CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

Department of Pathology, Microbiology and Immunology (VM), University of California, Davis, Davis, California, United States
Journal of Virology (Impact Factor: 4.44). 08/2005; 79(14):9228-35. DOI: 10.1128/JVI.79.14.9228-9235.2005
Source: PubMed


In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency
virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly
massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear
infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the
timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain
infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal
tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response
in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in
these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing
to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is “too late and too little” to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that
rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

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    • "The accelerated secondary response observed in mice primed with adjuvanted vaccines in this prime-boost model suggests that the CD8+ T cells generated by this regimen may have properties that reduce the delay in the response of HIV-specific central memory CD8+ T cells upon exposure to the virus. This acceleration of the response could help to overcome the kinetic mismatch between viral replication and the generation of effective immune control, which may be partly responsible for the failure to clear infection by viruses that attack the immune system directly such as SIV or HIV [38]. Furthermore, with incorporation of the potent Th1-biasing α-C-GC glycolipid, the immune enhancing role of the adjuvant on the secondary response was retained when the priming vaccine was delivered subcutaneously. "
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    ABSTRACT: Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8 + T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8 + T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid a-galactosylceramide (a-GC) into rBCG-SIV gag significantly enhanced CD8 + T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of a-GC to enhance CD8 + T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an a-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8 + T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Studies in humanized mice and non-human primate models of HIV have revealed that HIV-infected CD4+ T cells are motile and infected cell migration and trafficking contribute to the spread of virus in vivo [2], [3]. The outcome of infection depends on a race between expansion of infection versus containment by effective immune responses [2], [4], [5], [6]. HIV-specific CD8+ T cells contribute to control of viremia in natural infection and following vaccination, but the characteristics of protective responses are still being defined [7], [8], [9], [10]. "
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    ABSTRACT: The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4(+) T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8(+) T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4(+) T-cells and HIV-specific CD8(+) T-cells. CTLs engaged motile HIV-infected targets, but ∼50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8(+) T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8(+) T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as "avidity" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8(+) T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "The hypothesis underlying these studies was that SIVΔnef vaccination might protect in part by converting the “too little and too late” CD8 T cell response to these immunodominant epitopes in unvaccinated animals [22], [23] to an “enough and soon enough” response in the vaccinated animals, sufficient to contain infection at the portal of entry or the lymphoid tissues (LTs) to which infection subsequently spreads. This hypothesis was founded in previous studies in the SIV-rhesus macaque vaginal challenge model [22], [23], which models HIV-1 transmission to women, where the CD8 T cell response was described as “too little and too late” for the following reasons. First, the peak of the immunodominant response occurred after the peak of virus replication in the lymphoid tissues (LT) that are the principal sites of virus production, persistence and pathology, such as the massive depletion of CD4 T cells in the gut, and thus too late to prevent this loss. "
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    ABSTRACT: Live-attenuated SIV vaccines (LAVs) have been the most effective to date in preventing or partially controlling infection by wild-type SIV in non-human primate models of HIV-1 transmission to women acting by mechanisms of protection that are not well understood. To gain insights into mechanisms of protection by LAVs that could aid development of effective vaccines to prevent HIV-1 transmission to women, we used in situ tetramer staining to determine whether increased densities or changes in the local distribution of SIV-specific CD8 T cells correlated with the maturation of SIVΔnef vaccine-induced protection prior to and after intra-vaginal challenge with wild-type SIVmac251. We evaluated the immunodominant Mamu-A1*001:01/Gag (CM9) and Mamu-A1*001:01/Tat (SL8) epitope response in genital and lymphoid tissues, and found that tetramer+ cells were present at all time points examined. In the cervical vaginal tissues, most tetramer+ cells were distributed diffusely throughout the lamina propria or co-localized with other CD8 T cells within lymphoid aggregates. The distribution and densities of the tetramer+ cells at the portal of entry did not correlate with the maturation of protection or change after challenge. Given these findings, we discuss the possibility that changes in other aspects of the immune system, including the quality of the resident population of virus-specific effector CD8 T cells could contribute to maturation of protection, as well as the potential for vaccine strategies that further increase the size and quality of this effector population to prevent HIV-1 transmission.
    Full-text · Article · Dec 2013 · PLoS ONE
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