HHV-6 & Immune Suppression/Autoimmunity

HHV-6 (especially HHV-6A) can cause selective immunosuppression in the otherwise immunocompetent host through a variety of mechanisms (Lusso 2006).  HHV-6A was shown to accelerate progression from HIV infection to 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.  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:

  • HHV-6 infection is associated with transient hypogammaglobulinemia (Kano 2004).
  • Depletion of CD4+ T lymphocytes via direct infection and induction of apoptosis (Grivel 2003Lusso 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 2002Smith 2005).
  • Suppression of the ability of macrophages and dendritic cells to produce IL-12p70 upon stimulation with interferon gamma (Smith 20032005).
  • Suppression of IL-2 secretion (Flamand 1995).
  • Disturbance of key immune activation pathways and cytokine networks, including an upregulation of TNF-alpha, RANTES, IL-1beta and IL-10 (Flamand 1991, Arena 1999Grivel 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 1991Sullivan 2008).
  • Suppression of IFN-beta gene induction by IE proteins from HHV-6, interfering with innate antiviral response  (Jaworska 2007).
  • In a 2012 study, 30% of children with transient neutropenia were found to have an associated HHV-6 infection (Husain 2012).

HHV-6 in Autoimmunity

A role for HHV-6 has been proposed in several autoimmune disorders, including autoimmune hemolytic anemia/neutropenia (Yagasaki 2010), autoimmune acute hepatitis (Grima 2008), and multiple sclerosis (Tejada-Simon 2003, many), among others. A 2012 study has linked HHV-6A to Hashimoto’s thyroiditis (HT), a common autoimmune thyroid disease (AITD) (Caselli 2012).  The study found that HHV-6 was detected significantly more frequently among thyroid fine needle aspirates (FNA) from HT individuals than controls (82% vs. 10%, respectively), and low-grade acute infection was identified in all HHV-6 positive HT samples compared to 0% of controls.  In addition, the group demonstrated that thyroid cells infected with both HHV-6A and HHV-6B became susceptible to NK-mediated killing, providing evidence of a potential mechanism for HHV-6-induced autoimmunity.

For more information, download the HHV-6 Foundation’s IDWeek 2012 handout on HHV-6 & Immunosuppression, HIV/AIDS, and Autoimmunity

Key Papers: HHV-6 & Immune Suppression/Autoimmunity

Caselli

2012

Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s Thyroiditis
Husain

2012

Infectious etiologies of transient neutropenia in previously healthy children
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).


Website development by inStyle Technologies