Silencers of HTLV-1 and HTLV-2: the pX-encoded latency-maintenance factors

Robert Harrod

doi:10.1186/s12977-019-0487-9

Abstract

Of the members of the primate T cell lymphotropic virus (PTLV) family, only the human T-cell leukemia virus type-1 (HTLV-1) causes disease in humans—as the etiological agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other auto-inflammatory disorders. Despite having significant genomic organizational and structural similarities, the closely related human T-cell lymphotropic virus type-2 (HTLV-2) is considered apathogenic and has been linked with benign lymphoproliferation and mild neurological symptoms in certain infected patients. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infections in vivo. The conserved pX sequences of HTLV-1 and HTLV-2 encode several ancillary factors which have been shown to negatively regulate proviral gene expression, while simultaneously activating host cellular proliferative and pro-survival pathways. In particular, the ORF-II proteins, HTLV-1 p30II and HTLV-2 p28II, suppress Tax-dependent transactivation from the viral promoter—whereas p30II also inhibits PU.1-mediated inflammatory-signaling, differentially augments the expression of p53-regulated metabolic/pro-survival genes, and induces lymphoproliferation which could promote mitotic proviral replication. The ubiquitinated form of the HTLV-1 p13II protein localizes to nuclear speckles and interferes with recruitment of the p300 coactivator by the viral transactivator Tax. Further, the antisense-encoded HTLV-1 HBZ and HTLV-2 APH-2 proteins and mRNAs negatively regulate Tax-dependent proviral gene expression and activate inflammatory signaling associated with enhanced T-cell lymphoproliferation. This review will summarize our current understanding of the pX latency-maintenance factors of HTLV-1 and HTLV-2 and discuss how these products may contribute to the differences in pathogenicity between the human PTLVs.

Highlights

The primate T-cell lymphotropic virus (PTLV) family consists of the simian T-cell lymphotropic virus types 1–5 (STLV types 1–5) and human T-cell lymphotropic virus types 1–4 (HTLV types 1–4), which includes the human T-cell leukemia virus type-1 (HTLV-1) and the related human T-cell lymphotropic virus type-2 (HTLV2, subtypes 2a, 2b, and 2d) [1–10]
The human T-cell lymphotropic virus type-2 (HTLV-2) Tax-2 oncoprotein was observed to be less efficient at transforming rat fibroblasts in vitro [135]; and Semmes et al [134] have demonstrated that Tax-2 does not induce significant genomic DNA-damage resulting in the formation of micronuclei/microsatellites, as compared to Tax-1 in transfected COS cells
The antisense basic leucine zipper (bZIP) proteins, HTLV-1 basic leucine zipper factor (HBZ) and antisense protein of HTLV-2 (APH-2), both repress Tax-dependent transactivation and gene expression from the viral 5′ long terminal repeat (LTR) and inhibit NF-κBsignaling through interactions with the p65RelA subunit which prevents its binding to κB-responsive enhancer elements [27, 30, 47, 66, 67, 70]

Summary

Introduction

The primate T-cell lymphotropic virus (PTLV) family consists of the simian T-cell lymphotropic virus types 1–5 (STLV types 1–5) and human T-cell lymphotropic virus types 1–4 (HTLV types 1–4), which includes the human T-cell leukemia virus type-1 (HTLV-1) and the related human T-cell lymphotropic virus type-2 (HTLV2, subtypes 2a, 2b, and 2d) [1–10]. These genes are expressed through alternative mRNA-splicing, and many (i.e., HTLV-1 HBZ, p 30II and p 13II, and the HTLV-2 APH-2 and p28II proteins; Fig. 1a, b) negatively regulate Tax-dependent transcriptional activity and maintain the latent silencing of proviral gene expression to promote viral persistence in vivo [16– 21].

Results

Conclusion