Hijacking Host Immunity by the Human T-Cell Leukemia Virus Type-1: Implications for Therapeutic and Preventive Vaccines

Abstract

Human T-cell Leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. High viral DNA burden (VL) in peripheral blood mononuclear cells is a documented risk factor for ATLL and HAM/TSP, and patients with HAM/TSP have a higher VL in cerebrospinal fluid than in peripheral blood. VL alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including host immune response. HTLV-1 infection is life-long; CD4+-infected cells are not eradicated by the immune response because HTLV-1 inhibits the function of dendritic cells, monocytes, Natural Killer cells, and adaptive cytotoxic CD8+ responses. Although the majority of infected CD4+ T-cells adopt a resting phenotype, antigen stimulation may result in bursts of viral expression. The antigen-dependent “on-off” viral expression creates “conditional latency” that when combined with ineffective host responses precludes virus eradication. Epidemiological and clinical data suggest that the continuous attempt of the host immunity to eliminate infected cells results in chronic immune activation that can be further exacerbated by co-morbidities, resulting in the development of severe disease. We review cell and animal model studies that uncovered mechanisms used by HTLV-1 to usurp and/or counteract host immunity.

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells

“…Alterations in immune responses are associated with HTLV-1 infection and contribute to disease development [ 10 , 27 , 28 , 71 , 72 , 73 , 74 ]. While CD4 cells are the primary target of HTLV-1, the virus is also found in CD8, monocytes, macrophages, and dendritic cells from infected individuals [ 75 , 76 , 77 , 78 , 79 , 80 ].…”

“…Immune dysregulation is a common feature in HTLV-1 infection [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], and although there is a strong innate and adaptive response to the virus, it results in a lifelong persistent infection of primarily T lymphocytes [ 21 , 22 , 23 , 24 , 25 , 26 ]. This is likely linked to the ability of the virus to counteract host responses [ 27 , 28 ].…”

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

“…While the overall genomic homology of HTLV-1c with HTLV-1a is 92.5%, we identified several key differences at the nucleotide level which could impact viral gene expression. The HTLV-1c 3′regulatory region encoding tax , hbz , and orf-I and orf-II products, that are central for viral transcription [ 22 , 36 ], cellular transformation [ 21 , 37 , 38 ], transmission [ 26 , 39 ] and hijacking host immunity [ 39 ], is consistently retained in all participants. However, the observed increased genomic divergence from subtype-A in the subtype-C regulatory region near the 3′end of the genome could profoundly impact viral pathogenesis.…”