Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. It is estimated that at least 20 million people are infected worldwide by this oncogenic virus. Infected individuals are at risk of developing a fatal malignancy, adult T-cell leukemia (ATL), and a severe progressive neurologic disease, HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). According to Robert Gallo, who discovered this retrovirus in 1980, HTLV-1 is to be considered the most potent microbial human carcinogen. Many issues concerning its life cycle and pathobiology are still unsolved or controversial, and new approaches for diagnosis, prevention, and treatment of HTLV-1 infection are in high demand.
In this present Research Topic, we will focus on the following research themes:
1. Identification of biomarkers. Besides ATL and HAM/TSP, a broad spectrum of inflammatory diseases are associated with HTLV-1 infection, including uveitis, dermatitis, rheumatic disorders, and myositis. The mechanisms leading to these conditions are still poorly understood and no robust marker of disease is cur-rently available. Whole-genome sequencing studies are currently aimed at identifying driver mutations and markers to enable early diagnosis and patient risk stratification.
2. New therapeutic approaches. Current treatments for ATL and HAM/TSP are unfortunately non-curative and new therapeutic approaches based on a deeper knowledge of molecular mechanisms would be highly desirable.
3. Mechanisms of viral persistence, replication and pathogenesis. HTLV-1 persistence is strictly linked to its cross-talk with host cell proteins. This is mediated by viral genes promoting viral replication and transcrip-tion. Other issues are to be considered: viral entry, replication and persistence, cellular mechanisms leading to ATL and control of the infection by the immune response. Comparison of HTLV-1 with the closely related non-oncogenic virus HTLV-2 may reveal important pathogenic traits.
4. Role of non-coding RNAs in HTLV-1 infection and pathogenesis. The capacity of HTLV-1 infection to alter the profile of microRNAs and other small noncoding RNAs in infected T-cells is well established. The regula-tory proteins Tax and HBZ are known to affect expression of individual microRNAs, several of which are implicated in cell turnover and transformation as well as infectivity. There is also evidence that both Tax and the post-transcriptional regulatory protein Rex, are able to interfere with pathways leading to mi-croRNA production. The transcriptional regulatory properties of Tax and HBZ also implicate them in the mechanisms governing the expression of cellular long non-coding RNAs with a role in cell turnover.
5. Animal models to study HTLV-1 pathogenesis. Different animal models have been developed to study HTLV-tumorigenesis, including Tax and HBZ transgenic mice. Spread and tissue invasion of ATL cells is inves-tigated in highly Immune-deficient mouse strains (NOG and NSG). The recent development of humanized mice after injection of human CD34+ umbilical cord stem cells (HUSC) also offers a useful tool to study leu-kemia/lymphoma development.
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. It is estimated that at least 20 million people are infected worldwide by this oncogenic virus. Infected individuals are at risk of developing a fatal malignancy, adult T-cell leukemia (ATL), and a severe progressive neurologic disease, HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). According to Robert Gallo, who discovered this retrovirus in 1980, HTLV-1 is to be considered the most potent microbial human carcinogen. Many issues concerning its life cycle and pathobiology are still unsolved or controversial, and new approaches for diagnosis, prevention, and treatment of HTLV-1 infection are in high demand.
In this present Research Topic, we will focus on the following research themes:
1. Identification of biomarkers. Besides ATL and HAM/TSP, a broad spectrum of inflammatory diseases are associated with HTLV-1 infection, including uveitis, dermatitis, rheumatic disorders, and myositis. The mechanisms leading to these conditions are still poorly understood and no robust marker of disease is cur-rently available. Whole-genome sequencing studies are currently aimed at identifying driver mutations and markers to enable early diagnosis and patient risk stratification.
2. New therapeutic approaches. Current treatments for ATL and HAM/TSP are unfortunately non-curative and new therapeutic approaches based on a deeper knowledge of molecular mechanisms would be highly desirable.
3. Mechanisms of viral persistence, replication and pathogenesis. HTLV-1 persistence is strictly linked to its cross-talk with host cell proteins. This is mediated by viral genes promoting viral replication and transcrip-tion. Other issues are to be considered: viral entry, replication and persistence, cellular mechanisms leading to ATL and control of the infection by the immune response. Comparison of HTLV-1 with the closely related non-oncogenic virus HTLV-2 may reveal important pathogenic traits.
4. Role of non-coding RNAs in HTLV-1 infection and pathogenesis. The capacity of HTLV-1 infection to alter the profile of microRNAs and other small noncoding RNAs in infected T-cells is well established. The regula-tory proteins Tax and HBZ are known to affect expression of individual microRNAs, several of which are implicated in cell turnover and transformation as well as infectivity. There is also evidence that both Tax and the post-transcriptional regulatory protein Rex, are able to interfere with pathways leading to mi-croRNA production. The transcriptional regulatory properties of Tax and HBZ also implicate them in the mechanisms governing the expression of cellular long non-coding RNAs with a role in cell turnover.
5. Animal models to study HTLV-1 pathogenesis. Different animal models have been developed to study HTLV-tumorigenesis, including Tax and HBZ transgenic mice. Spread and tissue invasion of ATL cells is inves-tigated in highly Immune-deficient mouse strains (NOG and NSG). The recent development of humanized mice after injection of human CD34+ umbilical cord stem cells (HUSC) also offers a useful tool to study leu-kemia/lymphoma development.