Herpesviruses Slide Set

Human Herpesvirus


HHV-6 was first isolated in 1985. They were isolated from attempted cultures for HIV from 6 patients in the USA. A peculiar CPE became available and on EM, a herpesvirus was seen. At first, it was thought that this virus was EBV or CMV but soon it became obvious that it is a new herpesvirus. It was soon established that similar viruses were isolated worldwide form patients who were immunosuppressed or who had lymphoproliferative disorders. The culture system used for this virus was the same as for HIV and HTLV. The virus was originally named HBLV and people were very excited about the prospects of a new herpesvirus associated with various haematological malignancies. However, such an association became less and less tenuous. In 1988, HHV-6 became associated with the condition roseala infantum or sixth disease. In the past 2 years, a new virus HHV-7 was discovered which was similar to HHV-6. The relationship between HHV-6 and HHV-7 is thought to be analogous of that between HSV-1 and HSV-2.

A. Properties

Belong to the betaherpesvirus subfamily of herpesviruses
dsDNA enveloped viruses of icosahedral symmetry
Do not antigenically cross react with other herpesviruses.
Like other herpesviruses, HHV-6 is capable of reactivation which are probably asymptomatic.
HHV-6 comprises 2 forms: HHV-6A and HHV6-B, with different biological properties e.g. cell tropism, tissue distribution and reactivity to monoclonal antibodies. They are officially considered as distinct species rather than variants of one species.
HHV-6B causes roseala infantum, whereas HHV-6A has been isolated mainly in immunocompromised hosts and yet to be firmly associated with specific diseases.
The genome is a dsDNA with 170 kbp. Probes against HHV-6 do not cross hybridize with HSV, VZV, and EBV.
However, there is significant homology with CMV, up to 50%. It is classified as a Beta 2 herpesvirus ie. in the same group as CMV.
A new virus, HHV-7 is thought to be similar and related to HHV-6B in the same way as HSV-1 to HSV-2.
Like HHV-6B, HHV-7 is associated with roseala infantum, although it causes the disease less frequently than HHV-6B

HHV-6 particles on the surface of a lymphocyte 

Growth Characteristics

Restricted range of susceptible cells - it was originally classified as HBLV as it was isolated from B-lymphocytes. In fact it is T cells which are more susceptible. HHV-6 can superinfect EBV and HIV positive cell lines. The predominant susceptible cell type is immature T cells which express OKT4. However the virus receptor is not CD4, as in the case of HIV. HHV-6 infected cells are not immortalized. Four day after inoculation into B cells, ballooning is seen. It is apparent that a lytic infection is present. In less permissive cells, CPE is still apparent. However, even when one had good CPE, poor expression is seen. Supernatants taken from these cell cultures are non-infectious. The infected cells in the culture are full of infectious particles but no budding form the cells take place. Therefore there is incomplete virus replication present.

B. Epidemiology

HHV-6B is acquired rapidly after the age of 4 months, as the protective effects of maternal antibody wears off. In contrast, EBV is acquired less rapidly after the age of 4 months. 30% of babies already have CMV infection by the age of 4 months. It is clear that maternal antibodies do not protect against CMV infection. The CMV and EBV infection was asymptomatic in babies. The virus is ubiquitous and is found worldwide. It is thought that the most likely route for transmission is breast feeding as well as aerosol transmission and saliva from mothers to babies. Breast feeding though, is unlikely to play the major role in the transmission, as babies who are not breast fed were shown to have acquired antibody rapidly as well. Sexual spread is not thought to be a route of transmission of the virus.

C. Clinical Manifestations

HHV-6B is the causative agent for roseala Infantum. Most cases occur in infants between the ages of 4 months and two years, with over half the cases occurring in the second 6 months of life. Secondary cases are rare in clinical practice. A spiking fever develops over a period of 2 days followed by a mild rash. The fever is high enough to cause febrile convulsions. There are reports that the virus can cause encephalitic symptoms, possibly due to prolonged seizure. It is now also associated with a glandular fever like illness. It is also associated with hepatitis part of the IM syndrome. The glandular fever tends to occur in the late teens and twenties, as in the case of EBV. However, he proportion of susceptible individuals reaching these ages is very small compared with EBV, as infection by HHV-6B is acquired at a much earlier age.

Roseala Infantum

Immunocompromized patients - In immunocompromized patients, HHV-6A reactivation is associated with a worse outcome. Such reactivation occurs in 33-48% of patients undergoing hematopoietic stem-cell transplantation. For example, in these patients, reactivation of HHV-6 has been associated with CMV reactivation and increased severity of CMV disease. Other clinical conditions associated with HHV-6 reactivation in this population include hepatitis, idiopathic pneumonitis, bone-marrow suppression, encephalitis, fever and rash, graft versus host disease (GVHD), and delayed engraftment. Although reactivation of HHV-6 accounts for most infections, transmissions of HHV-6 with the donor allograft, solid organ, or hematopoietic stem cell have also been reported.

In the beginning it was thought that this virus may be involved in lymphomas. However, enthusiasm was very much dampened when it was shown that up to 100% of people may eventually be infected. Therefore, It remains uncertain whether there is any association with lymphoma or other lymphoproliferative syndromes. The virus has also been associated with lymphadenopathy.

Association with AIDS - the virus can co-infect HIV infected cells. It is able to transactivate the LTR region of the HIV and thus increase the efficiency of HIV infection. Therefore it is possible that it may act as a co-factor for AIDS. But more work needs to be done on this topic.

