KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine

Abstract

Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered.

Fig. 1. The Kaposi sarcoma epidemic.

U.S. National Cancer Institute’s Surveillance, Epidemiology and End-Results (SEER) data for San Franciscan men shows the emergence and magnitude of this epidemic cancer caused by transmissible KSHV infection during the AIDS epidemic (Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Bishop, K., Kosary, C.L., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D.R., Chen, H.S., Feuer, E.J., Cronin, K.A. (eds). SEER Cancer Statistics Review, 1975–2014, National Cancer Institute, Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/).

Fig. 2. Global patterns of KSHV spread with KSHV endemic and hyperendemic areas (red).

Molecular epidemiology studies indicate that KSHV evolved with humans and spread primarily through human migrations. KSHV D and E strains may represent modern remnants of an ancestral KSHV strain migrating with early humans that was subsequently lost from most Asian and European populations after settlement, leaving endemic and hyperendemic geographic pockets in Okinawan islands and in South America. Additional viral strains (e.g., A, B, C, and Z) appear to have re-emerged in Africa and the spread of some strains may represent secondary out-migrations to Mediterranean, Western Chinese, and North American populations within historical periods. Unlike other human herpesviruses, KSHV is not ubiquitous and current global patterns are consistent with the potential for human immune clearance of this virus.

Fig. 3. Schematic diagram of major Kaposi sarcoma herpesvirus membrane structural glycoproteins.

Individual viral components are indicated. The viral genome is a linear double-stranded DNA enclosed in an icosahedral capsid. This nucleocapsid is surrounded by the tegument. The tegument is a dense amorphous proteinaceous structure. The viral envelope is a lipid bilayer membrane of host origin that contains ten different KSHV glycoproteins. Conserved glycoproteins that are potential preventive vaccine antigens include gB, gH, gL, gM, and gN, and accessory glycoproteins gK8.1, ORF4, ORF27, ORF28, and ORF68.