Web-based textbook on the Human Herpesviruses (1388 pp).
What is Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8)?
KSHV is a virus belonging to the family of herpesviruses, which has seven other members that infect humans. Herpesviruses are a group of similar viruses, most of which are extremely common infections that you have probably been exposed to. Some herpesviruses cause diseases while infection with others generally do not cause symptoms. The lay term “herpes” usually refers to herpesvirus type 1, which causes cold sores on the lips (more than 90% of people are infected with herpesvirus type 1), or herpesvirus type 2, which is a sexually transmitted disease that causes “cold sores” on the genitals (about 25% of US adults are infected with herpes type 2). Since both herpes type 2 and KSHV are sexually transmitted (at least in developed countries), they primarily infect adults.
KSHV was discovered in 1994 and so our understanding of it is just beginning. The virus has two names that are commonly used: KSHV which is its descriptive name and HHV8 which is its formal name. Both names are essentially interchangeable. KSHV is different from herpes type 1 and 2 in that it causes a blood vessel cancer called Kaposi’s sarcoma (KS), a lymphoma (a cancer of the lymphocyte) called body cavity-based lymphoma and some forms of severe lymph node enlargement, called Castleman’s disease. Some early scientific reports suggested that it might also cause multiple myeloma, however, many scientists now believe that this is very unlikely.
KSHV is completely different from the HIV virus which causes AIDS, although KSHV-related diseases frequently occur among AIDS patients. In North America, probably less than 10% of the general population has been infected with KSHV and the rate may even be lower. The rates of KSHV infection in the general population of Mediterranean countries (Italy, Greece, Israel, Saudi Arabia) are higher than in North America and Northern Europe. Adult populations in some portions of Africa have very high infection rates (>5
0%). In several respects the global patterns of KSHV infection appear to be similar to those of the hepatitis B virus although we are still at an early stage of understanding the epidemiology of KSHV.How is it transmitted?
This virus appears to be able to be transmitted in several different ways. It can be transmitted through sexual contact, like herpes type 2. Gay and bisexual men are most susceptible to infection in the United States and other parts of the developed world. For gay and bisexual men, “deep-kissing” (inserting the tongue deeply into partner’s mouth) has been thought to be a risk factor. Other scientists suspect that oral-genital or oral-anal contact may play a role in transmission. One risk factor for KSHV, like other sexually transmitted diseases, is having a large number of sex partners. KSHV infection rates as high as 25-35% have been found among some communities of gay men. The KSHV infection rate among gay men has probably dramatically declined since the early 1980s with widespread community use of safe sex techniques. However, it is completely erroneous to assume that KSHV is only an infection of gay men. It is unknown whether or not it can be sexually transmitted among heterosexuals or whether other nonsexual routes are prominent. Our best guess is that italso can be transmitted through heterosexual genital-genital sex, but this is much less efficient than homosexual contact. Regardless, safe sex practices probably prevent the transmission of KSHV.
KSHV is also probably transmitted to some extent through nonsexual routes, perhaps from oral contact (kissing), particularly in Mediterranean and African countries. In Africa (unlike the US and Europe), KSHV infection spreads through casual contact among children and young adults. Again, the precise means by which the virus is transmitted is not known with certainty, but it may have to do with oral contact. Transmission directly from a pregnant mother to her fetus appears to be rare, although very young children can become infected after birth, particularly in Africa. This is a common feature for some herpesviruses in that infection with these viruses is general and occurs at an early age in impoverished countries. As socioeconomic status and hygiene improves in a society, infections occur less frequently and, on average, first exposure is at a later age than in developing countries.
KSHV can be transmitted during organ transplantation. About 1 in 500 transplant patients develop KS after transplantation. Some of these patients became infected by receiving an infected organ whereas others were infected prior to receiving the transplant. Although donor screening may reduce transplant transmission in the future, this is currently not widely available. Recently, studies have suggested that KSHV can be transmitted through needle-sharing among drug users but it is much less efficient than other viruses such as hepatitis B virus.
What happens if you are infected with KSHV?
