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: 4.44). 02/2007; 81(1):434-8. DOI: 10.1128/JVI.01754-06
Source: PubMed


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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    ABSTRACT: T cells reactive to tumor antigens and viral antigens lose their reactivity when exposed to the antigen-rich environment of a larger tumor bed or viral load. Such non-responsive T cells are termed exhausted. T cell exhaustion affects both CD8+ and CD4+ T cells. T cell exhaustion is attributed to the functional impairment of T cells to produce cytokines, of which the most important may be Interleukin 2 (IL2). IL2 performs functions critical for the elimination of cancer cells and virus infected cells. In one such function, IL2 promotes CD8+ T cell and natural killer (NK) cell cytolytic activities. Other functions include regulating naïve T cell differentiation into Th1 and Th2 subsets upon exposure to antigens. Thus, the signaling pathways contributing to T cell exhaustion could be linked to the signaling pathways contributing to IL2 loss. This review will discuss the process of T cell exhaustion and the signaling pathways that could be contributing to T cell exhaustion.
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    • "Upon antigenic stimulation, differentiation of naïve CD8+ T cells, which eventually gives rise to the different compartments of T-cell memory subsets, has a substantial effect on the CD8+ T cell pool (Lanzavecchia and Sallusto, 2002). Impairment of this might contribute to the dysfunctional, ineffective anti-HIV-1 response (Wherry and Ahmed, 2004), unsettling the proliferative capacity of epitope-specific CD8 T cells that are inversely related to the plasma HIV-1 RNA load (Day et al., 2007). In addition, it has been shown that removal of antigen due to either initiation of cART or development of epitope escape mutations, results in diminished HIV-1-specific CD8 T-cell response over time (Janbazian et al., 2012). "
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    ABSTRACT: Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1 patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1 patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.
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    • "While many cell surface markers, activation profiles, and functional parameters of both ex vivo HIV-specific CD8+ and CD4+ T cells have been shown to correlate with control of viremia [8], [30], [31], [32], [33] few, if any, can potentially mediate direct control of HIV replication through the lysis of infected cells [34]. Our lab has shown that Tim-3 expressing CD8+ T cells are dysfunctional in terms of polyfunctionality, proliferative ability, cytokine release and inhibitory receptor expression [15]. "
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    ABSTRACT: Cytotoxic CD8(+) T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell 'exhaustion' is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8(+) T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3(+) CD8(+) T cells to make perforin and 2) the direct ability of Tim-3(+) CD8(+) T cells to kill autologous HIV infected CD4(+) target cells. Surprisingly, Tim-3(+) CD8(+) T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8(+) T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4(+) T cells and d) their ability to suppress HIV infection of CD4(+) T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8(+) T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8(+) T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.
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