No abstract

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM͞TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus inf luence susceptibility to HAM͞TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM͞TSP (P < 0.0001), preventing 28% of potential cases of HAM͞TSP. Furthermore, HLA-A*02 ؉ healthy HTLV-I carriers have a proviral load one-third that (P ‫؍‬ 0.014) of HLA-A*02 ؊ HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM͞TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

No abstract

To investigate the role of viral expression in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1), a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) of HTLV-1 tax messenger RNA (mRNA) using ABI Prism 7700 Sequence Detection System was developed. Using this system, the HTLV-1 tax mRNA load was compared with HTLV-1 proviral DNA load, HTLV-1 Tax protein expression, HTLV-1 Tax-specific CD8(+) T-cell frequency, and disease severity of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This approach was a sensitive and specific technique for the precise quantification of HTLV-1 tax mRNA. The total amount of HTLV-1 tax mRNA and mRNA expression level in HTLV-1-infected cells (mRNA/DNA ratio) were higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The HTLV-1 tax mRNA load correlated with the HTLV-1 proviral DNA load ex vivo, the Tax protein expression in vitro, and the Tax-specific CD8(+) T-cell frequency ex vivo. The HTLV-1 tax mRNA load also correlated with disease severity in HAM/TSP patients. These data suggest that increased HTLV-1 expression plays an important role in the pathogenesis of HAM/TSP, and the HTLV-1 tax mRNA level could be a useful predictor of disease progression in patients with HAM/TSP.

No abstract

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.

The inflammatory disease human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM/TSP) occurs in only 1–2% of HTLV-I-infected individuals and is associated with a high provirus load of HTLV-I. We hypothesize that a person’s risk of developing HAM/TSP depends upon the efficiency of their immune response to the virus, which differs between individuals because of polymorphism in genes that influence this response. Previously we showed that the possession of HLA-A*02 was associated with a lower risk of HAM/TSP, and with a lower provirus load in healthy carriers of HTLV-I. However, HLA-A*02 did not account for all the observed difference in the risk of HAM/TSP. Here we present evidence, in the same study population in Japan, that HLA-Cw*08 was also associated with disease protection (probability value, two-tailed test = 0.002) and with a lower proviral load in healthy carriers. Possession of the A*02 and/or Cw*08 genes prevented 36% of potential HAM/TSP cases. In contrast, HLA-B*5401 was associated with a higher susceptibility to HAM/TSP (probability value, two-tailed test = 0.0003) and with a higher provirus load in HAM/TSP patients. At a given provirus load, B*5401 appeared to increase the risk of disease. The fraction of HAM/TSP cases attributable to B*5401 was 17%. Furthermore, individuals who were heterozygous at all three HLA class I loci have a lower HTLV-I provirus load than those who were homozygous at one or more loci. These results are consistent with the proposal that a strong class I-restricted CTL response to HTLV-I reduces the proviral load and hence the risk of disease.

No abstract