Hirons, Ashley

Yurick, David

Jansz, Natasha

Ellenberg, Paula

Franchini, Genoveffa

Einsiedel, Lloyd

Khoury, Georges

Purcell, Damian F J

2024-07-17

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.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.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.

(Hirons) The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia.

(Yurick) The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia.

(Yurick) UCB Pharma, Smyrna, GA, USA.

(Jansz) Mater Research Institute-University of Queensland, TRI Building, Woolloongabba, QLD, Australia.

(Ellenberg) The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia.

(Ellenberg) Burnet Institute, Melbourne, VIC, Australia.

(Franchini) Animal Models and Retroviral Vaccines Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

(Einsiedel) Department of Medicine, Alice Springs Hospital, Alice Springs, NT, Australia.

(Khoury) The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia.

(Khoury) Kite Pharma, Santa Monica, CA, USA.

(Purcell) The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia. dfjp@unimelb.edu.au.

Retrovirology 2024 21 1 14-w

1742-4690

https://pubmed.ncbi.nlm.nih.gov/39014486/?otool=iaurydwlib

https://hdl.handle.net/10137/13464

Human T-lymphotropic virus 1

HTLV-I Infections

Australia

Phylogeny

Retroviridae Proteins

Genetic Variation

Viral Regulatory and Accessory Proteins

Sequence Analysis, DNA

Viral Proteins

Basic-Leucine Zipper Transcription Factors

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

Journal Article

Publication