Herpes Virus Type 8

Article Author:
Ayesan Rewane
Article Editor:
Prasanna Tadi
Updated:
7/20/2020 9:07:43 AM
PubMed Link:
Herpes Virus Type 8

Introduction

Viruses are known to cause up to 20% of all human cancers. The Human Herpesvirus-8 (HHV-8), also called Kaposi sarcoma Herpesvirus (KSHV) and Epstein-Barr virus (EBV/ HHV4) both belong to the family of DNA viruses Herpeseviridae. They are the only two members of the Herpesvirus known to cause human cancers. EBV is known to cause Burkitt lymphoma. Other oncogenic viruses include the Human Papillomavirus (HPV), Hepatitis B (HBV), Human T-cell lymphotropic virus-1 (HTLV-1).[1] In 1994, the HHV- 8 was isolated as the cause of the skin malignancy Kaposi sarcoma (KS). Since the discovery, several prevalence studies have shown a unique pattern of the geographical distribution of this virus with no established explanation for this pattern.[2][3]

Etiology

HHV-8-Associated Tumors

The HHV-8 or KSHV is a double-stranded DNA virus subclassified as gammaherpesviruses. The gammaherpesviruses are a lymphotropic virus that undergoes lytic replication in epithelial cells such as skin, blood vessels, and organs. These viruses can establish latency in their host cells for a lifetime. The HHV-8 goes into a latency period in the B-lymphocytic cells and vascular endothelium. It intermittently undergoes a period of lytic replication, especially in favorable conditions like immunodeficiency, malnutrition, solid organ transplant, and so on. It causes Kaposi sarcoma (a vascular malignancy) and B cell lymphoproliferative diseases such as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). The likelihood of HHV-8-associated malignancies is significantly higher amongst individuals living with HIV; however, these malignancies can occur without HIV coinfection. In rare cases where KS is diagnosed in non-AIDS patients, it is usually in elderly Mediterranean men or iatrogenic immunosuppression, including the transplant population.[1][4][5][6] 

Kaposi Sarcoma (KS)Moritz Kaposi, the dermatologist, first discovered the disease in 1872 among elderly European men. KS is typically regarded as an AIDS-defining condition, HHV-8 is the cause of approximately 95% of all cases of KS, regardless of the HIV/AIDS status. KS is a type of malignancy that affects the lymphovascular system and presents as pigmented skin lesions. There are four epidemiological forms of KS categorized as endemic KS, classic KS, and AIDS-associated KS and iatrogenic KS.[1][2][5]

Classic or sporadic KS – This form of KS is commonly seen in elderly Jewish and Mediterranean, Eastern European HIV-negative men, and clinically less aggressive. The classic KS typically presents as an upper and lower limb skin lesion, sparing the lymph nodes and visceral. Iatrogenic KS – KS in organ transplantation, this is relatively less aggressive and presents with lymphadenopathy and visceral involvement. Epidemic or AIDS-associated KS – This is the most common and clinically aggressive form. Endemic KS – KS in Africa and highly aggressive KS in adults, lymphadenopathy in children.[2][5][7]

Primary Effusion Lymphomas (PELs)PELs are rare lymphomatous effusions, also known as body cavity-based lymphoma (BCBL), and commonly associated with AIDS. It rarely occurs in individuals without HIV and is characterized as non-Hodgkin lymphoma. This disease is unique because it occurs as an effusion in the pleural, pericardial, or peritoneal cavities without the presence of a mass, although masses may occur in the lymph nodes, lungs, and gastrointestinal tract.[5][8]

Multicentric Castleman Disease (MCD) MCD is a rare form of lymphoproliferative disorder, it has an estimated equal prevalence in both HIV/AIDS positive and negative patients. The virus can be isolated in almost all cases in the HIV infected population and about half the HIV negative patients.[8] The typical features of the disease are systemic symptoms like fever, chills, and generalized lymphadenopathy and can occur even in patients with fairly normal CD4 cell counts. The diagnosis requires a high level of suspicion as it can easily be missed for a bacterial infection. MCD should be managed promptly because it can rapidly progress to a sepsis-like syndrome. If left untreated, MCD can progress to large B cell lymphoma.[2][9]

