Low incidence of HTLV-1 infection in Andean highlanders with NFKB1 haplotype

Abstract

Abstract Human T-cell lymphotropic virus type I (HTLV-1) is a retrovirus infecting T-lymphocytes recognized as the causative agent of adult T-cell leukemia/lymphoma (ATL). Approximately 5 % of individuals infected with this virus develop ATL after a prolonged latency period, often several decades (PMID: 36800643). The genome of HTLV-1 involves the regulatory protein Tax which plays a central role in the survival, proliferation, and transformation of HTLV-1-infected cells into malignant cells. By constitutively activating the IKK complex, Tax-1 oncoprotein induces persistent NF-κB activation that drives the proliferation and survival of infected T-cells, thereby contributing to leukemogenesis in ATL (PMID: 29685460). Persistent activation of NF-kB induces canonical and noncanonical pathways that entail a key role for host cell transformation, hence its importance as a target in therapeutics (PMID: 20845110). Reports display that canonical NF-κB activation by Tax would likely be disrupted, impairing key oncogenic mechanisms of HTLV-1 (PMID: 29515558; PMID: 29722927). Concerning NF-κB, it has been reported of a NFKB1 rs230511 haplotype enriched in the Andean population, which entailing an alternative splicing that skips exons 4 and 5 involves a loss of function affecting the functional levels of NFKB1, and inflammatory-related genes (PMID: 39971917). Andean region is known to be endemic for HTLV-1 (PMID: 23162541), therefore in order to elucidate the incidence of HTLV-1 in Andean with NFKB1 haplotype, we performed a screening to normal blood donors and hematologic diseases patients. A total of 462 blood samples were collected from individuals living in the Bolivian Andean region at 4000 meters above sea level where NFKB1 rs230511 haplotype prevalence stand for 95 %, and genotypic frequency corresponds CC 5 %, CT 33%, TT 62% and the allele frequency reflects T=0,88, C=0,12. (Blood, ASH 2316,2018; Hematol Mex 2023; 24(2):52-67). Among the samples, 247 were from normal blood donors (152 females with an average age of 24 years and 95 males with an average age of 32 years), the remaining 215 samples came from patients with hematologic diseases (109 females with average age 51 years and 106 males with average age 53 years). Of these patients, 46 were diagnosed with chronic myeloid leukemia (CML), while 169 had other non-malignant hematologic conditions. All specimens were screened using both the ASSURE HTLV-I/II Rapid Test and HTLV-I/II ELISA 4.0 (MP Biomedicals Asia Pacific). Any reactive samples were subsequently confirmed with a supplementary western blot assay (HTLV BLOT 2.4, MP Biomedicals Asia Pacific). Interestingly, out of 462 specimens, only one tested positive for HTLV-1 (0,22 %). This positive case corresponded to a patient with a hematologic disease who had received massive blood transfusions (>20 units). Results display an extremely low HTLV-1 Incidence in Bolivian Andean region compared to other ethnic groups where prevalence exceeds 10%. This low incidence may be related to the fact that approximately 95% of the Andean population carries a nonfunctional NFKB1 haplotype, potentially limiting HTLV-1 pathogenesis. Further studies focusing anti-HTLV-1 antibody responses in individuals with NFKB1 deletion are needed to understand the molecular mechanism concerned.