Molecular analysis of HTLV-2 APH-2 in viral transformation, persistence and host immune response
Year: 2011
Type: article
Abstract: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are two closely related human retroviruses that share a common genome structure and a high level of nucleotide sequence homology.However, they display distinct differences in pathogenicity.HTLV-1 has been identified as a causal agent for adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas HTLV-2 appears much less pathogenic without conclusive disease association.Chapter 1 reviews important aspects of HTLV-1 pathobiology and highlights insightful comparative studies between HTLV-1 and HTLV-2.Chapter 2 and chapter 3 focus on APH-2, the antisense protein of HTLV-2, which shares functional homology to HTLV-1 HBZ as a negative viral regulator.However, our data indicate that APH-2 and HBZ possess distinct functions that might contribute to differences in pathogenicity between HTLV-1 and HTLV-2.In chapter 2, we investigated the contribution of APH-2 to HTLV-2-mediated immortalization of primary T-lymphocytes in vitro and HTLV-1 infection in a rabbit animal model.HTLV-2 APH-2 mutant viruses were generated and evaluated for viral gene expression, protein production, and immortalization capacity.In short-term proliferation and long-term immortalization assays, APH-2 mutant viruses were indistinguishable from wild-type HTLV-1 suggesting that APH-2 is dispensable for viral replication and cellular immortalization in culture.Rabbits inoculated with irradiated cells expressing HTLV-2 APH-2 mutant viruses became persistently iii infected.In addition, these rabbits displayed an increased antibody response to viral gene products and a higher proviral load in PBMCs as compared to wild type HTLV-2 infected animals.These observations indicate that APH-2 is not required for viral survival and persistence in vivo during the early stage of infection, which is contrary to what has been observed for HTLV-1 HBZ.To broaden our knowledge of the contribution of antisense proteins to HTLV biology, in chapter 3 we further examined the role of APH-2 and HBZ in regulating the host immune response.We found that both APH-2 and HBZ can potentially reduce type I interferon (IFN) production by inhibiting IFN regulatory factor 7 (IRF-7)-mediated gene transcription.This result indicates that HTLV-1 and HTLV-2 have evolved a common way to antagonize host immune attack upon viral infection.Chapter 4 focuses on the cellular tropism of HTLV-1 and HTLV-2 during the early stage after infection.In culture, both HTLV-1 and HTLV-2 transform T cells; HTLV-1 predominantly transforms CD4 + T cells, while HTLV-2 mainly transforms CD8 + T cells.In vivo, CD4 + T cells are the primary target cells for HTLV-1 in ATL patients even though CD8 + T cells serve as a natural reservoir in HAM/TSP patients and asymptomatic carriers.The HTLV-2 proviral burden has been shown to be higher in CD8 + T cells than in CD4 + T cells in infected individuals.Since most individuals are chronically infected at the time of detection, the early T cell preference of HTLV-1 and HTLV-2 in an immunocompetent host is not known.In chapter 4, we utilized the rabbit animal model to measure the early HTLV-1 and HTLV-2 proviral loads and gene expression patterns in purified CD4 + and CD8 + T cells over time.Our data indicate that the viruses do not exhibit cellular preference during the initial infection stage and the preferential transformation tropism is probably due to a selective clonal viii 5. Yin H, Kannian P, Diisinger N, Haynes Robyn, Green PL: Human T-cell Leukemia Virus Type 2 APH-2 down modulates Tax-mediated transcription, but is dispensable for viral replication and persistence in vivo.Blood, (Submitted)
Author: Han Yin
Institution: The Ohio State University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2278964314