CD8(+) T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8(+) T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8(+) T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8(+) T cells from infected donors. We report that attributes of CD8(+) T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8(+) T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8(+) T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.
"First, the frequency of T cells, antigen sensitivity of TCRs (T-cell receptors) and the amount of antigen load required for TCR activation are effectors of the multifunctional T-cell response. Studies have shown that HIV-specific CD8+ T cells with high antigen sensitivity display multifunctional secretory profiles . Experiments with the TH1 CD4+ cell model in mice indicated that multifunctionality appeared with an increased concentration of the ligand . "
[Show abstract][Hide abstract] ABSTRACT: More than 60 million people in the world have been diagnosed with human immunodeficiency virus (HIV) infections since the virus was recognized as the causative agent of acquired immunodeficiency syndrome (AIDS) in the 1980s. Even though more than half of the infected patients have died, effective disease treatment and prevention measures have not been established. Antiretroviral therapy is the only proven HIV treatment which sustains suppression of patient viremia. Current routine approaches to treat HIV infections are targeted at developing vaccines that will induce humoral or cell memory immune responses. However, developing an effective vaccine has been challenging because the HIV mutates rapidly, which allows the virus to evade immune surveillances established against the previous strain. In addition, the virus is able to quickly establish a reservoir and treatment is difficult because of the general lack of knowledge about HIV immune response mechanisms. This review introduces common disease symptoms and the progression of HIV infection with a brief summary of the current treatment approaches. Different cellular immune responses against HIV are also discussed, with emphasis on a nanotechnology research that has focused on probing T cell response to HIV infection. Furthermore, we discuss recent noteworthy nanotechnology updates on T cell response screening that are focused on HIV infection. Finally, we review potential future treatment strategies based on the correlations between T cell response and HIV infection.
"This property is a critical attribute of effector cells. Multiple studies have shown that higher functional avidity is associated with superior in vivo efficacy for pathogen clearance , –. "
[Show abstract][Hide abstract] ABSTRACT: CD4+ T cell differentiation has been shown to be regulated by the cytokine milieu present during activation as well as peptide MHC levels. However, the extent to which these two important regulatory signals work in concert to shape CD4+ T cell function has not been investigated. Using a murine OT-II transgenic TCR model of in vitro differentiation, we demonstrate that the ability of CD4+ T cells to commit to a distinct lineage, i.e. Th1 vs. Th2 vs. Th17, is restricted by the amount of peptide antigen present in the stimulating environment. In addition, whether cells succumb to inhibitory effects associated with high dose antigen is dependent on the array of cytokine signals encountered. Specifically, stimulation with high dose antigen in Th1 or Th17 conditions promoted efficient generation of functional cells, while Th2 polarizing conditions did not. Finally, we found that the peptide sensitivity of an effector cell was determined by the combined actions of cytokine and peptide level, with Th1 cells exhibiting the highest avidity, followed by Th17 and Th2 cells. Together, these data show that the interplay of antigen and cytokine signals shape both the differentiation fate and avidity setpoint of CD4+ T cells.
PLoS ONE 06/2014; 9(6):e100175. DOI:10.1371/journal.pone.0100175 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Human Leukocyte Antigen (HLA) class I restricted Cytotoxic T Lymphocytes (CTLs) exert substantial evolutionary pressure on HIV-1, as evidenced by the reproducible selection of HLA-restricted immune escape mutations in the viral genome. An escape mutation from tyrosine to phenylalanine at the 135th amino acid (Y135F) of the HIV-1 nef gene is frequently observed in patients with HLA-A*24:02, an HLA Class I allele expressed in ~70% of Japanese persons. The selection of CTL escape mutations could theoretically result in the de novo creation of novel epitopes, however, the extent to which such dynamic “CTL epitope switching” occurs in HIV-1 remains incompletely known.
Two overlapping epitopes in HIV-1 nef, Nef126-10 and Nef134-10, elicit the most frequent CTL responses restricted by HLA-A*24:02. Thirty-five of 46 (76%) HLA-A*24:02-positive patients harbored the Y135F mutation in their plasma HIV-1 RNA. Nef codon 135 plays a crucial role in both epitopes, as it represents the C-terminal anchor for Nef126-10 and the N-terminal anchor for Nef134-10. While the majority of patients with 135F exhibited CTL responses to Nef126-10, none harboring the “wild-type” (global HIV-1 subtype B consensus) Y135 did so, suggesting that Nef126-10 is not efficiently presented in persons harboring Y135. Consistent with this, peptide binding and limiting dilution experiments confirmed F, but not Y, as a suitable C-terminal anchor for HLA-A*24:02. Moreover, experiments utilizing antigen specific CTL clones to recognize endogenously-expressed peptides with or without Y135F indicated that this mutation disrupted the antigen expression of Nef134-10. Critically, the selection of Y135F also launched the expression of Nef126-10, indicating that the latter epitope is created as a result of escape within the former.
Our data represent the first example of the de novo creation of a novel overlapping CTL epitope as a direct result of HLA-driven immune escape in a neighboring epitope. The robust targeting of Nef126-10 following transmission (or in vivo selection) of HIV-1 containing Y135F may explain in part the previously reported stable plasma viral loads over time in the Japanese population, despite the high prevalence of both HLA-A*24:02 and Nef-Y135F in circulating HIV-1 sequences.
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