Search for host genetic factors associated with neurological complications (HAM/TSP) in Peruvian HTLV-1 infected individuals

Michael John Talledo Albujar

Research output: ThesisDoctoral dissertation - Doctoral dissertation

Abstract

Infection by the human T-cell leukemia virus type 1 (HTLV-1) retrovirus is widely spread throughout the world. This infection is also endemic in Peru with an estimated 150,000- 450,000 infected individuals. Between 1 and 10% of HTLV-1 infected individuals develops a disease manifestation associated with this infection. HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a major manifestation of HTLV-1 infection. HAM/TSP is a neurodegenerative disease that causes difficulties in the movement of lower limbs. No differences in viral genotypes have been associated with HAM/TSP disease. A high proviral load has consistently been associated with HAM/TSP, but there is important overlap with asymptomatic carriers (AC). In view of these findings, it is hypothesized that that host genetic factors play a role in the etiology of HAM/TSP. This thesis aims at finding genetic factors associated with HAM/TSP in Peruvian HTLV-1 infected individuals. In a first approach we tried to confirm previous findings of SNPs associated with HAM/TSP in Japan. However, no replication was found in Peruvian HTLV-1 infected individuals. In a second study we analyzed variants in KIR genes, but found no differences in allele frequencies between HAM/TSP and AC. In a third study we evaluated the frequency distribution of SNPs belonging to several candidate genes between cases and controls. Ancestry Informative markers were used to control for population stratification. Variants in two genes, NKG2D and NFKBIA, were associated with HAM/TSP disease. In a final study we studied the expression of the NFKBIA gene, and found it to be underexpressed in HAM/TSP compared to AC. The NFKBIA encodes the protein IkB which is an inhibitor of the NF-kB pathway and prevents the entrance of NF-kB into the nucleus. On the basis of these findings we hypothesize that HAM/TSP patients have less IkB protein than AC, exerting less inhibition. This might be one of the reasons why HAM/TSP patients show more activation of the NF-kB pathway than AC.
Original languageEnglish
Publisher
Publication statusPublished - 2016

Keywords

  • B780-tropical-medicine

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