The proviral landscape in HTLV-1 infection

Human T-cell lymphotropic virus type 1 (HTLV-1) integrates into host DNA, resulting in life-long infection that underlies malignant and inflammatory disease, and early all-cause mortality. HTLV-1c subtype prevails in remote Aboriginal Communities in Central Australia, where pulmonary disease is common. The phenotypic properties of HTLV-1c+ CD4+ T-cells, and the proviral DNA landscape from 6 people living with HTLV-1c were determined, and compared with an HTLV-1c-infected humanised mouse model. PBMCs from people living with HTLV-1c at Alice Springs Hospital (n=6), and splenocytes from HTLV-1c-infected humanised NOD-scid IL2Rgammanull mice (n=2) were collected, and integrated proviruses were amplified by limiting dilution nested PCR and subjected to long-read sequencing to generate individual, contiguous genomic sequences, to determine the proviral diversity of HTLV-1c infection. All participants had an expanded subset of chronically activated CD4+ T-cells with lung-homing potential. In these cells we detected defective HTLV-1c proviral genomes, with preferential retention of the hbz virulence factor in participants with associated pulmonary disease. Chimeric HTLV-1c provirus incorporating cellular sequences were detected, some of which have coding potential. Full-length proviruses were rarely detected, with one donor harbouring this reservoir in CCR4- CD4+ T-cells. Despite extensive genetic and structural diversity of defective HTLV-1c proviruses, hbz presents as a promising therapeutic target.