Epidemiology

There are seven known subtypes of HHV-8/KSHV (A, B, C, D, E, F, and Z).[10][11] The universal prevalence of KSHV is about 5% to 20%, and it is endemic in sub-Saharan Africa. It is more likely that the high prevalence in the endemic region may be due to transmission through saliva as the virus is high in the adults as well as children in this region.[3] It may also be probably due to the prevalence of malaria infection. The U.S. has the least prevalence, estimated to be less than 10%. It is two-three times more common in men than women globally, more common in men who have sex with men compared to heterosexual men, especially in the non-endemic regions. Women have the lowest prevalence of the virus among all sexual categories. It has not been firmly established to be a sexually transmitted infection. There is only very little chance that it is transmitted via blood products and perinatally.[1][2][3] It can be transmitted through body fluids, mainly saliva, and most infections are subclinical and can go unnoticed.[4]

Pathophysiology

KSHV is a large enveloped, linear double-stranded DNA virus belonging to the subfamily, gammaherpesvirus, genera-rhadinovirus. It has an icosahedral capsid, a tegument (containing proteins and RNAs). The DNA virus produces several proteins that enable the virus to evade the host’s immunity, replicates in the nucleus, and produces its potential oncogenic effects. These proteins interact with the various metabolic pathways of the cell such as the nuclear factor-kappaB (NF-kappaB), phosphoinositide 3-kinase (PI3K), replication and transcription activator (RTA), Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK). The most expressed protein is Latency-associated nuclear antigen-1 (LANA), which is important for latency and oncogenesis. Also, Viral cyclin is known to inhibit the tumor suppressor genes (p53 and retinoblastoma (RB) prevent apoptosis by controlling the cell cycle.[1][2][5][12][13] 

Several other viral lytic proteins are significant in cancer formation to include the viral G protein-coupled receptor (vGPCR), K1, K15, and viral IL-6, are known to increase the activity of cellular growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). These play significant roles in angiogenesis and oncogenesis. The knowledge of these various pathogenic processes of KSHV has improved the production of medications to treat several of the HHV-8 related diseases and malignancies.[4][13]

Major KSHV Proteins and FunctionsThe HHV-8 has several viral products that are important for infecting, establish latency and cancer formation, including:

  • Latency-associated nuclear antigen-1 (LANA) - which is the major latency antigen.
  • Kaposins - these are latent proteins with A, B, and C subtypes, the B subtype is the most important for tumorigenesis.
  • Rta protein (ORF50) - it is a major initiator of viral reactivation.
  • Viral IL-6 (vIL-6) - a major blocker of interferon signaling by binding to gp130
  • Viral cyclin (v-cyclin)
  • Viral Fas ligand ICE inhibitory protein (v-FLIP)
  • Viral IL-6 (vIL-6) - a protein known to block interferon signaling by directly binding to gp130.[1][3][4][5]

Histopathology

Kaposi sarcoma: The gold standard of diagnosis is a skin biopsy for histopathology. The macular or patch, plaque, nodular KS lesions all vary in histology. However, the presence of spindle-shaped cells is confirmatory and is seen in all forms of KS. The typical characteristics of spindle cells are elongated cytoplasm and nuclei, which may have inclusions of hyaline or hemosiderin.[2][10]

Multicentric Castleman disease (MCD): The lymph node histology typically shows germinal center expansion and proliferation of vascular endothelium. The infected cells significantly express IL-6.[8]

Primary effusion lymphomas (PELs): The typical PEL histological features are consistent with anaplastic large cell and large cell immunoblastic lymphomas and significantly express CD45.[8]

