High level of genomic divergence in orf-I p12 and hbz genes of HTLV-1 subtype-C in Central Australia.

BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) infection remains a largely neglected public health problem, particularly in resource-poor areas with high burden of communicable and non-communicable diseases, such as some remote populations in Central Australia where an estimated 37% of adults are infected with HTLV-1. Most of our understanding of HTLV-1 infection comes from studies of the globally spread subtype-A (HTLV-1a), with few molecular studies reported with the Austral-Melanesian subtype-C (HTLV-1c) predominant in the Indo-Pacific and Oceania regions. RESULTS: Using a primer walking strategy and direct sequencing, we constructed HTLV-1c genomic consensus sequences from 22 First Nations participants living with HTLV-1c in Central Australia. Phylogenetic and pairwise analysis of this subtype-C proviral gDNA showed higher levels of genomic divergence in comparison to previously published HTLV-1a genomes. While the overall genomic homology between subtypes was 92.5%, the lowest nucleotide and amino acid sequence identity occurred near the 3' end of the proviral genome coding regulatory genes, especially overlapping hbz (85.37%, 77.46%, respectively) and orf-I product p12 (82.00%, 70.30%, respectively). Strikingly, the HTLV-1c genomic consensus sequences uniformly showed a defective translation start codon for the immune regulatory proteins p12/p8 encoded by the HTLV-1A orf-I. Deletions in the proviral genome were detected in many subjects, particularly in the structural gag, pol and env genes. Similarly, using a droplet digital PCR assay measuring the copies of gag and tax per reference host genome, we quantitatively confirmed that provirus retains the tax gene region at higher levels than gag. CONCLUSIONS: Our genomic analysis of HTLV-1c in Central Australia in conjunction with earlier Melanesian HTLV-1c sequences, elucidate substantial differences with respect to the globally spread HTLV-1a. Future studies should address the impact these genomic differences have on infection and the regionally distinctive frequency of associated pulmonary disease. Understanding the host and virus subtype factors which contribute to the differential morbidity observed, is crucial for the development of much needed therapeutics and vaccine strategies against this highly endemic infection in remote First Nations communities in Central Australia.

Human T-cell lymphotropic virus type-1: a lifelong persistent infection, yet never truly silent.

Human T-cell lymphotropic virus type-1 (HTLV-1) has a large global burden and in some key communities, such as Indigenous Australians living in remote areas, greater than 45% of people are infected. Despite HTLV-1 causing serious malignancy and myelopathic paraparesis, and a significant association with a range of inflammatory comorbidities and secondary infections that shorten lifespan, few biomedical interventions are available. HTLV-1 starkly contrasts with other blood-borne sexually transmitted viral infections, such as, HIV, hepatitis B virus, and hepatitis C virus, with no antiviral treatments that reduce virus-infected cells, no rapid diagnostics or biomarker assays suitable for use in remote settings, and no effective vaccine. We review how the replication strategies and molecular properties of HTLV-1 establish a long-term stealthy viral pathogenesis through a fine-tuned balance of persistence, immune cell dysfunction, and proliferation of proviral infected cells that collectively present robust barriers to treatment and prevention. An understanding of the nature of the HTLV-1 provirus and opposing actions of viral-coded negative-sense HBZ and positive-sense regulatory proteins Tax, p12 and its cleaved product p8, and p30, is needed to improve the biomedical tools for preventing transmission and improving the long-term health of people with this lifelong infection.