For most persons, probably not much. It is highly likely that over 95% of persons who are healthy and infected with KSHV do not have symptoms and never will. However, once exposed to KSHV, infection is probably life-long and the immune system of healthy adults keeps the virus in check at extremely low levels. This is much more common that you would think and is probably true for a number of viruses, including the seven other herpesviruses. All people are human-virus chimeras and have been for millions of years. It’s nice toknow that you are never alone.
The real problem with KSHV occurs when an infected person becomes immunosuppressed. This occurs among transplant patients and patients receiving chemotherapy. But most prominently, it is a major problem for persons with AIDS. KS was the skin cancer that the character played by Tom Hanks in Philadelphia developed, causing him to get fired by his law firm. Up to 50% of AIDS patients early in the AIDS epidemic developed KS (the percentage is far lower now). Therefore, this cancer has become closely associated with AIDS, although it can also occur in persons without HIV infection. There is good evidence that if someone is infected with KSHV and becomes immunosuppressed, then their chances of developing clinically detectable disease due to KSHV is higher than for other common viral infections, such as Epstein-Barr virus.
Infection with KSHV is diagnosed by a blood test and a number of research groups are trying to find the optimal method for virus detection. None of the current assays have been submitted to the FDA for approval yet and testing is therefore not generally available except on a research basis. Once an appropriate assay is developed, difficult questions about who should be tested and what should they do if they are KSHV positive will have to be addressed.
It now seems likely that early in the AIDS epidemic there were actually two simultaneous virus epidemics: the well-recognized epidemic of HIV and a second ‘silent’ epidemic of KSHV. Only those persons who became immunosuppressed by HIV developed KS. KSHV is probably less transmissible than HIV, certainly this is true from blood products and sharing needles, and so only the fraction of persons developing AIDS were infected with KSHV and developed KS. Gay and bisexual men were most susceptible to infection with both viruses and the rates of KS in this group greatly exceeded those for other AIDS patients. But if the KSHV epidemic had not occurred, the same HIV patients would have developed AIDS. They just would not have developed KS as a manifestation of AIDS (AIDS-KS) but they would have been susceptible to other opportunistic infections. This appears to be the case now in Thailand where KSHV is uncommon and few Thai AIDS patients develop KS.
KSHV-related disease can also occur in persons without obvious immunodeficiency, but this is rare and primarily occurs among elderly men. Older gay men without HIV infection develop KS more frequently than older heterosexual men without HIV, probably because the virus is more common in this population. Before the AIDS epidemic, less than 5 KS cases occurred per million population per year, and most of whom were in persons over 65 years old. The rarity of KS in healthy adults is probably due to the fact that KSHV infection is uncommon and few persons with intact immune systems develop detectable KS disease even when infected. KS in an otherwise healthy adult is often a slow growing tumor that can be controlled by surgery or radiation therapy applied locally to the site of the tumor.
The African Epidemic
There has been a major epidemic of KS in some parts of Africa, especially Eastern and Southern Africa, concurrent with the African HIV pandemic. KS is now the most common tumor reported in several African cancer registries. While most African KS patients are also HIV infected, these areas also have the world’s highest rates of this disease for nonHIV-infected persons.
KS in childhood is virtually nonexistent in North America or Europe, but it can occur in some areas of Africa. Unlike adults who usually have a slow-growing and frequently controllable form of KS, childhood KS is aggressive and rapidly fatal. An effective vaccine to prevent KSHV infection is the best and only practical method for dealing with this problem. The development of vaccines ed against diseases in poorer countries is a chronic problem since there is little financial incentive for their development. Further, the burden of KSHV infection on these countries has to be carefully weighed against other public health problems such as diarrhea, measles, HIV and tuberculosis, where limited public health dollars may have a greater impact. Nonetheless, development of affordable, safe and effective treatment for African childhood KS should remain an important and achievable goal.
Is there a treatment of KSHV?
Existing therapies, although often effective, the tumor cells rather than the virus. One hope is that a antiviral drug which is relatively nontoxic can be found to kill the virus and revert the tumor cells back to normal. Drugs have been developed to treat other herpesvirus infections, and some of these drugs, such as ganciclovir are very effective in preventing KS, but it is not clear whether or not they can treat tumors that already exist. Effective treatment regimens against HIV have been also shown to be dramatically effective for many cases of AIDS-KS. Treatment of the underlying immune deficiency appears to be the optimal approach (currently) for controlling the tumor caused by KSHV. In many cases of severe AIDS-KS, treatment with effective antiHIV therapy will cause the KS tumors to completely regress.