History and Physical

The most common manifestation of Kaposi sarcoma is the skin lesion; however, in some cases, it can affect multiple organs and systems of the body. Hence the presentation depends on the system involved.Skin: Lesions that are usually colored (red, brown, or purple) and has a variety of dermatological presentations described as a patch, plaque, or a nodule. Ulcerated skin lesions can be painful and, however, high risk of cellulitis, given the vascular obstruction that can also occur from the lesions. Edema is a common complication; lesions around the eye may cause periorbital and facial swelling as well as the destruction of vision in severe cases.Gastrointestinal: Intestinal lesions may be asymptomatic, cause abdominal discomfort, bloody stools, weight loss, constipation, and intestinal obstruction.Pulmonary: lesions will be associated with respiratory symptoms like cough, shortness of breath, and hemoptysis.[2][8] 

Evaluation

The diagnosis of HHV-8 associated malignancies is based on the clinical presentation and mainly tissue biopsy for histology. Biopsy of skin lesion KS and lymph note for MCD. Also, tumor marker immunofluorescence staining is often utilized, the KSHV – LANA, which is often very specific for KS. Others include complete blood count, serum chemistry, and HIV testing, as well as pertinent imaging for complete diagnostic workup.[9][10]

Treatment / Management

KS: The early initiation of antiretroviral therapy in AIDS-associated KS can lead to possible regression of the disease.[2] In the treatment of KS, several factors are to be considered, which include the staging of the disease, immune status, and extent of disease involvement. Localized intralesional chemotherapy with vinblastine, surgeries, and radiotherapy are options for small lesions. The World Health Organization recommends the use of antiretroviral therapy in the treatment of mild or moderate Kaposi sarcoma. In severe cases, are a combination of antiretroviral therapy, and systemic chemotherapy is recommended. Commonly used for severe cases is paclitaxel or pegylated liposomal doxorubicin. The antiviral combination of ganciclovir/valganciclovir, foscarnet/cidofovir, and valacyclovir/famciclovir have been shown to treat HHV-8 associated diseases and may have the potential to prevent the formation of Kaposi sarcoma.[1][2][8]

PEL: combination chemotherapy-based treatment includes CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and modified DA-EPOCH (etoposide, doxorubicin, vincristine, cyclophosphamide). Both have an overall survival rate of approximately 40% when used with combination antiretroviral therapy in HIV/AIDS patients.[9] Options for treatment in a non-AIDS patient include liposomal anthracycline, which may be combined with bortezomib and prednisone. Radiation therapy is an option for individuals who are unable to tolerate chemotherapy or have chemo-resistant PEL.[8]

MCD: Generally, combination chemotherapy with (CHOP or CVAD) is indicated, especially for systemic symptoms. Other treatment modalities are surgical excision, radiation, and immunological agents such as steroids, rituximab (anti-CD20), atlizumab (anti- IL-6 antibody) can be used the treatment of MCD. Rituximab can be used alone or in combination therapy.[8][9] 

There are several medications in different stages of clinical trials that target the various stages of the pathogenesis of HHV-8 associated diseases. Some of these include the NF-κB inhibitor (berberine, cepharanthine, bortezomib), which targets various stages of the oncogenic process. Others include medications targeting interleukin-2, interleukin-6, mTOR, MAPK/RTK signaling pathways, and angiogenesis.[1][4][14]

Differential Diagnosis

  • Chancroid
  • Candidiasis
  • Herpes zoster
  • HIV lymphadenitis
  • Hand foot and mouth disease
  • Kaposi sarcoma
  • Kaposi sarcoma inflammatory cytokine syndrome (KICS)
  • Syphilis

Enhancing Healthcare Team Outcomes

The optimal patient outcome for HHV-8-associated malignancies, especially Kaposi's sarcoma, involves a multidisciplinary approach. MCD and PEL may cause multisystemic disease in severe cases and may be complicated with HIV/AIDS as well as other infections. Kaposi sarcoma skin lesions can cause many psychological consequences, especially if located anywhere visible such as the face.[2] 

Frequently, KS may be challenging to diagnose for pathologists because of its histologic similarity to a variety of malignancies. Also, the treatment can be challenging as well; most treatment goals are palliative and not curative. However, chemotherapy is optimal in quality of life improvement.[2]


References

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