Other disease associations - HHV-6 had been associated with febrile convulsions, meningitis, encephalitis, and possibly multiple sclerosis. HHV-6 has also been associated with disease in immunocompromised patients such as transplant recipients. However it is very difficult to prove such association because other CMV is almost always reactivated at the same time as HHV-6.

D. Diagnosis

The detection, quantification, and sequencing of HHV-6 nucleic acids have been combined to become the gold standard of diagnostic procedures applied to HHV-6A and HHV-6B. By means of numerous assays based on real-time PCR, HHV-6 DNA can be detected and reproducibly quantified in a broad range of clinical specimens, including whole blood, cerebrospinal fluid, and any other bodily fluid or tissue. Virus isolation is not practicable as a routine diagnostic procedure. If it is to be attempted, the patient's peripheral blood mononuclear cells are cultured are the presence of PHA stimulant for 3-6 days. They are then co-cultivated with similarly stimulated cord blood lymphocytes. Serology is generally used to make a diagnosis in a routine laboratory. Both IgM and IgG can be demonstrated by immunofluorescence. One problem is that HHV-6 reactivates frequently causing a rise in both serum IgM and IgG. This has been shown to happen with concomitant primary EBV infections and during primary or reactivating CMV infections. It is thought that the serological response to HHV-6 in these instances is due to reactivation of latent virus as the result of an infection with another agent rather than indicating antibody cross-reactivity.

E. Management

Cases of roseala infantum are sporadic and outbreaks have not been described in families or paediatric wards. Most cases of roseala are relatively mild and do not require hospitalization. It is probably very difficult and probably inadvisable to avoid infection.


Other Herpesviruses

1. HHV-7

HHV-7 was first isolated in 1989 from the peripheral blood lymphocytes of a healthy individual. Since then, HHV-7 has been isolated from the saliva of as many as 75% of healthy adults. Antibodies to HHV-7 can be detected in the serum specimens from 90% of the normal population. There is data to suggest that it is able to cause roseala infantum.

2. Human Herpes Virus 8 (HHV-8)

Through the use of a new molecular biology technique known as representational differential analysis (RDA), whereby the genetic material present in a suspected infected cell is compared to that of an un-infected cell of the same type, herpesvirus-like DNA sequences were discovered in the majority of Kaposi’s sarcoma. This new herpesvirus has now been named HHV-8. There is cumulating evidence for a role of this virus in Kaposi's sarcoma. Since its discovery by in 1994, HHV-8 has been identified in virtually all AIDS- and non-AIDS-related KS lesions. At the same time, several research teams have identified the virus in a subset of other less-uncommon pathologic conditions, including primary effusion lymphomas and multicentric Castleman’s disease. But while a definitive link exists between HHV-8 and these specific malignancies, the precise role that it plays in their development is not completely understood. The pathogenesis of KS is, in fact, a multifactorial process. Some of the factors known to play a role in its development, aside from HHV-8, include altered expression and response to cytokines and angiogenesis. Whether these factors result from or are independent of viral infection is unresolved at this time. Nevertheless, therapeutic strategies have targeted these factors and are now entering clinical trials.


Kaposi's Sarcoma affecting the forearm


Serologic assays for KSHV/ HHV-8 antibodies are now available to test for the presence of the virus. The assays depend on cell lines derived from body cavity-based primary effusion lymphomas, which are infected with up to 100 copies of the virus and are a rich source of a viral latency-associated nuclear antigen (LANA). Studies using LANA assays have found that close to 100% of sera from non-AIDS KS patients are positive for HHV-8 antibodies. In AIDS-related KS, there is a lower (~80%) LANA positivity rate as measured by existing seroassays, probably due to decreased antibody production in patients with late-stage HIV disease.

The rates of HHV-8 infection in the general population of Mediterranean countries (Italy, Greece, Israel, Saudi Arabia), where classic KS is seen with relatively high frequency, are higher than in North America and Northern Europe. Adult populations in some portions of Africa, where KS has long been quite common also, have very high infection rates (>50%). Additional studies have found a strong link between HHV-8 antibody seropositivity and the risk of developing KS. In HIV-negative blood donors, anti-LANA seropositivity rates are 1% to 2%, whereas about 30% of HIV-positive gay men have been found to be seropositive. Moreover, the concordance of positive LANA serologies with KS prevalence implies that clinically healthy HIV-positive men who are HHV-8-positive have a high risk of progression to KS once immunodeficiency supervenes. The HHV-8 seropositivity rate among HIV-positive hemophiliacs or transfusion recipients, on the other hand, has been reported to be only 2% to 3%. Similarly, only 3% to 4% of HIV-positive heterosexual women are KSHV/HHV-8-positive. Indeed HHV-8 is unique among human herpesviruses in that it is not ubiquitous in distribution.It is not known why KS predominates in males. It is possible that hormones play an important role in this regard.

3. Herpes B Simiae

Herpes B Simiae causes disease in old world monkeys similar to that of HSV in humans. In rare instances, it may be transmitted to humans, usually through a monkey bite, where it may cause a severe fatal disease with encephalitis. There had only been 22 reported cases in the literature, of which one case resulted from person-to-person transmission. IV acyclovir and/or ganciclovir had been used in the treatment of suspected cases but their exact value has yet to be determined. The control of infection depends of good procedures in animal houses, where possible, the Herpes B status of the monkeys should be determined and only those which are known to be free of the virus should be used.


Herpesviruses Slide Set