Human gammaherpesvirus 8: Infectious substances pathogen safety data sheet

Section I – Infectious agent

Name

Human gammaherpesvirus 8

Agent type

Virus

Taxonomy

Family

Orthoherpesviridae

Genus

Rhadinovirus

Species

Rhadinovirus humangamma8

Synonym or cross-reference

HHV-8; Kaposi's sarcoma-associated herpesvirus (KSHV), Human Herpesvirus 8^{Footnote 1Footnote 2}, Kaposi's sarcoma^{Footnote 3Footnote 4}, KSHV inflammatory cytokine syndrome^{Footnote 4}, primary effusion lymphoma^{Footnote 1}, and HHV-8-associated multicentric Castleman's disease^{Footnote 1}.

Characteristics

Brief description

Herpesviruses are large double-stranded DNA viruses surrounded by an icosadeltahedral protein capsid^{Footnote 1Footnote 5Footnote 6}. The capsid is surrounded by another protein layer called the tegument, which is enclosed in a lipid envelope derived in part from host cell membrane^{Footnote 6}. The diameter of human gammaherpesvirus 8 (HHV-8) ranges from 120-150 nm^{Footnote 6}. The genome is 165-170 kbp in length^{Footnote 7} and is linear in the viral capsid, but circularizes after infection of a host cell^{Footnote 1}. On average, the G+C content of the genome is 59% but can vary in different areas of the genome^{Footnote 1}. Herpesviruses have six defined DNA genomic sequence arrangements (A-F), with HHV-8 having a class C arrangement^{Footnote 1Footnote 5}.

Properties

Primary infection begins when HHV-8 surface glycoproteins interact with host cell receptors for the nucleocapsid to enter the cell through endocytosis, and the viral genome enters the host cell nucleus^{Footnote 7}. HHV-8 primarily infects B-cells and endothelial cells in vivo, but can infect other cell types in vitro^{Footnote 7}.

HHV-8 has a biphasic lifecycle. Following clearance of primary infection, a latent, non-infective state is typically established in lymphoid tissue^{Footnote 5}. In the latent state, the circular genome is attached to the cellular chromosome and is replicated by cell division and thereby transmitted to daughter cells^{Footnote 7}. The viral genome is undetected by the immune system as it only expresses a small amount of genes^{Footnote 7}.

The latent stage is followed by a lytic stage in reactivated cases. The mechanism of reactivation in previously healthy patients is unknown; however, a weakening of the immune system (e.g. post organ transplantation) is thought to facilitate reactivation^{Footnote 1}. In immunocompromised patients, the virus is able to bypass the immune system and cause disease^{Footnote 4Footnote 8Footnote 9}. Various factors, such as protein stimuli and physiological or chemical substances, can also reactivate HHV-8^{Footnote 7}. The viral genes are expressed within the host cell to produce proteins that are necessary for assembling the viral particles. The virus acquires the teguments and envelopes from the host cell cytoplasm and membrane before being released and infecting other hosts^{Footnote 7}.

Section II – Hazard identification

Pathogenicity and toxicity

In healthy individuals, HHV-8 infection is generally non-life threatening^{Footnote 1}. Primary HHV-8 infection can be asymptomatic^{Footnote 10}. Mild, non-specific symptoms, including lymphadenopathy, diarrhea, fatigue, and localized rash, were observed in human immunodeficiency virus (HIV)-negative individuals^{Footnote 1Footnote 10}. In immunocompetent children, symptoms of primary HHV-8 infection include fever and maculopapular rash^{Footnote 11}. HHV-8 primary infection can be severe in immunocompromised or immunosuppressed individuals^{Footnote 1Footnote 12Footnote 13Footnote 14Footnote 15}. Additionally, viral reactivation is possible and has been documented in immunosuppressed individuals following peripheral blood stem cell transplantation^{Footnote 12Footnote 13Footnote 14}.

HHV-8 infection is associated with various diseases, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and KS inflammatory cytokine syndrome (KICS)^{Footnote 1Footnote 16}. HHV-8 is thought to be the etiological agent of KS, which is the most common disease associated with HHV-8 infection, disproportionately affecting men who have sex with men (MSM) and HIV/AIDS-infected individuals. Classic KS presents as an indolent tumor, mostly forming in the lower extremities, mainly affecting elderly men^{Footnote 15}. It is not usually fatal. KS in individuals with AIDS (AIDS-KS) presents as multiple tumors on the limbs, trunk, and/or face^{Footnote 1}. The tumors are more aggressive than those observed in classic KS. AIDS-KS can spread into the chest cavity, increasing the likelihood of death^{Footnote 3Footnote 4Footnote 15Footnote 17}. Endemic KS occurs in sub-Saharan Africa; in children it is an aggressive, multifocal, lymphadenopathic form, whereas in adults, clinical presentation resembles that of classic KS^{Footnote 9}. Iatrogenic KS occurs following solid organ allograft and typically presents as cutaneous KS lesions^{Footnote 15}.

