Introduction
An estimated 90,000 to 100,000 people in the United States are infected with human T-cell lymphotropic virus type 1 (HTLV-1), an enveloped, single-stranded RNA delta-type retrovirus of the subfamily Oncovirinae. HTLV-1 infects T cells, mainly CD4 T cells, and transmission requires cell-to-cell contact. The three main modes of transmission are from mother to child (mainly through breastfeeding), sexual contact, and unscreened blood transfusions or organ transplants. Most HTLV-1-infected individuals are lifelong asymptomatic carriers, with only 2% to 5% developing disease. The virus was first isolated in 1979 from peripheral blood lymphocytes in a patient thought to have T-cell lymphoma.
Methods
The National Toxicology Program (NTP) conducted a cancer hazard evaluation of HTLV-1 infection for possible listing in the Report on Carcinogens (RoC). The evaluation included the findings from studies reported in the IARC monograph in Volume 100B, as well as from human cancer studies and mechanistic studies and reviews published after the IARC review. For each cancer site, the evidence from human and mechanistic studies was integrated considering the following guidelines: Hill’s characteristics of causality, multicausality epidemiology considerations and concepts of direct and indirect carcinogenesis proposed several virus experts. Finally, the RoC’s listing criteria were applied to the assessment to reach an overall cancer hazard conclusion.
Results and discussion
NTP concluded there was sufficient evidence of HTLV-1 causing acute T cell leukemia/lymphoma (ATLL), a rare and aggressive T cell cancer. Many case series studies found consistent evidence of HTLV-1 infections in over 500 ATLL cases. Several cohort studies found higher rates of death from ATLL among HTLV-1 carriers. Some found this rate higher in men than in women. Other prospective studies found the risk of developing ATLL was greater with higher proviral load or higher anti-HTLV-1 antibody levels. Molecular studies of almost all ATLL tumors found that the virus is integrated in a monoclonal fashion, indicating infection precedes disease, and some tumors express Tax, a key HTLV-1 protein. Mechanistic studies found that Tax can immortalize T cells both in vitro and in immunodeficient mice and support the evidence from human studies. Because of the high prevalence of HTLV-1 infection (over 90%) and monoclonal integration in almost all ATLL cases, HTLV-1 monoclonal integration is part of the diagnostic definition of ATLL.
NTP cancer hazard conclusion and significance
The conclusion of the cancer hazard evaluation was that HTLV-1should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of HTLV-1 in the 14th RoC. The rationale for the listing was sufficient evidence from studies in humans (epidemiological and molecular) for ATLL. Globally, HTLV-1 is estimated to be responsible for approximately 10,000 cancers per year.
National Toxicology Program (NTP). 2016. Report on Carcinogens monograph on human T-cell lymphotropic virus type 1. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 09. https://doi.org/10.22427/ROC-MGRAPH-09