A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load

Department of Immunology, Imperial College, London, UK.
Journal of General Virology (Impact Factor: 3.18). 06/2005; 86(Pt 5):1515-23. DOI: 10.1099/vir.0.80766-0
Source: PubMed


The CD8+ lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent viruses. Consequently, it remains controversial as to whether CD8+ cells have a biologically significant impact on viral burden and disease progression in infections such as human immunodeficiency virus-1 and human T-lymphotropic virus type I (HTLV-I). Experiments to ascertain the impact of CD8+ cells on viral burden based on CD8+ cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8+ lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-I-infected CD4+ cells were cleared by autologous CD8+ cells ex vivo. It was demonstrated that CD8+ cells reduced the lifespan of infected CD4+ cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells in vivo. Furthermore, it was shown that HTLV-I-infected individuals vary considerably in the rate at which their CD8+ cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8+ cells cleared infected cells. This novel approach demonstrates that CD8+ cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8+ cell response to other viruses and malignancies and may be of particular importance in assessing vaccines.

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    • "This is considerably slower than ex vivo estimates of the rate of CTL lysis, which are approximately 1 d À 1 . This translates into a half life of approximately 1 day for an HTLV-1-infected CD4 þ T cell ex vivo (Asquith et al., 2005). Discrepancies between in vitro and in vivo estimates are not uncommon and are probably attributable to factors such as the time CTL need to find their target which will be very different in vivo and in vitro. "
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    ABSTRACT: Table 1. HLA class I binding of peptides from different HTLV-1 proteins has a differential impact on both proviral load and HAM/TSP risk. Left hand column: The HTLV-1 proteins were ranked according to whether they targeting them was associated with asymptomatic status. This list could be viewed as the “rank order of targets for a vaccine designed to reduce HAM/TSP risk”. Right hand column: The HTLV-1 proteins were ranked according to whether targeting them was associated with reduced proviral load. This list could be viewed as the “rank order of targets for a vaccine designed to reduce proviral load”. List reproduced from (MacNamara et al., 2010).
    Full-text · Article · Jan 2013 · Virology
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    • "Using this assay, we have found that the rate of elimination of Tax-expressing cells is inversely proportional to proviral load, suggesting that a more efficient CTL response has the effect of lowering proviral load [34]. The CTL efficiency parameter measured by this assay could explain up to 50% of the observed variation among infected individuals in proviral load [34]. Although the precise epitope specificity of CTLs responsible for elimination of Tax-expressing cells is not defined in this assay, we also observed that the rate of infected cell elimination is proportional to the sensitivity with which Taxspecific CTLs detect peptides presented on target cells and that naturally infected cells expressing high levels of Tax protein are killed significantly faster than cells expressing lower levels of Tax [35]. "
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    ABSTRACT: ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL.
    Full-text · Article · Dec 2012
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    • "Other viral antigens, including polymerase (Elovaara et al., 1993), TOF, ROF (Pique et al., 2000), and HBZ, (Macnamara et al., 2010) have also been shown to be targets of CTLs. Elimination of CD8 + cells from the PBMCs from HAM/TSP patients induces HTLV-1 expression during subsequent cell culture (Asquith et al., 2005), clearly indicating that CD8 + HTLV-1-specific CTLs contribute to the control of HTLV-1-infected cells. A series of experiments using a rat model of HTLV-1-infected T-cell lymphoma indicated that inhibition of the T-cell response accelerated tumor development (Hanabuchi et al., 2000), and further showed that vaccination with a Tax-encoding DNA or peptides corresponding to a major epitope for Tax-specific CTLs lead to the eradication of such tumors (Ohashi et al., 2000; Hanabuchi et al., 2001). "
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    ABSTRACT: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis in small subsets of HTLV-1 carriers. HTLV-1-specific T-cell responses play critical roles in anti-viral and anti-tumor host defense during HTLV-1 infections. Some HTLV-1 carriers exhibit selective loss or anergy of HTLV-1-specific T-cells at an asymptomatic stage. This is also observed in ATL patients and may therefore be an underlying risk factor of ATL in combination with elevated proviral loads. HTLV-1-specific T-cells often recognize the viral oncoprotein Tax, indicating expression of Tax protein in vivo, although levels of HTLV-1 gene expression are known to be very low. A type-I interferon (IFN) response can be induced by HTLV-1-infected cells and suppresses HTLV-1 expression in vitro, suggesting a role of type-I IFN response in viral suppression and pathogenesis in vivo. Both acquired and innate immune responses control the status of HTLV-1-infected cells and could be the important determinants in the development of HTLV-1-mediated malignant and inflammatory diseases.
    Full-text · Article · Sep 2012 · Frontiers in Microbiology
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