Kaposi's Sarcoma Virus

Part 8 of “The human herpesviruses: much more than you wanted to know”

Semi-related note: A new paper is out in Science presenting more evidence that EBV causes multiple sclerosis. The new paper is very similar to one from 2010 I referenced in my EBV post; the same research group has collected even more data from the same population.

0. Actionable advice

• Don’t get HIV.

• If you have HIV, get antiretroviral treatment.

• If you’re immunosuppressed, avoid contact with other people’s saliva.

1. Virology

Kaposi’s sarcoma herpesvirus (KSHV, also known as HHV8), is a gammaherpesvirus. In terms of the viral genome, overall life cycle, and oncogenesis, it is similar to EBV, the other human gammaherpesvirus. Here, I will give a brief overview of some important and/or unique aspects of KSHV virology. For a deep dive into KSHV and Kaposi’s sarcoma, I highly recommend a 2010 review by Mesri et al. (1), which is my source for most of the information in this section.

KSHV latency is characterized by the expression of the latency-associated nuclear antigen (LANA), a viral protein that promotes replication of the viral episome, ensures that it is distributed to both daughter cells when a cell divides (2), and additionally interferes with host tumor suppressors such as p53 and Rb. Thus, it is functionally similar to EBNA1 in EBV, although its sequence and structure is different. A few other viral genes besides LANA, such as vcyclin and vFLIP, are also expressed during latency and promote the proliferation of the host cell. Interestingly, KSHV can lengthen the telomeres of the host cell, enabling it to proliferate more (3).

Viral activation depends on a transactivating viral transcription factor, RTA. Conceptually this is similar to the role of VP16 in HSV activation. After activation, an additional set of viral genes is expressed, including genes directly involved in viral replication as well as genes that suppress apoptosis and activate pro-inflammatory host signaling pathways. The presence of a small fraction of lytic KSHV replication in Kaposi’s sarcoma tumors creates an inflammatory environment that favors tumor growth.

Many herpesviruses have stolen genes from the host organism and express viral orthologs. In this aspect, KSHV is a repeat offender. Out of 87 proteins encoded by the virus, 14 are of host origin, a high fraction for a virus (Figure 1). Some, such as an interleukin-6 mimic (vIL6), interfere with the host immune system, while others, such as a constitutively active cyclin (vcyclin), drive the infected cell to progress through the cell cycle and divide.

Figure 1: KSHV genome structure. Genes highlighted in yellow are orthologs of host genes (i.e. they originated in the host genome, but the virus has adapted them for its own use). Figure from Mehri et al. 2010 (1)

2. Kaposi’s sarcoma

Usually, infection with KSHV is completely asymptomatic. In immunocompetent individuals, the rate of KSHV-associated malignancies is less than 1 in 100,000. The rate is slightly higher in some ethnic groups (especially elderly Middle Eastern and Ashkenazi Jewish people), which may reflect host genetic predispositions (1). Still, the vast majority of malignancies occur in immunosuppressed people, such as AIDS patients and transplant recipients. Whereas the rare Kaposi’s sarcoma cases in immunocompetent people usually progress slowly, the cancer in immunosuppressed people can be highly aggressive. In fact, one of the first signs of the AIDS pandemic was an increase in Kaposi’s sarcoma cases in homosexual men (4). Untreated AIDS patients who are positive for KSHV have a ~50% chance of developing Kaposi’s sarcoma (5). (I expect the rate would be even higher, except many die from other infections before they can develop KSHV.)

The cancer Kaposi’s sarcoma begins in infected endothelial cells (blood vessel or lymphatic lining). Tumors consist of characteristic spindle-shaped cells that express KSHV LANA (5). Kaposi’s sarcoma cells depend on host inflammatory cytokines to stimulate their proliferation (1). Although most cells within a tumor are latently infected, a small proportion of viral reactivation and lytic replication causes an inflammatory environment and promotes tumor growth. Treatment is difficult once the cancer is established (5), so prevention (by antiretroviral treatment of HIV-infected patients) is important.

In addition to Kaposi’s sarcoma, KSHV can also cause the relatively rare cancers primary effusion lymphoma, diffuse large B-cell lymphoma, and Castleman disease (5). These also occur mainly in immunosuppressed individuals.

3. Epidemiology

KSHV is the least prevalent human herpesvirus. Within the United States, a sample of 122 blood donors (in 1996) found none positive for KSHV (6). The same study found a 4% prevalence in Italy and a 51% prevalence in Uganda. Although there were a few studies after 1996 in the United States, this 1996 study is still the biggest that I could find. It seems that interest in KSHV has decreased now that effective AIDS treatments are available.

More recent data are available for other countries (Figure 2). Prevalence among women ranges from 3.8% (Spain) to 46% (Nigeria) (7). Within each population, the rate decreases with increasing educational attainment (probably a proxy for socio-economic class). Sub-Saharan Africa has the greatest burden of disease from KSHV, mainly due to the AIDS pandemic, but intriguingly, Kaposi’s sarcoma also occurs there in some HIV-negative people (1). I speculate that something is similar here to Burkitt’s lymphoma and EBV, where other infections such as malaria stress the immune system and allow oncogenesis.

Figure 2: Global distribution of KSHV prevalence. Figure from Mehri et al. 2010 (1), compiling data from several other studies. Within each country, prevalence within certain subpopulations may be much higher than average.

4. Conclusions

KSHV is the herpesvirus I’m least worried about, since it’s not very prevalent and serious complications of infection are rare. It’s interesting from a biologist’s perspective, but efforts to treat or prevent KSHV infection would be better spent on treating or preventing AIDS, which is the underlying cause of most Kaposi’s sarcoma cases.

5. References

1.         E. A. Mesri, E. Cesarman, C. Boshoff, Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 10, 707–719 (2010).

2.         M. E. Ballestas, P. A. Chatis, K. M. Kaye, Efficient Persistence of Extrachromosomal KSHV DNA Mediated by Latency-Associated Nuclear Antigen. Science. 284, 641–644 (1999).

3.         T. P. Lippert, P. Marzec, A. I. Idilli, G. Sarek, A. Vancevska, M. Bower, P. J. Farrell, P. M. Ojala, N. Feldhahn, S. J. Boulton, Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres. Nat Commun. 12, 512 (2021).

4.         Centers for Disease Control (CDC), Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR Morb Mortal Wkly Rep. 30, 305–308 (1981).

5.         P. H. Gonçalves, T. S. Uldrick, R. Yarchoan, HIV-associated Kaposi sarcoma and related diseases. AIDS. 31, 1903–1916 (2017).

6.         S. J. Gao, L. Kingsley, M. Li, W. Zheng, C. Parravicini, J. Ziegler, R. Newton, C. R. Rinaldo, A. Saah, J. Phair, R. Detels, Y. Chang, P. S. Moore, KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nat Med. 2, 925–928 (1996).

7.         S. de Sanjose, G. Mbisa, S. Perez‐Alvarez, Y. Benavente, S. Sukvirach, N. T. Hieu, H. Shin, P. T. H. Anh, J. Thomas, E. Lazcano, E. Matos, R. Herrero, N. Muñoz, M. Molano, S. Franceschi, D. Whitby, Geographic Variation in the Prevalence of Kaposi Sarcoma–Associated Herpesvirus and Risk Factors for Transmission. J INFECT DIS. 199, 1449–1456 (2009).