cell Proliferation through Induction of Cell Cycle Arrest in Infected Cells in the G2/M Phase
Shirai	2009	Hypogammaglobulinemia with a clinical course similar to that of drug-induced hypersensitivity syndrome
Sullivan	2008	Downregulation of the T-cell receptor complex and impairment of T-cell activation by human herpesvirus 6 u24 protein.
Jaworska	2007	Inhibition of transcription of the beta interferon gene by the human herpesvirus 6 immediate-early 1 protein.
Lusso	2007	Human herpesvirus 6A accelerates AIDS progression in macaques.
Cermelli	2006	Human herpesvirus-6 dysregulates monocyte-mediated anticryptococcal defences
Wang	2006	Human herpesvirus-6-specific interleukin 10-producing CD4 T cells suppress the CD4 T-cell response in infected individuals
Nakashima	2006	Drug-Induced Hypersensitivity Syndrome Associated with Transient Hypogammaglobulinaemia and Increase in Serum IgE Level
Kumagai	2006	Time Course Characteristics of Human Herpesvirus 6 Specific Cellular Immune Response and Natural Killer Cell Activity in Patients With Exanthema Subitum
Niiya	2006	Human herpesvirus 6 impairs differentiation of monocytes to dendritic cells
Lusso	2006	HHV-6 and the immune system: mechanisms of immunomodulation and viral escape
Janelle	2006	Phenotypic alterations and survival of monocytes following infection by human herpesvirus-6.
Smith	2005	Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6
Kano	2004	Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia
Russell	2004	CD46: a complement regulator and pathogen receptor that mediates links between innate and acquired immune function.
Aihira	2003	Carbamazepine-induced hypersensitivity syndrome associated with transient hypogammaglobulinaemia and reactivation of human herpesvirus 6 infection demonstrated by real-time quantitative polymerase chain reaction
Grivel	2003	Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo
Boeckh	2003	Immunosuppressive Effects of Beta-herpesviruses
Smith	2003	Selective suppression of IL-12 production by human herpesvirus 6
Isomura	2003	Interaction of Human Herpesvirus 6 With Human CD34 Positive Cells
Kakimoto	2002	Phenotypic and functional alterations of dendritic cells induced by human herpesvirus 6 infection.
Grivel	2000	Human immunodeficiency virus type 1 induces apoptosis in CD4(+) but not in CD8(+) T cells in ex vivo-infected human lymphoid tissue.
Arena	1999	Altered cytokine production after human herpes virus type 6 infection.
Flamand	1995	Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation.
Flamand	1991	Human herpesvirus 6 induces interleukin-1 beta and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures.
Lusso	1991	Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3.
Lusso	1988	In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6).

HHV-6 & Immune Suppression/Autoimmunity

Key Papers: HHV-6 & Immune Suppression/Autoimmunity

HHV-6 Associations