PEL is characterized by body-cavity-based-lymphoma and typically affects HIV-positive men with low CD4 T-cell count^{Footnote 18}. PEL accounts for 0.13% of AIDS-related malignancies in the USA, and is frequently found in patients with prior KS^{Footnote 1}. When found in non-HIV patients, it is mainly non-life threatening^{Footnote 1Footnote 19Footnote 20}.

MCD, a rare lymphoproliferative disorder, is usually systemic and individuals present heterogeneous symptoms, including an enlargement of multiple lymph node regions. More than 90% of AIDS patients with MCD are HHV-8 positive, while non-HIV infected MCD cases are HHV-8 positive in approximately 40% of patients^{Footnote 1}.

KICS is characterized by many clinical symptoms, including fever, fatigue, systemic inflammation, organ failure, hepatitis, anemia, and high viral load^{Footnote 17Footnote 21}. This syndrome has only been recently reported, mainly in solid organ transplant and HIV patients^{Footnote 22}. Symptoms are severe and associated with high mortality. The median survival from diagnosis is 14 months^{Footnote 17}.

Epidemiology

HHV-8 occurs worldwide, with an estimated seroprevalence of 5-20%^{Footnote 22}. In regions with high seroprevalence, which include sub-Saharan Africa and the Brazilian Amazon (>50%), infection is most frequent in childhood^{Footnote 22Footnote 23}. Regions with intermediate seroprevalence include Mediterranean countries, the Caribbean, Eastern Europe, and the Middle East (5-20%)^{Footnote 22}. Classic KS is more prevalent in Mediterranean populations^{Footnote 23}. In populations with low asymptomatic seroprevalence, such as North America, Asia, and Western Europe (<10%), HHV-8 is mainly limited to HIV/AIDS patients and MSM^{Footnote 22Footnote 24}. Immunodeficiency (e.g. due to HIV/AIDS) is the most significant risk factor for HHV-8 infection and disease^{Footnote 1Footnote 3}. HIV-positive individuals are twice as likely to be HHV-8-seropositive relative to HIV-negative persons^{Footnote 23}. Global seroprevalence of HHV-8 in MSM is 33%^{Footnote 25}. Other risk factors include increasing age, number of sexual partners, history of sexually transmitted diseases, and risky sexual behaviours^{Footnote 22Footnote 25}.

Host range

Natural host(s)

Humans^{Footnote 1Footnote 5}.

Other host(s)

Rhesus macaques have been experimentally infected with HHV-8^{Footnote 26}. Recombinant HHV-8 has been used to infect marmosets, mice, and tree shrews experimentally^{Footnote 27Footnote 28Footnote 29}.

Infectious dose

The specific infectivity, defined as the ratio between 50% tissue culture infective dose (TCID₅₀) and the number of viral DNA copies, of HHV-8 ranges from 3.5 x 10^-5 to 1.27 x 10^{-6Footnote 30}.

Incubation period

Unknown. HHV-8 enters a latent stage post-infection that may last for several years or may never be expressed symptomatically^{Footnote 1}. In one transplant patient, symptoms appeared 17 days after transplantation^{Footnote 31}, while in a study of 220 renal transplant patients, 2 developed KS within 2 years^{Footnote 8}. Viral shedding rate varies greatly across individuals, ranging from 1-42 days, with duration affected by viral quantity, presence of HIV or KS, and age^{Footnote 32Footnote 33}.

Communicability

HHV-8 is transmitted primarily through exposure to saliva from an HHV-8-infected individual by sexual or asexual intimate direct contact^{Footnote 1Footnote 9Footnote 34Footnote 35}. HHV-8 could also be spread through genital secretions^{Footnote 36}. Although infrequent, HHV-8 can be transmitted between intravenous drug users^{Footnote 34Footnote 37}. Rare cases of HHV-8 transmission through solid-organ or peripheral blood stem cell transplantation have been documented^{Footnote 8Footnote 38}.

Section III – Dissemination

Reservoir

Humans^{Footnote 39}.

Zoonosis

None.

Vectors

None.

Section IV – Stability and viability

Drug susceptibility/resistance

Foscarnet, ganciclovir, cidofovir, and adefovir inhibit HHV-8 replication in the lytic phase^{Footnote 9Footnote 17}, but are not effective for latent phase infection or associated diseases^{Footnote 9}.

No drug resistance reported for HHV-8; however other herpesviruses have shown resistance to the common antiviral drugs, including acyclovir^{Footnote 40}.

Susceptibility to disinfectants

Quaternary ammonium compounds, chlorhexidine (0.02%), rubbing alcohol (1:1 mixture), sodium hypochlorite (0.2%), and alkaline glutaraldehyde (2%) are effective against herpesviruses^{Footnote 41Footnote 42Footnote 43Footnote 44Footnote 45}.

Physical inactivation

HHV-8 can be inactivated under UV light at 200 mJ/cm² for 30 minutes^{Footnote 46}. Herpesviruses are generally inactivated by heating in solution at 56°C for 10 minutes and exposure to pH values less than 5 or greater than 11^{Footnote 47}.

Survival outside host

HHV-8 can survive in non-leukoreduced whole blood stored at 4 to 8°C for at least 4 days^{Footnote 48}. Other herpesviruses have a half-life of 1.4 hours on skin at 32°C, or 22 and 58 minutes on metal disks at 32°C and 22°C, respectively^{Footnote 49}.

