Preserved CD4+ Central Memory T Cells and Survival in Vaccinated SIV-Challenged Monkeys

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 07/2006; 312(5779):1530-3. DOI: 10.1126/science.1124226
Source: PubMed


Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)–infected monkeys only
transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid
DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged them with pathogenic SIV. Although
these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged
survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates
of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.

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Available from: David C Montefiori, Jul 09, 2014
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    • "Studies performed in rhesus macaques, immunized with plasmid DNA and replication defective adenoviral vectors encoding simian immunodeficiency virus (SIV) proteins and then challenged with pathogenic SIV, indicate that the preservation of vaccine induced antigen-specific central memory CD4+ T cells is essential for better outcome and survival following pathogenic SIV challenge [47]. Others suggest that central memory CD8+ T cells correlate with protection against SIV in rhesus macaques immunized with a vaccine candidate (DNA prime followed by a boost with the highly attenuated NYVAC-based SIV vaccine) [48]. "
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    ABSTRACT: The enzyme-linked immunospot (ELISPOT) assay has advanced into a useful and widely applicable tool for the evaluation of T-cell responses in both humans and animal models of diseases and/or vaccine candidates. Using synthetic peptides (either individually or as overlapping peptide mixtures) or whole antigens, total lymphocyte or isolated T-cell subset responses can be assessed either after short-term stimulation (standard ELISPOT) or after their expansion during a 10-day culture (cultured ELISPOT). Both assays detect different antigen-specific immune responses allowing the analysis of effector memory T cells and central memory T cells. This paper describes the principle of ELISPOT assays and discusses their application in the evaluation of immune correlates of clinical interest with a focus on the vaccine field.
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    • "Among them, heterologous prime-boost vaccination using naked plasmid DNA for priming followed by a booster injection of recombinant replication-deficient human adenovirus 5 (AdHu5) has recently received significant attention. This strategy has proved successful in some relevant experimental models such as simian immunodeficiency virus (SIV), malaria, Marburg, and Ebola virus infection, and Chagas disease (American trypanosomiasis), providing a considerable degree of protective immunity (Gilbert et al., 2002; Casimiro et al., 2003, 2005; Santra et al., 2005; Acierno et al., 2006; Letvin et al., 2006; Mattapallil et al., 2006; Sun et al., 2006; Wilson et al., 2006; de Alencar et al., 2009; Geisbert et al., 2010; Hensley et al., 2010; Martins et al., 2010; Dominguez et al., 2011; Rigato et al., 2011). These relative successes obtained in pre-clinical experimental models fueled human phase I trials (Freel et al., 2010; Jaoko et al., 2010; Koup et al., 2010; Schooley et al., 2010; Churchyard et al., 2011; De Rosa et al., 2011). "
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    ABSTRACT: Owing to the importance of major histocompatibility complex class Ia-restricted CD8(+) T cells for host survival following viral, bacterial, fungal, or parasitic infection, it has become largely accepted that these cells should be considered in the design of a new generation of vaccines. For the past 20 years, solid evidence has been provided that the heterologous prime-boost regimen achieves the best results in terms of induction of long-lived protective CD8(+) T cells against a variety of experimental infections. Although this regimen has often been used experimentally, as is the case for many vaccines, the mechanism behind the efficacy of this vaccination regimen is still largely unknown. The main purpose of this review is to examine the characteristics of the protective CD8(+) T cells generated by this vaccination regimen. Part of its efficacy certainly relies on the generation and maintenance of large numbers of specific lymphocytes. Other specific characteristics may also be important, and studies on this direction have only recently been initiated. So far, the characterization of these protective, long-lived T cell populations suggests that there is a high frequency of polyfunctional T cells; these cells cover a large breadth and display a T effector memory (TEM) phenotype. These TEM cells are capable of proliferating after an infectious challenge and are highly refractory to apoptosis due to a control of the expression of pro-apoptotic receptors such as CD95. Also, they do not undergo significant long-term immunological erosion. Understanding the mechanisms that control the generation and maintenance of the protective activity of these long-lived TEM cells will certainly provide important insights into the physiology of CD8(+) T cells and pave the way for the design of new or improved vaccines.
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    • "In SIV-infected macaques the ultimate loss of CD4 EM cells is in large part driven by lack of replenishment of this compartment by CD4 CM cells [18]. Other studies have shown that vaccinated macaques survive longer when CD4 CM cell numbers are preserved [19] and that HIV-1 viral controllers tend to preserve CD4 CM cell numbers [20]. However, in this study we did not observe a percentage difference in the CD4 subsets (naïve, CM and EM) between the CD4 High and CD4 Low groups during the 1st year of HIV infection. "
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    ABSTRACT: CD4+ central memory T cells play a critical role in the pathogenesis of simian immunodeficiency virus disease, and the CCR5 density on the surface of CD4 T cells is an important factor in human immunodeficiency virus (HIV)-1 disease progression. We hypothesized that quantifying central memory cells and CCR5 expression in the early stages of HIV-infection could provide useful prognostic information. We enrolled two different groups of acute HIV-infected subjects. One group progressed to CD4 T cell numbers below 250 cells/µl within 2 years (CD4 Low group), while the other group maintained CD4 cell counts above 450 cells/µl over 2 years (CD4 High group). We compared the CCR5 levels and percentage of CD4 subsets between the two groups during the 1st year of HIV infection. We found no differences between the two groups regarding the percentage of naïve, central memory and effector memory subsets of CD4 cells during the 1st year of HIV-1 infection. CCR5 levels on CD4+ CM subset was higher in the CD4 Low group compared with the CD4 High group during the 1st year of HIV-1 infection. High CCR5 levels on CD4 central memory cells in acute HIV infection are mostly associated with rapid disease progression. Our data suggest that low CCR5 expression on CD4 central memory cells protects CD4 cells from direct virus infection and favors the preservation of CD4(+) T cell homeostasis.
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