Phenotypic and Functional Profile of HIV-Inhibitory CD8 T Cells Elicited by Natural Infection and Heterologous Prime/Boost Vaccination

Abstract

Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8؉ T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8 ؉ T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8؉ T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8 ؉ T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8 ؉ T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1␤ (MIP-1␤) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8؉ T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8 ؉ T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.

Flow Cytometric Analysis of Myeloid Cells in Human Blood, Bronchoalveolar Lavage, and Lung Tissues

“…Use of this methodology has proven highly successful in characterizing cells in the blood and other organ systems. For example, the development of standardized staining panels for lymphocyte phenotyping has allowed the rapid detailed characterization of immune responses in large patient cohorts to examine responses to vaccination or infection (1)(2)(3). At present, no analogous immunophenotyping panels exist for the characterization of immune responses in bronchoalveolar lavage (BAL) or lung tissues.…”

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 + T-Cell Antiviral Activity and Correlates with Preservation of the CD4 + T-Cell Compartment

“…In-depth analyses of this cellular population, performed in different cohorts and models, suggest that specificity, quality, and phenotype are all determinants of CD8 ϩ T-cell ability to mediate control: specificity in terms of viral targets (11)(12)(13)(14)(15); quality in terms of avidity and capacity to mediate viral suppression, proliferate, and secrete a broad spectrum of chemokines and cytokines (16)(17)(18)(19)(20); and phenotype in terms of memory sub-subsets and expression of exhaustion markers (21)(22)(23).…”

Optimized ReplicatingRenillaLuciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function

“…3,4,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Among formerly described replication-competent HIV-1 reporter vectors were those designed with a bicistronic EGFP-IRES-nef cassette in place of nef, in which the EGFP gene is downstream of env, and nef is under translational control of an internal ribosome entry site (IRES) from encephalomyocarditis virus (EMCV).…”