Considerable evidence indicates that CD8+ cells play a critical role in controlling HIV/SIV disease progression, but neither the quantity nor breadth of the HIV-specific CD8+ T cell response as measured using standard approaches (MHC class I tetramer and single function analysis) conclusively correlate with control of replication or disease progression. Recently, using a novel polyfunctional analytical approach, we have identified patterns of CD8+ T cell function that appear to provide discriminate HIV disease progression status. HIV-infected subjects during chronic uncontrolled infection possess functionally limited HIV-specific CD8+ T cell responses, whereas long-term nonprogressors maintain polyfunctional responses. We believe that these polyfunctional patterns may enable us to identify correlates of natural immune protection and, furthermore, that they may have implications for vaccine development strategies. It is pertinent to define HIV-specific CD8+ T cell responses during acute infection, as the events during this period define future disease progression. Furthermore, an effective HIV vaccine will need to stimulate responses protective during this particular phase of infection. Our goals are to define the polyfunctional and phenotypic characteristics of HIV-specific CD8+ T cells that arise during primary infection, determine how they are modulated, and define their relationship to viral control and disease course. We will also determine if these responses can be altered by vaccination, using as a model a DNA/Adenovirus approach and exploiting the unique resource of a small number of vaccinated individuals who became HIV infected. Together, these studies will provide critical information regarding immune correlates of protection against which HIV vaccine candidates can be measured for potential protective effects. Lay Description: Development of a vaccine against HIV requires the understanding of the natural immune responses against HIV after infection occurs. In this proposal, we will determine how the immune system fights HIV during early infection and apply this knowledge to the development and testing of HIV vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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HIV/AIDS Vaccines Study Section (VACC)
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Embry, Alan C
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University of Pennsylvania
Schools of Medicine
United States
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Reuter, Morgan A; Del Rio Estrada, Perla M; Buggert, Marcus et al. (2017) HIV-Specific CD8+ T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue. Cell Rep 21:3458-3470
Tauriainen, Johanna; Scharf, Lydia; Frederiksen, Juliet et al. (2017) Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Sci Rep 7:40354
Knox, James J; Kaplan, David E; Betts, Michael R (2017) T-bet-expressing B cells during HIV and HCV infections. Cell Immunol 321:26-34
Demers, Korey R; Makedonas, George; Buggert, Marcus et al. (2016) Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection. PLoS Pathog 12:e1005805
Buggert, Marcus; Frederiksen, Juliet; Lund, Ole et al. (2016) CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection. AIDS 30:2415-2426
Pombo, Carolina; Wherry, E John; Gostick, Emma et al. (2015) Elevated Expression of CD160 and 2B4 Defines a Cytolytic HIV-Specific CD8+ T-Cell Population in Elite Controllers. J Infect Dis 212:1376-86
Buggert, Marcus; Tauriainen, Johanna; Yamamoto, Takuya et al. (2014) T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog 10:e1004251
Herati, Ramin Sedaghat; Reuter, Morgan A; Dolfi, Douglas V et al. (2014) Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J Immunol 193:3528-37
Frentsch, Marco; Stark, Regina; Matzmohr, Nadine et al. (2013) CD40L expression permits CD8+ T cells to execute immunologic helper functions. Blood 122:405-12
Demers, Korey R; Reuter, Morgan A; Betts, Michael R (2013) CD8(+) T-cell effector function and transcriptional regulation during HIV pathogenesis. Immunol Rev 254:190-206

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