HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection

Abstract

CD8+ T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8+ T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8+ T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8+ T cell response through to the least effective CD8+ T cell response. We conclude that CD8+ T cells play an important role in the control of HTLV-1 and that CD8+ cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8+ T cell response.

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

“…Moreover, a more recent paper confirmed that HBZ plays a central role in HTLV-1 persistence and the authors suggested that, despite Tax being the immunodominant antigen, the CD8ϩ-T cells specific to HBZ are the most effective at controlling HTLV-1. 46 The VPA-induced HBZ decrease also could enable the infected cells to escape this efficient immune response, thereby limiting the therapeutic impact on the virus reservoir within treated patients.VPA induced moderate and dose-dependent apoptosis of cultured CD4 ϩ lymphocytes. Apoptosis rates were similar in lymphocytes from HAM/TSP patients and ACs, and there was no evidence of specific elimination of HTLV-1-infected cells.…”

Human T-Lymphotropic Viruses (HTLV)

“…On the other hand, individuals presenting efficient HTLV-1-specific CD8+ cells to lyse infected cells, would eliminate high rate of infected cells, mantaining the proviral load in low level. This lytic efficiency may be related to HLA class I binding affinity to viral peptides, avidity to antigens and expression of cytolytic genes (Jeffery et al, 1999;Kattan et al, 2009;MacNamara et al, 2010;Vine et al, 2004).…”

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…The Tax protein is an immunodominant antigen in HTLV-1 infections. Therefore, CTL activity is predominantly restricted to products of the HTLV-1 Tax gene, although HTLV-1 Env, Pol, Rof, Tof, and HBZ (Elovaara et al, 1993;Hilburn et al, 2011;Macnamara et al, 2010;Pique et al, 2000) could also be target proteins of HTLV-1-specific CTL. In a study that utilized properties of the CTL antigen recognition system, human MHC class I HLA-A2(*0201) tetramers loaded with HTLV-1 Tax peptide were used to detect HTLV-1 Tax specific HLA-A2-restricted CD8 + cells (Bieganowska et al, 1999, Greten et al, 1998.…”