Induction of Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8⁺and CD4⁺T-Cell Reactivity by Dendritic Cells Loaded with HIV-1 X4-Infected Apoptotic Cells

Abstract

T-cell responses to X4 strains of human immunodeficiency virus type 1 (HIV-1) are considered important in controlling progression of HIV-1 infection. We investigated the ability of dendritic cells (DC) and various forms of HIV-1 X4 antigen to induce anti-HIV-1 T-cell responses in autologous peripheral blood mononuclear cells from HIV-1-infected persons. Immature DC loaded with HIV-1 IIIB-infected, autologous, apoptotic CD8− cells and matured with CD40 ligand induced gamma interferon production in autologous CD8+ and CD4+ T cells. In contrast, mature DC loaded with HIV-1 IIIB-infected, necrotic cells or directly infected with cell-free HIV-1 IIIB were poorly immunogenic. Thus, HIV-1-infected cells undergoing apoptosis serve as a rich source of X4 antigen for CD8+ and CD4+ T cells by DC. This may be an important mechanism of HIV-1 immunogenicity and provides a strategy for immunotherapy of HIV-1-infected patients on combination antiretroviral therapy

Dendritic cells cross-present HIV antigens from live as well as apoptotic infected CD4 + T lymphocytes

“…Conversely, HIV epitope presentation after direct infection of DC was not detectable, even with high amounts of replicative virus. Efficient presentation after DC infection by live or defective virus probably needs recognition by high-avidity CD8 ϩ T clones (13) whereas it was not found in another study using PBMC from patients (11). Therefore, in vivo, cross-presentation should allow recognition of cells expressing very low amounts of viral proteins by naive or average-avidity memory CD8 ϩ T lymphocytes.…”

“…6) and CD40 expression (not shown) increased when DC were incubated with primary CD4 ϩ T cell blasts, whether these blasts were apoptotic or not, independently of HIV infection. In former studies, when PBMC from HIV-infected patients and not T cell lines were used, soluble CD40L or CD4 ϩ T cell help or LPS were indeed required (11). From all these data, and because HIV infects predominantly activated lymphocytes (40), it is likely that, in vivo, live and apoptotic HIV-infected T lymphocytes can supply antigens and costimulation signals for MHC class I-restricted presentation by DC and thus immunostimulation.…”

“…The different MHC class I-restricted presentation pathways that have been described for HIV antigens in DC, i.e., classical presentation after direct infection and cross-presentation after defective virus entry (13) or after phagocytosis of infected apoptotic CD4 ϩ T lymphocytes (11,12), had never been compared quantitatively. Our experiments attempted to reproduce in vivo conditions by using CD8 ϩ T cell lines with a relative low avidity or even CD8 ϩ cells purified from HIV ϩ patient PBMC.…”

“…HLA-A2), Gag 20 -28 (RLRPGGKKK, HLA-A3), and human T-lymphotrophic virus-1 Tax [11][12][13][14][15][16][17][18][19] (LLFGYPVYV, HLA-A2) were from Neosystem (Strasbourg, France). The following mAbs were used: anti-MHC class I W6͞32 ascitis (1:100), anti-CD11c (pure or phycoerythrin-labeled) and anti-CD3-FITC (Becton Dickinson), and GaMIg-Cy5 (Caltag, South San Francisco, CA).…”

“…DC have developed specific cross-presentation pathways that allow MHC class I-restricted presentation of the antigens contained in these apoptotic cells to CD8 ϩ T lymphocytes (9,10). DC from HIV ϩ patients can activate autologous CD4 ϩ and CD8 ϩ lymphocytes after coculture with infected apoptotic cells (11,12). An alternative source of HIV antigens for DC may be defective viral particles, which can fuse with the plasma membrane and be cross-presented without viral replication (13).…”