There is no vaccine for KSHV and there is little commercial interest from vaccine or drug manufacturers at present in developing them. Because this virus appears to be under exquisite control by the immune system, it should be a very good candidate for a successful vaccine. Hopefully, this situation will change in the next few years.
What’s so interesting about KSHV?
Aside from its importance to various human diseases, KSHV turns out to be a fascinating virus. KS had been thought to be due to an infection for decades, but no one was able to successfully grow the “KS agent” directly from tumors. It was found by isolating its DNA directly from a KS tumor without growing the virus in the laboratory, and it represents one of a handful of new agents of human disease that have been discovered in this way. More importantly, it shows that there are likely to be other unknown viruses and bacteria causing chronic human diseases. One of the major triumphs of the molecular biology revolution was the development of tools allowing us to discover new agents this way.
There are good reasons for scientists to have a keen interest in KSHV. Viruses in general have adapted over millions of years of evolution to insinuate themselves into the workings of the host cells they infect. Frequently viral proteins will very precisely bind to cellular proteins to alter the cell for the benefit of the invading virus. Many viruses which cause tumors, such as KSHV, possess viral proteins (oncoproteins) which bind to and inhibit cellular proteins to control cell growth. These cell proteins normally prevent tumors from developing and are called tumor suppressor proteins. Several of the most important tumor suppressor proteins were first discovered because they were antagonized by viral oncoproteins. Since then, it has become clear that various tumor suppressor proteins are involved in preventing all cancers from arising, not just cancers caused by viruses.
Cancers are simply made from cells that have continued to grow beyond normal limits. This can occur if mutations or viruses have interrupted signals that should’ve told the cell to stop dividing or if the cell lives longer than it should so that there is an abnormal accumulation of cells. Usually, both of these processes are abnormal in cancer cells (the water tap is turned on and there is a stopper in the drain). There are hundreds of proteins encoded by genes which potentially could affect these processes scattered throughout the human genome. Further, cancers arise from different combinations of these genes being active or inactive and so the process of understanding the fundamental basis for tumorigenesis is daunting. But viruses have small genomes and it is easier to look at viral oncoproteins in various combinations to see how they affect the growth of cells. If we know precisely how a virus causes a cancer, then we are likely to find new key checkpoints to prevent nonviral cancers as well.
The oncogenes most viruses carry are so highly evolved and specialized that we can not easily guess their functions. Current knowledge about these viral genes comes from years of difficult and painstaking research. KSHV, however, is “easy pickins.” Rather than developing its own oncoproteins, KSHV has stolen many genes from the host cell (a process called ‘molecular piracy’ or ‘molecular mimicry’). The only other two human viruses which come close to the degree of molecular piracy shown by KSHV are smallpox virus (which is nearly extinct hopefully) and its relative, molluscum contagiosum virus. These KSHV genes are readily recognizable to cell biologists since they control key aspects of cell regulation, allowing the cell to replicate, to prevent cell death and to shut off immune responses in infected cells. Evolution has tailor-made KSHV proteins to interfere with the human cell and biologists who have no interest in viruses per se are likely to find them interesting as tools to perturb cellular pathways.
Why have some viruses, like KSHV, evolved to cause cancers while other viruses do nothing worse than cause the common cold? Even more perplexing, some viruses like adenovirus cause fulminant cancers in some animals and cold symptoms in others. Our lab is working under the hypothesis that this is because cells use some of the tumor suppressor proteins to do double-duty to both control tumors and eliminate viral infection.
Once a virus infects a cell, it is little more than a strand of nucleic acid and the best way to stop this nucleic acid from dividing and eventually infecting other cells is to shut off all replication of nucleic acids. This also is precisely what cells do to stop themselves from dividing. Further, if controlling nucleic acid replication doesn’t work, the cell can also kill itself through a specific mechanism called apoptosis. This form of cellular seppuku can be effectively used to rid the host of virus-infected cells. Cells that have lost control of replication through a mutation also undergo apoptosis as a natural defense against cancer. However, if the virus fights back by stealing proteins that normally shut-off these defenses, then it might accidentally trigger a cell under the right circumstances to become a cancer cell. This is accidental in the sense that the viral genes probably are not meant to cause tumors, since killing your host is a poor way to ensure your survival even if he or she is trying to kill you.
