Publications (6)0 Total impact
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I.M.M. Schellens,
K. Pogany,
G.H.A. Westerlaken,
J.A.M. Borghans,
F Miedema,
I.G. Valkengoed,
F P Kroon,
J M Lange,
K Brinkman,
J M Prins,
D. van Baarle
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ABSTRACT: Background: T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8+ and CD4+ T cells producing IFNc and IL-2 have been associated with control of viremia and are therefore hypothesized to be truly protective and determine subsequent clinical outcome. However, the cause-effect relationship between HIV-specific cellular immunity and disease progression is unknown. We investigated in a large prospective cohort study involving 96 individuals of the Amsterdam Cohort Studies with a known date of seroconversion whether the presence of cytokine-producing HIV-specific CD8+ T cells early in infection was associated with AIDS-free survival time. Methods and Findings: The number and percentage of IFNc and IL-2 producing CD8+ T cells was measured after in vitro stimulation with an overlapping Gag-peptide pool in T cells sampled approximately one year after seroconversion. Kaplan- Meier survival analysis and Cox proportional hazard models showed that frequencies of cytokine-producing Gag-specific CD8+ T cells (IFNc, IL-2 or both) shortly after seroconversion were neither associated with time to AIDS nor with the rate of CD4+ T-cell decline. Conclusions: These data show that high numbers of functional HIV-specific CD8+ T cells can be found early in HIV infection, irrespective of subsequent clinical outcome. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.
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ABSTRACT: The human leukocyte antigen (HLA) B57 allele and the closely related HLA-B5801 allele are overrepresented among human immunodeficiency virus type 1 (HIV-1)–infected individuals with a long-term nonprogressive clinical course of disease (known as “long-term nonprogressors” [LTNPs]). These alleles are, however, also present among individuals with normal disease progression (known as “progressors”). In a comparison of HLAB57/ 5801–expressing progressors and LTNPs, we observed a similar prevalence of escape mutations in 4 Nef epitopes and a similar reactivity of CD8+ T cells against 3 of 4 of these epitopes and their autologous escape variants. However, LTNPs tended to have frequent and preserved CD8+ T cell interferon- responses against the wild-typeHW9Nef epitope, whereas progressors did not maintain a specific CD8+ T cell response. This finding is in line with the findings of a more exhausted phenotype ofCD8+ Tcells in progressors, as is demonstrated by their enhanced level of expression of inhibitory receptor“programmeddeath 1” (PD-1).Theresults of the present study suggest that preservation of HW9-specific T cell responses is associated with a more benign clinical course of infection.
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ABSTRACT: Background: Most consensus HIV-1-specific cytotoxic T lymphocytes epitopes presented via intensively studied HLA molecules are thought to be known Objective: To identify possible novel HIV-1 epitopes for HLA-B27 and HLA-B57; two HLA types which are abundantly studied because of their correlation with slow HIV disease progression. Methods: HIV-1 consensus subtype B sequences were analysed using peptide prediction programs based on major histocompatibility complex binding, proteasomal cleavage and TAP (transporter associated with antigen processing) transport. Recognition of the novel identified epitopes by cytotoxic T lymphocytes was tested using interferon-γ ELISpot assay. Results: In total, 22 novel epitopes predicted to be presented by either HLA-B27 or HLA-B57 were selected. Of these, 86% elicited significant immune responses in HIV-1- infected individuals. Conclusions: These data show that numerous HIV-1 epitopes rema
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I.M.M. Schellens
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ABSTRACT: This thesis focuses on the impact of HLA class I restricted T cells on HIV-1 disease progression. It is generally accepted that cytotoxic T lymphocytes (CTL) play an important role in controlling HIV replication. In line with this, it has been well established that HLA class I alleles influence the rate of progression to AIDS. Both HLA heterozygosity as well as the presence of particular HLA alleles (e.g. HLA-B27 and B57) appear to be associated with relatively slow disease progression. The mechanism however via which these HLA alleles are associated with relatively slow disease progression remains largely unclear. In this thesis, several of the hypotheses were tested. We could show that CTL responses restricted via the protective HLA alleles HLA-B27 or B57 were lost at least as fast as CTL responses restricted via the non-protective HLA allele HLA-A2, indicating that maintenance of CTL responses per se is not the main determinant of protection against progression to AIDS. Furthermore, we showed that the low frequency of HLA-B27 and B57 in the human population is not the reason why these HLA alleles are associated with relatively slow HIV-1 disease progression. When comparing the number of CTL escape mutations that have been accumulating since the start of the epidemic for different HLA molecules, we did not find any evidence that adaptation of HIV to the human immune system has mainly occurred for CTL restricted by common HLA alleles. In contrast, we found that most CTL escape mutations have been accumulating for CTL restricted by the relatively rare HLA molecules HLA-B27 and B57. Our data suggest that instead of the frequency of HLA molecules in the human population it is the selection pressure exerted by the HLA-restricted CTL that determines the number of escape mutations that have accumulated throughout the epidemic. Moreover, we found that HLA-B27 and B57 have a strikingly different effect on the total HIV-specific T cell response in individuals expressing these HLA alleles. HLA-B57 clearly dominates the total CTL response, which might be mediated by the strong interaction between HLA-B57-peptide complexes and the T cell receptor. In sharp contrast, expression of HLA-B27 seems to preserve the total CTL response, leading to increased responses towards peptides restricted through not only HLA-B27 but also other HLA alleles expressed by the individual. These data suggest a different mechanism of protection for HLA-B27 and B57. Additionally, we investigated whether the presence of cytokine-producing HIV-specific CD8+ T cells early in infection was associated with AIDS-free survival time. We showed that regardless of subsequent clinical outcome, high frequencies of cytokine-producing CD4+ and CD8+ T cells can be found shortly after seroconversion. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.
