40 Years Anniversary of HTLV-1 Discovery

Dear Colleagues,

The discovery of the retroviral reverse transcriptase in 1970 and the subsequent declaration of the “War on Cancer” led to an intense surge of research activity directed towards the identification of human cancer retroviruses. Many cancer researchers abandoned this search, largely due to flawed results caused by a variety of objects. The laboratory of Dr. Robert C. Gallo continued to pursue this goal. Their research involved the development of specific assays along with new cell culture methods, leading to the identification and initial characterization of human T cell leukemia virus type 1 (HTLV-1), which was produced by a T cell line from a lymphoma patient (Poiesz et. al., 1980, Proc. Natl. Acad. Sci. USA 77:7415-7419). This rapidly led to other reports describing the characterization of some of the HTLV-1 proteins, evidence of integrated proviral DNA in infected cells, and serological assays for antibodies indicative of HTLV-1 infection.

Roughly 15 million people are infected with HTLV-1 and many millions with HTLV type 2 (HTLV-2) worldwide. HTLV-1 is associated with the T-lymphocytic malignancy, adult T cell leukemia/lymphoma (ATLL), in about 2% of individuals infected, with another 2–3% developing a neurologic disorder called HTLV-associated myelopathy (HAM). HTLV-2 causes HAM in approximately 1–2% of infected individuals, however does not cause ATLL. HTLV-1 and HTLV-2 have served as highly informative models for the study of the epidemiology and pathogenesis of virus-associated cancers as well as autoimmune conditions such as multiple sclerosis. Two more recently identified members—HTLV-3 and HTLV-4—have been discovered in bushmeat hunters from central Africa, which has further emphasized the unmet need for continual surveillance for emerging new human retroviruses and their capacity to cause disease. The COVID-19 pandemic has highlighted the critical importance of the threats posed by emerging viruses in the human population, which can have catastrophe results if society is not well prepared for such public health crises.

The HTLV-1 oncoprotein Tax-1 is both necessary and sufficient for viral transformation, while Tax-2 (encoded by HTLV-2) does not induce tumors in animal models. The HTLVs encode for other regulatory proteins, including the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-mediated gene expression and is encoded as an anti-sense viral transcript. Another important protein is the HTLV-1 p30II protein, which can act as an agonist of Tax-mediated transcription and serve as a multifunctional repressor of cellular gene expression.

The study of HTLV-1-mediated leukemogenesis remains an important area of investigation. The focus of ongoing research remains centered upon: (i) the Tax effects on cellular transformation; (ii) the consequences of perturbing cell cycle control and genome stability; (iii) the role of HBZ and p30II on viral pathogenesis; (iv) HTLV-1 latency and reactivation; as well as (v) the development of therapeutic approaches. The study of HAM pathogenesis continues to hold promise as a model for neuroimmunologic diseases. New and exciting progress continues to be made in the basic understanding of viral replication of the HTLVs, particularly in virus assembly and particle structure.

The high prevalence rate of HTLV-1 infection among the indigenous population of Central Australia has further emphasized the important public health issues that have yet to be addressed, despite the basic epidemiology of HTLV-1 and HTLV-2 being reasonably well defined – i.e., emergence patterns in new host populations, transmission prevention, improved blood donor screening, and the potential human transmission of HTLV-3 and HTLV-4. Clinical research is particularly needed in order to potentially develop HTLV-1 and HTLV-2 vaccines, as well as the development of treatment options for ATLL and HAM.

The year 2020 marked the 40th anniversary of the discovery of HTLV-1, and this Special Issue highlights the many unmet research needs to be addressed in order to develop effective treatments and a cure for HTLV-1 infection.

Prof. Louis M. Mansky
Guest Editor

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