Section V – First aid/medical

Surveillance

Diagnosis is done through a combination of clinical and histologic evaluation^{Footnote 1Footnote 4Footnote 37}. There are currently four laboratory methods to detect antibodies to HHV-8: enzyme-linked immunosorbent assay (ELISA), immunofluorescent assay (IFA), Western blot, and immunohistochemistry (IHC) testing^{Footnote 1}. HHV-8 can also be detected in clinical samples using PCR^{Footnote 9}.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook.

First aid/treatment

Treatment depends on the viral phase of the infection and presentation of the disease. Antiviral drugs (e.g., foscarnet, ganciclovir, cidofovir, adefovir) can be used to treat individuals with lytic phase infections^{Footnote 9}. Treatment of tumors may include surgical removal, radiotherapy^{Footnote 41}, and/or chemotherapy drugs, such as liposomal anthracyclines and taxanes^{Footnote 50Footnote 51}. In AIDS-KS cases, highly active antiretroviral therapy (HAART) drugs in combination with chemotherapy can be used to help prevent mortality^{Footnote 51Footnote 52}. Immunotherapy used for 3-6 months has been used in a few clinical cases of mostly endemic and classic KS with positive effects^{Footnote 51}.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the Canadian Biosafety Handbook.

Immunization

No vaccine is currently available.

Note: More information on the medical surveillance program can be found in the Canadian Biosafety Handbook, and by consulting the Canadian Immunization Guide.

Prophylaxis

None.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the Canadian Biosafety Handbook.

Section VI – Laboratory hazard

Laboratory-acquired infections

None have been reported to date.

Note: Please consult the Canadian Biosafety Standard and Canadian Biosafety Handbook for additional details on requirements for reporting exposure incidents. A Canadian biosafety guideline describing notification and reporting procedures is also available.

Sources/specimens

Blood and saliva are the primary sources of concern^{Footnote 1}. All bodily fluids or organs are a potential source of infection^{Footnote 1}.

Primary hazards

Autoinoculation with infectious material and mucous membrane exposure to infectious material are primary hazards associated with exposure to HHV-8^{Footnote 1Footnote 34Footnote 36Footnote 37Footnote 38}.

Special hazards

None.

Section VII – Exposure controls/personal protection

Risk group classification

HHV-8 is a Risk Group 2 Human Pathogen and Risk Group 1 Animal Pathogen^{Footnote 53Footnote 54}.

Containment requirements

Containment Level 2 facilities, equipment, and operational practices outlined in the Canadian Biosafety Standard for work involving infectious or potentially infectious materials, animals, or cultures.

Protective clothing

The applicable Containment Level 2 requirements for personal protective equipment and clothing outlined in the Canadian Biosafety Standard are to be followed. The personal protective equipment could include the use of a lab coat and dedicated footwear (e.g., boots, shoes) or additional protective footwear (e.g., boot or shoe covers) where floors may be contaminated (e.g., animal cubicles, PM rooms), gloves when direct skin contact with infected materials or animals is unavoidable, and eye protection where there is a known or potential risk of exposure to splashes.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone and work activities must be documented.

Other precautions

A biological safety cabinet (BSC) or other primary containment devices to be used for activities with open vessels, based on the risks associated with the inherent characteristics of the regulated material, the potential to produce infectious aerosols or aerosolized toxins, the handling of high concentrations of regulated materials, or the handling of large volumes of regulated materials.

Use of needles and syringes to be strictly limited. Bending, shearing, re-capping, or removing needles from syringes to be avoided, and if necessary, performed only as specified in standard operating procedures (SOPs). Additional precautions are required with work involving animals or large-scale activities.

For diagnostic laboratories handling primary specimens that may contain HHV-8, the following resources may be consulted:

• Human Diagnostic Activities Biosafety Guideline
• Local Risk Assessment Biosafety Guideline

Section VIII – Handling and storage

Spills

Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time before clean up (Canadian Biosafety Handbook).

Disposal

All materials/substances that have come in contact with the regulated materials should be completely decontaminated before they are removed from the containment zone or standard operating procedures (SOPs) to be in place to safely and securely move or transport waste out of the containment zone to a designated decontamination area / third party. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (Canadian Biosafety Handbook).

Storage

Containment Level 2: The applicable Containment Level 2 requirements for storage outlined in the Canadian Biosafety Standard are to be followed. Primary containers of regulated materials removed from the containment zone to be labelled, leakproof, impact resistant, and kept either in locked storage equipment or within an area with limited access.

Section IX – Regulatory and other information

Canadian regulatory information

Controlled activities with HHV-8 require a Human Pathogens and Toxins licence issued by the Public Health Agency of Canada.

The following is a non-exhaustive list of applicable designations, regulations, or legislations:

• Human Pathogen and Toxins Act and Human Pathogens and Toxins Regulations
• Transportation of Dangerous Goods Regulations

Last file update

October 2023

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, directives and standards applicable to the import, transport, and use of pathogens and toxins in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

Copyright ^© Public Health Agency of Canada, 2023, Canada