Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4 + T-Cell Clones

HIV-1 Ag-specific CD4+ T cell proliferative responses in human subjects with advanced, untreated HIV-1 disease are often weak or undetectable. Conversely, HIV-1-specific CD4+ T cell proliferation is occasionally detected following suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). These observations suggest that unchecked HIV-1 replication may lead to depletion or dysfunction of HIV-1-specific CD4+ T cells, and that these defects may be partially corrected by viral suppression and subsequent immune reconstitution. However, the impact of this immune reconstitution on the repertoire of HIV-1-specific CD4+ T cells has not been thoroughly evaluated. To examine the HIV-1-specific CD4+ T cell repertoire in this clinical setting, we established HIV-1 p24-specific CD4+ T cell clones from a successfully HAART-treated subject whose pretreatment peripheral CD4 count was 0 cells/μl. Eleven different p24-specific CD4+ T cell clonotypes were distinguished among 13 clones obtained. Most clones produced both IFN-γ and IL-4 upon Ag stimulation. Clones targeted eight distinct epitopes that varied in their conservancy among HIV-1 strains, and responses were restricted by one of three MHC II molecules. Clones showed a range of functional avidities for both protein and peptide Ags. Additional studies confirmed that multiple HIV-1 p24-derived epitopes were targeted by IFN-γ-producing CD4+ cells from subjects first treated with HAART during advanced HIV-1 disease (median, 4.5 peptides/subject; range, 3–6). These results suggest that in HAART-treated subjects whose peripheral CD4+ T cell pools were once severely depleted, the HIV-1-specific CD4+ T cell repertoire may include a diverse array of clonotypes targeting multiple HIV-1 epitopes.

Section: Discussionsupporting

confidence: 83%

Section: Leading To Increases In Naive Cd4mentioning

confidence: 99%

Diverse Repertoire of HIV-1 p24-Specific, IFN-γ-Producing CD4+ T Cell Clones Following Immune Reconstitution on Highly Active Antiretroviral Therapy

Boritz¹,

Palmer

Livingston³

et al. 2003

“…On occasion, HIV-infected individuals demonstrated CD4 ϩ perforin ϩ T cells reacting to HIV Ags (p24 whole protein) by cytokine secretion, but this number was generally much smaller than of CMV-specific CD4 ϩ CTLs (data not shown). In vitro, cytotoxic CD4 ϩ T cell clones have been grown from a range of hosts, with specificities for a variety of Ags, including HIV, EBV, dengue, and melanoma-derived Ags, as well as autoantigens (12,(23)(24)(25)(26). Similarly, the specificity of CD4 ϩ CD27 Ϫ T cells in PBMC has been ascribed to a range of Ags, including tetanus toxoid and various allergens (27).…”

Section: Cells Represent a Subset Of Ag-experienced Cellsmentioning

confidence: 99%

Characterization of CD4+ CTLs Ex Vivo

Appay

Zaunders

Papagno

et al. 2002

490

460

The cytotoxic potential of CD8+ T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4+ T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4+ T cells have been the subject of debate. Here we show that a population of CD4+ perforin+ T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4+ T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4+ T cells. The existence of CD4+ cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

“…Recognition of CD4 ϩ T cell epitopes on class II molecules was also assessed in cytotoxicity assays (Fig. 3C), taking advantage of the cytotoxic potential of these CD4 ϩ clones (27,40). In assays using an HLA-B42-restricted, CD8…”

Section: Presentation Of Hsp-complexed Hiv-1 Gag P24 32-mer Peptidementioning

confidence: 99%

Heat Shock Protein-Mediated Cross-Presentation of Exogenous HIV Antigen on HLA Class I and Class II

SenGupta

Norris

Suscovich

et al. 2004

Self Cite

Strong CD4+ and CD8+ T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4+ and CD8+ T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8+ T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.