Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED
Neoplasms of an infectious etiology account for about 16% of all cancers, which amounts to about two million cases per year, considering virus-, bacteria- and parasite-derived cancers. Interestingly, this number is significantly higher for developing countries, in which it can be as high as 30%, while in highly industrialized countries, such as the US, it can be as low as 5% . The bases for this difference are not clear, but it may be due to the prevalence of the oncogenic infectious agents, or to additional co-factors causally linked to the infectious neoplasms.
Virus-derived cancers almost always originate from established chronic viral infections, because the mechanisms of viral persistence in the infected host are compatible with oncogenesis. Indeed, all human oncogenic viruses express proteins, and/or non-coding RNAs with the capacity to transform cells in culture and induce cancer in transgenic animals . Viral oncogenes tend to enhance cell proliferation and survival, aiming to maintain the pool of infected cells during persistent infections. The International Agency for Research on Cancer (IARC) acknowledges seven viruses as direct human oncogenic agents: the Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV), human T cell lymphotropic virus type 1 (HTLV-1), high risk human papillomaviruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Merkel cell polyomavirus (MCPyV) . Although the human immunodeficiency virus (HIV) is also causally associated with several neoplasms, it is as an indirect oncogenic agent, due to the immunosuppression it imposes upon the infected host.
The Epstein–Barr virus (EBV) was the first oncogenic virus discovered 56 years ago by Dr. Anthony Epstein and Dr. Ivonne Barr. EBV was initially observed in samples of Burkitt lymphoma (BL) coming from the equatorial Africa, which represents the perfect example of the unequal geographical distribution of neoplasms of infectious origin. While EBV is responsible for close to 100% of the BL originating in this region, EBV only accounts for about 20% of all BLs in developed countries (see below). We later understood that whilst EBV is evenly distributed around the world, the African BL is also associated with repetitive infections with Plasmodium falciparum, an important co-factor of this neoplasm and a parasite endemic to this area. Today, BL is classified within three distinct clinical types, endemic (malaria- and EBV-associated), sporadic (derived from areas in which malaria is not holoendemic) and immunodeficiency-associated .
The world distribution of the oncogenic viruses varies significantly, while most adults are already infected with EBV, HPV and MCPyV indistinct of the geographic region, the others tend to be more prevalent in specific populations . Even today, despite the global means of transportation and increased immigration that have allowed a more heterogeneous mix of populations, the prevalence of KSHV and HTLV-1 infection is still restricted to particular geographical areas, implying mechanisms of viral persistence in the population that are not explained by mere socioeconomic factors, but in which genetic susceptibilities, ethnic origin, culture and the prevalence of co-factors may be critical (see below). Like EBV, KSHV and HTLV-1 are associated with lymphoid neoplasms . While EBV mainly infects and persists in B cells, KSHV and HTLV-1 persist in B cells and T cells, respectively, and, as such, they have been associated with B and T cell lymphomas .
Latin America (LA) comprises the land from Mexico to Argentina and the Spanish speaking Caribbean, countries with a complex mix of geographies, climates, politics, cultures, ethnicities and different levels of socioeconomic development, and, in which, a high prevalence of oncogenic viruses, acute tropical diseases and malnourishment collide. Early epidemiological studies documented a high seroprevalence of KSHV and HTLV-1 in some regions of LA, and to this day, it is common to find in the scientific literature that these viruses are endemic to LA (see below). However, the loco- regional estimation of their prevalence and induced morbidity remains poorly known. The RIAL- CYTED harbors a multidisciplinary Ibero-American network of clinical and basic researchers created to form a platform of multi-center cooperation focusing on increasing our knowledge of lymphoma, particularly for more underdeveloped or developing regions. This network aims to improve the diagnosis and prognosis of these neoplasms throughout LA by way of homogenizing its identification and classification. With that purpose, in this review, we sought to systematically organize and analyze the literature related to the lymphotropic and lymphomagenic viruses EBV, KSHV and HTLV-1, in order to better understand their loco-regional distribution and the risk our population carries in terms of developing lymphoma.
To this end, we explored three web search engines, PubMed, Google Scholar and SciELO, to access all related scientific publications in English, Portuguese and Spanish. Searches were done with the name of each LA country plus the name of each virus individually: Epstein–Barr virus or EBV; KSHV, KSV, HHV8 or Kaposi sarcoma virus; HTLV-1, ATLV or human T-cell lymphoma virus 1. All collected publications were read and classified according to the content; sero-epidemiological studies of KSHV and HTLV-1 viruses were considered, in order to discuss their association with lymphoma in specific regions, while EBV sero-epidemiological studies were discarded, since it is well known that there is a worldwide high prevalence in both developed and developing countries. In case reports and when series of lymphomas were included, we assessed the methods of viral diagnosis, prioritizing those studies in which the presence of the virus was addressed in the lymphoma sample by means of immune or molecular methods. The search was carried out from February 2019 to December 2019, and, although we aimed to include all papers found, regardless of the date of publication, many journals do not have online versions of the documents prior to the 1990s. Moreover, many old studies did not comply with more recent lymphoma classification. The results are disclosed in the next sections for each particular virus.