p30 protein: a critical regulator of HTLV-1 viral latency and host immunity

Abstract

The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated with the virus impress the great need for basic and translational research to prevent and treat HTLV-1 infection. The genome of the virus's most common subtype, HTLV-1A, encodes structural, enzymatic, and regulatory proteins that contribute to viral persistence and pathogenesis. Among these is the p30 protein encoded by the doubly spliced Tax-orf II mRNA, a nuclear/nucleolar protein with both transcriptional and post-transcriptional activity. The p30 protein inhibits the productive replication cycle via nuclear retention of the mRNA that encodes for both the viral transcriptional trans-activator Tax, and the Rex proteins that regulate the transport of incompletely spliced viral mRNA to the cytoplasm. In myeloid cells, p30 inhibits the PU-1 transcription factor that regulates interferon expression and is a critical mediator of innate and adaptive immunity. Furthermore, p30 alters gene expression, cell cycle progression, and DNA damage responses in T-cells, raising the hypothesis that p30 may directly contribute to T cell transformation. By fine-tuning viral expression while also inhibiting host innate responses, p30 is likely essential for viral infection and persistence. This concept is supported by the finding that macaques, a natural host for the closely genetically related simian T-cell leukemia virus 1 (STLV-1), exposed to an HTLV-1 knockout for p30 expression by a single point mutation do not became infected unless reversion and selection of the wild type HTLV-1 genotype occurs. All together, these data suggest that inhibition of p30 may help to curb and eventually eradicate viral infection by exposing infected cells to an effective host immune response.

Mechanisms of Oncogenesis by HTLV-1 Tax

“…The HTLV-1 regulatory genes Tax, Rex, p21, p12, p13 and p30 are all encoded by various open reading frames (ORFs) in the pX region located in the 3' end of the genome [43][44][45]. The accessory genes p12, p13 and p30 play significant roles in establishing and maintaining viral persistence, whereas Rex regulates post-transcriptional viral gene expression and increases the stability of viral RNA for the latency phase of the viral life cycle [46][47][48][49].…”

Strength in Diversity: Nuclear Export of Viral RNAs

“…It has been suggested that RxRE plays a role in HTLV-1 mRNA polyadenylation, where the poly(A) signal and actual poly(A) site are unusually far apart [ 160 , 161 ]. Rex has also been shown to interact with viral p30 protein to balance viral gene expression and infection latency [ 162 ] (reviewed in [ 163 ]).…”

Immunopathogenesis and Cellular Interactions in Human T-Cell Leukemia Virus Type 1 Associated Myelopathy/Tropical Spastic Paraparesis

“…p30 contributes to evasion of immune system surveillance by binding to tax/rex mRNA, facilitating its nuclear retention and reduced expression in infected cells. p30 also interferes with the immune response by downregulating TLR4 and disrupting interferon signaling via interacting with transcription factor PU.1 (Moles et al, 2019). p13 is predominantly localized in the inner membrane of mitochondria of infected cells, where it increases the activity of electron transport chain and production of reactive oxygen species.…”

“…p30 contributes to evasion of immune system surveillance by binding to tax/rex mRNA, facilitating its nuclear retention and reduced expression in infected cells. p30 also interferes with the immune response by downregulating TLR4 and disrupting interferon signaling via interacting with transcription factor PU.1 ( Moles et al, 2019 ).…”

“…Dendritic cells are also known for their robust antiviral signaling with proinflammatory cytokines. Nevertheless, production of type 1 interferons by DCs provide modest benefit to patients possibly due to interference of tax with the intracellular antiviral signaling cascade ( Bangham, 2018 ), reduced interferon secretion in the majority of DCs ( Moles et al, 2019 ) and reduction in expression and phosphorylation of STAT1 in PBMCs ( Mozhgani et al, 2019 ). Recently, the visualization of DCs in choroid plexus of normal rats has led to the hypothesis that DC access to CNS antigens may play an important role in inflammatory and immune-mediated disorders of CNS ( McMenamin, 1999 ).…”