Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis.

Victoria Maksimova,Amanda R Panfil

doi:10.3390/v14010138

Victoria Maksimova, Amanda R Panfil

Open Access

https://doi.org/10.3390/v14010138

Copy DOI

Journal: Viruses	Publication Date: Jan 13, 2022
Citations: 2	License type: CC BY 4.0

Affiliation: The Ohio State University

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4+ T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic. In vitro, HTLV-1 primarily immortalizes or transforms CD4+ T-cells, while HTLV-2 displays a transformation tropism for CD8+ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.

Highlights

Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered [1], is highly endemic to regions such as Southwestern Japan, Sub-Saharan Africa, South America, and the Caribbean, with clusters of infection in the Middle East and Australo-Melanesia [2]
HTLV1 proviruses encoding HTLV-2 tax/rex immortalized CD4+ T-cells in cell culture, while HTLV2 proviruses encoding HTLV-1 tax/rex immortalized CD8+ T-cells. These findings suggested that tax/rex are not responsible for the diverging in vitro immortalization/transformation tropism of HTLV-1 and HTLV-2
Findings from HTLV transformation tropism studies hold clinical relevance, as the in vitro immortalization assay mimics natural cell-to-cell transmission and recapitulates in vivo tropism observed in patients

Summary

Introduction

Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered [1], is highly endemic to regions such as Southwestern Japan, Sub-Saharan Africa, South America, and the Caribbean, with clusters of infection in the Middle East and Australo-Melanesia [2]. A nationwide prospective study of asymptomatic HTLV-1 carriers in Japan determined that risk factors for ATL progression include high proviral load (>4 copies/100 peripheral blood mononuclear cells), a family history of ATL, older age, and the first opportunity for HTLV-1 testing occurring at the time of treatment for other conditions [32]. While Tax and Hbz are key contributors to HTLV-1-mediated disease development, a potential pathogenic role for the viral envelope (Env) has emerged from comparative studies between HTLV-1 and HTLV-2. These viruses share high genomic sequence homology and functional similarity of their gene products [46,47], but differ in their pathogenesis. This review will highlight the potential functions of Env beyond initial viral entry and infection in the context of cellular transformation studies involving HTLV-1 and HTLV-2

Env-Mediated Viral Entry

Distinct Transformation Preferences of HTLV-1 and HTLV-2

Role of Env in HTLV T-Cell Transformation Tropism

Role of Env in the Pathogenesis of Other Retroviruses

Immune Response to Env

Findings

Conclusions and Future Directions