Proliferative Capacity of Epitope-Specific CD8 T-Cell Responses Is Inversely Related to Viral Load in Chronic Human Immunodeficiency Virus Type 1 Infection

Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom.
Journal of Virology (Impact Factor: 4.65). 02/2007; 81(1):434-8. DOI: 10.1128/JVI.01754-06
Source: PubMed

ABSTRACT The relationship between the function of human immunodeficiency virus (HIV)-specific CD8 T-cell responses and viral load has not been defined. In this study, we used a panel of major histocompatibility complex class I tetramers to examine responses to frequently targeted CD8 T-cell epitopes in a large cohort of antiretroviral-therapy-naïve HIV type 1 clade C virus-infected persons in KwaZulu Natal, South Africa. In terms of effector functions of proliferation, cytokine production, and degranulation, only proliferation showed a significant correlation with viral load. This robust inverse relationship provides an important functional correlate of viral control relevant to both vaccine design and evaluation.

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    • "Antigen presentation and the relative amount of antigen presented through MHC class I play critical role in the process of T cell exhaustion [24] [25]. Whether high viral load through continuing replication of virus within the cells is sufficient to induce T cell exhaustion or additional mechanisms such as impairment of CD4 and NK cell activities are needed is still unclear [26]. Apart from LCMV, T cell exhaustion is also observed for many different chronic viruses including hepatitis C virus, hepatitis B Virus, HIV, and HTLV, etc. [27] [28]. "
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    • "The phenotypes of CD8 þ T cells that correlate with lower viral loads in chronic HIV infection are either central memory cells (Burgers et al. 2009) or effector memory cells (Hess et al. 2004; Addo et al. 2007) that do not express exhaustion markers such as PD-1 (Day et al. 2006; Petrovas et al. 2006; Trautmann et al. 2006). In terms of functional capacity, virus control has been associated with so-called polyfunctional CD8 T cells that secrete multiple cytokines (a property that is related to the sensitivity of antigen recognition) (Betts et al. 2006) as well as proliferative capacity (Day et al. 2007) and the ability to kill HIV-infected target cells (Yang et al. 1996; Migueles et al. 2008; Hersperger et al. 2010) or suppress HIV replication in vitro (Blackbourn et al. 1996; Yang et al. 1997; Spentzou et al. 2010). However, the qualitative properties of CD8 þ T-cell populations are also clearly impacted on by viral replication itself, thus rendering it difficult to disentangle cause from effect when interpreting associations between low viral load and particular phenotypic or functional profiles. "
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    • "Several features of the T-cell response to HIV have now been correlated with control of viral replication. These include preserved proliferative capacity (Day et al., 2007; Migueles et al., 2002; Rosenberg et al., 1997) and the ability to secrete multiple cytokines (CKs) (Betts et al., 2006; Harari et al., 2004; Kannanganat et al., 2007b). The specificity of the HIV proteins targeted by the T-cell response appears to be important, with a greater breadth of CD8 + epitopes targeted in Gag (Geldmacher et al., 2007; Kiepiela et al., 2007; Pereyra et al., 2008) or high-avidity CD8 + epitopes (Almeida et al., 2007) correlating with greater viral control. "
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