However, when the host is immunosuppressed or has mutations in other tumor suppressor genes, or if the virus infects a animal that is not its naturally adapted host, then the balance might shift towards tumor formation. This is one reason why scientists are concerned about the new introduction of viruses into the human population from animal reservoirs. This hypothesis is still at the stage of informed speculation, but there is considerable evidence to support this from both KSHV and other tumor viruses. At any rate, that’s why KSHV is so interesting.
To learn more about KS and KSHV:
The following are scientific articles on KSHV available at most medical libraries:
- Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M., and Moore, P. S. (1994). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 265, 1865-69.
- Moore, P. S., Boshoff, C., Weiss, R. A., and Chang, Y. (1996). Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 274 (5293), 1739-1744.
- Russo, J. J., Bohenzky, R. A., Chien, M. C., Chen, J., Yan, M., Maddalena, D., Parry, J. P., Peruzzi, D., Edelman, I. S., Chang, Y., and Moore, P. S. (1996). Nucleotide sequence of the Kaposi’s sarcoma-associated herpesvirus (HHV8). Proceedings of the National Academy of Sciences, USA. 93 (25), 14862-7.
- Cannon MJ, Dollard SC, Smith DK, Klein RS, Schuman P, Rich JD, Vlahov D, Pellett PE. Blood-Borne and Sexual Transmission of Human Herpesvirus 8 in Women with or at Risk for Human Immunodeficiency Virus Infection. N Engl J Med. 2001 Mar 1;344(9):637-643 .
- John Pauk, Meei-Li Huang, Scott J. Brodie, Anna Wald, David M. Koelle, Timothy Schacker, Connie Celum, Stacy Selke, Lawrence Corey, Mucosal Shedding of Human Herpesvirus 8 in Men .The New England Journal of Medicine — November 9, 2000 — Vol. 343, No. 19
- Karen Antman, Yuan Chang , Medical Progress: Kaposi’s Sarcoma. The New England Journal of Medicine — April 6, 2000 — Vol. 342, No. 14:1027-38
Boshoff, C., and Weiss, R. A. (1997). Aetiology of Kaposi’s sarcoma: current understanding and implications for therapy. Molecular Medicine Today. 3 (11), 488-94.
- Boshoff, C., and Moore, P. S. (1998). Kaposi’s sarcoma-associated herpesvirus: A newly recognized pathogen. In A’AIDS Clinical Review 1997/1998A” (P. A. Volberding and M. A. Jacobson, eds.), pp. 323-347. Marcel Dekker, Inc, New York.
- Cesarman, E., and Knowles, D. M. (1997). Kaposi’s sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Seminars in Diagnostic Pathology. 14 (1), 54-66.
- Ganem, D. (1997). KSHV and Kaposi’s sarcoma: the end of the beginning? Cell. 91, 157-60.
- Moore, P. S., and Chang, Y. (1998). KSHV-encoded oncogenes and oncogenesis. Journal of the National Cancer Institute . 23, 65-71.
- Moore, P. S., and Chang, Y. (1998). Kaposi’s sarcoma (KS), KS-associated herpesvirus, and the criteria for causality in the age of molecular biology. American Journal of Epidemiology . 147, 217-221.
- Moore, P. S., and Chang, Y. (1998). Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV. Trends in Genetics . 14 (4), 144-50.
- Offermann, M. K. (1996). HHV-8: a new herpesvirus associated with Kaposi’s sarcoma. Trends in Microbiology. 4 (10), 383-6.
- Tappero, J. W., Conant, M. A., Wolfe, S. F., and Berger, T. G. (1993). Kaposi’s sarcoma: epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy. J. Am. Acad. Dermatol. 28, 371-95. (Before KSHV was discovered).
- Schulz, T. F., Chang, Y., and Moore, P. S. (1998). Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8). In “Human Tumor Viruses” (D. J. McCance, ed.), pp.87-134. ASM Press, Washington D.C.