HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP

Abstract

BackgroundHuman T cell leukaemia virus type 1 (HTLV-1) is a retrovirus associated with human diseases such as adult T-cell leukaemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. In contrast to another human retrovirus, human immunodeficiency virus type 1 (HIV-1), HTLV-1 persists in the host not via vigorous virus production but mainly via proliferation and/or long-term survival in the form of silent proviruses in infected host cells. As a result, HTLV-1-infected cells rarely produce virus particles in vivo even without anti-retroviral treatment. That should be an advantage for the virus to escape from the host immune surveillance by minimizing the expression of viral antigens in host cells. However, why HIV-1 and HTLV-1 behave so differently during natural infection is not fully understood.ResultsWe performed cap analysis of gene expression (CAGE) using total RNAs and nascent, chromatin-associated, RNAs in the nucleus and found that HTLV-1 RNAs were processed post-transcriptionally in infected cells. RNA processing was evident for the sense viral transcripts but not the anti-sense ones. We also found a higher proportion of CG di-nucleotides in proviral sequences of HTLV-1-infected cells, when compared to the HIV-1 genomic sequence. It has been reported recently that CG dinucleotide content of viral sequence is associated with susceptibility to the antiviral ZC3HAV1 (ZAP), suggesting the involvement of this protein in the regulation of HTLV-1 transcripts. To analyse the effect of ZAP on HTLV-1 transcripts, we over-expressed it in HTLV-1-infected cells. We found there was a dose-dependent reduction in virus production with ZAP expression. We further knocked down endogenous ZAP with two independent targeting siRNAs and observed a significant increase in virus production in the culture supernatant. Other delta-type retroviruses such as simian T-cell leukaemia virus and bovine leukaemia virus, also contain high CG-dinucleotide contents in their viral genomes, suggesting that ZAP-mediated suppression of viral transcripts might be a common feature of delta-type retroviruses, which cause minimal viremia in their natural hosts.ConclusionsThe post-transcriptional regulatory mechanism involving ZAP might allow HTLV-1 to maintain a delicate balance required for prolonged survival in infected individuals.

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

“…ZAP has evolved under positive selection in primates with rapidly evolving residues concentrated at the PARP-like domain [ 248 ]. ZAP also restricts a variety of other viruses rich in CpG dinucleotides, including alphaviruses, filoviruses, and HBV as well as retrotransposons ( Table 1 ) [ 238 , 249 , 250 , 251 , 252 , 253 , 254 , 255 ].…”

Cellular Factors Targeting HIV-1 Transcription and Viral RNA Transcripts

“…On the other hand, elimination of viral RNA and decreased antigen expression might reduce the elimination of virally infected T cells, allowing them to return to a resting phenotype and become latent viral reservoirs. It has been reported that ZAP might play a role in regulating herpesvirus latency [103], and the knock-down of endogenous ZAP moderately enhanced the expression of Human T-cell leukaemia virus type 1 (HTLV-1) mRNA and proteins [104]. Despite significant CpG suppression, primary HIV-1 strains are not fully resistant against ZAP inhibition, and correlative analyses indicate that CpGs in the env region governing ZAP sensitivity might affect viral replication and disease progression in vivo [100].…”

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

“…Recently, Miyazato et al demonstrated that HTLV-1 is susceptible to the host antiviral system, which depends on ZAP-mediated viral RNA processing [42] and might be triggered by the burst of HTLV-1 expression observed during early infection. The authors suggest that this posttranscriptional regulation of HTLV-1 transcripts could be leveraged to minimize viral antigen expression, a strategy through which HTLV-1 achieves persistent infection in the host [43].…”