HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy

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 (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. 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 HAM/TSP 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.

Figure 1

Risk of HAM/TSP according to possession of A*02. ▴, log p(HAM | L) if A*02⁺, ■, log p(HAM | L) if A*02⁻, nd, not detectable by this assay, —, no A*02⁻ HAM/TSP patient had a logarithmic proviral load of 0.5–0.9. At a given provirus load, the risk of HAM/TSP is not affected by the presence or absence of A*02. However, as the possession of A*02 reduces the proviral load, the effect of A*02 is to reduce the risk of disease. For the calculation of HAM/TSP risk at a given proviral load, we used Bayes’ theorem. By using the standard notation for conditional probability, where p(HAM | L) denotes the probability of HAM/TSP in an HTLV-I-infected person with a given provirus load (L), we write: p(HAM | L) = [p(HAM) × p(L | HAM]/[p(HAM) × p(L | HAM) + p(HC) × p(L | HC)]. We estimated p(L | HAM] and p(L | HC) from the distribution of proviral load in the HAM/TSP and HC cohorts in the present study. p(HAM), the prevalence of HAM/TSP in the HTLV-I-positive population, is taken as 0.01.

Figure 2

Tetramer-positive CTL were found in both HAM/TSP patients and HCs. The mean frequency of HTLV-I-specific CTL does not differ between HAM/TSP patients and HCs (P = 0.58; two-tailed Mann–Whitney U-statistic). CD8⁺ cells from both A*0201⁺, A*0206⁺, and A*0207⁺ individuals bound the A*0201-Tax_11–19 tetramer. ■, A*0206; ▴, A*0207; ○, A*0201; ●, A*0210, Δ A*0201/A*0206; ■, A*0201/A*0207; ×, mean % tetramer ± SE.