scholarly journals SDF-1α Is a Potent Inducer of HIV-1-Specific CD8+T-Cell Chemotaxis, But Migration of CD8+T Cells Is Impaired at High Viral Loads

2008 ◽  
Vol 24 (7) ◽  
pp. 977-985 ◽  
Author(s):  
Amie L. Meditz ◽  
Rick Schlichtemeier ◽  
Joy M. Folkvord ◽  
Monique Givens ◽  
Kevin C. Lesh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Potent Inducer ◽  
Viral Loads ◽  
Hiv 1 ◽  
Cell Chemotaxis

IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3463-3471 ◽  
Author(s):  
Christoph Hess ◽  
Terry K. Means ◽  
Patrick Autissier ◽  
Tonia Woodberry ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Immune System Activation ◽  
Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

scholarly journals Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6351-6360 ◽  
Author(s):  
Jorge R. Almeida ◽  
Delphine Sauce ◽  
David A. Price ◽  
Laura Papagno ◽  
So Youn Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Basic Knowledge ◽  
Suppressive Activity ◽  
Antiviral Efficacy ◽  
Hiv 1

Abstract 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.

scholarly journals Cross-Reactive CD8 T-Cell Responses Elicited by Adenovirus Type 5-Based HIV-1 Vaccines Contributed to Early Viral Evolution in Vaccine Recipients Who Became Infected

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Sushma Boppana ◽  
Andrew Fiore-Gartland ◽  
Anju Bansal ◽  
Paul Goepfert
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Evolution ◽  
Cd8 T Cell ◽  
Cross Reactivity ◽  
Viral Control ◽  
Acute Hiv ◽  
Viral Sequences ◽  
Hiv 1

ABSTRACT Because of HIV’s vast sequence diversity, the ability of the CD8 T-cell response to recognize several variants of a single epitope is an important consideration for vaccine design. Cross-recognition of viral epitopes by CD8 T cells is associated with viral control during HIV-1 infection, but little is known about CD8 cross-reactivity in the context of HIV-1 vaccination. Here, we evaluated vaccine-induced CD8 cross-reactivity in two preventative HIV-1 vaccine efficacy trials, the MRKAd5 and DNA/rAd5 studies. Cross-reactive CD8 responses elicited by vaccination were similar in magnitude and frequency to those induced during acute HIV-1 infection. Although responses directed against variant epitopes were less avid than responses to vaccine-matched epitopes, we did not detect any difference in response polyfunctionality (the proportion of cells producing multiple effector molecules). And while depth, or the frequency of cross-reactive responses, did not correlate with viral loads in recipients who became infected, cross-reactivity did appear to influence early viral evolution. In comparing viral sequences of placebo versus vaccine recipients, we found that viral sequences from vaccinees encoded CD8 epitopes with more substitutions and greater biochemical dissimilarity. In other words, breakthrough sequences of vaccinees would be less cross-recognized by vaccine-induced responses. Additionally, vaccine-induced CD8 T cells poorly cross-recognized variant epitopes encoding HLA-I-associated adaptations, further supporting our conclusion that these responses play a role in driving early HIV-1 viral evolution. IMPORTANCE HIV-1 has exceptionally high sequence diversity, much of which is found within CD8 epitopes. Therefore, the ability of CD8 T cells to recognize multiple versions of a single epitope could be important for an effective vaccine. Here, we show that two previously tested vaccines induced a similar level of CD8 cross-reactivity to that seen in acute HIV-1 infection. Although this cross-reactivity did not seem to affect viral control in vaccine recipients who became infected, we identified several ways in which CD8 cross-reactivity appeared to influence HIV-1 viral evolution. First, we saw that strains isolated from infected vaccine recipients would likely be poorly cross-recognized by the vaccine-induced response. Second, we saw that adapted CD8 epitopes were poorly cross-recognized in both vaccination and infection. Collectively, we believe these results show that CD8 cross-reactivity could be an important consideration in future HIV-1 vaccine design.

scholarly journals Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Lydia Scharf ◽  
Christina B. Pedersen ◽  
Emil Johansson ◽  
Jacob Lindman ◽  
Lars R. Olsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Cd8 T Cells ◽  
Therapy Monitoring ◽  
Expression Patterns ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Hiv 1

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

scholarly journals Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

2019 ◽  
Vol 8 (12) ◽  
pp. 2089 ◽  
Author(s):  
Oscar Blanch-Lombarte ◽  
Cristina Gálvez ◽  
Boris Revollo ◽  
Esther Jiménez-Moyano ◽  
Josep M. Llibre ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Viral Reactivation ◽  
Viral Reservoir ◽  
Cell Responses ◽  
Hiv 1

Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8+ T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir. Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8+ T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load. Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8+ T-cells expressing HLA-DR+/CD38+ transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8+ T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence. Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8+ T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8+ T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

Abstract CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

scholarly journals Breadth of CD8 T-cell mediated inhibition of replication of diverse HIV-1 transmitted-founder isolates correlates with the breadth of recognition within a comprehensive HIV-1 Gag, Nef, Env and Pol potential T-cell epitope (PTE) peptide set

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260118
Author(s):  
Peter Hayes ◽  
Natalia Fernandez ◽  
Christina Ochsenbauer ◽  
Jama Dalel ◽  
Jonathan Hare ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Cell Numbers ◽  
Cell Responses ◽  
Hiv 1

Full characterisation of functional HIV-1-specific T-cell responses, including identification of recognised epitopes linked with functional antiviral responses, would aid development of effective vaccines but is hampered by HIV-1 sequence diversity. Typical approaches to identify T-cell epitopes utilising extensive peptide sets require subjects’ cell numbers that exceed feasible sample volumes. To address this, CD8 T-cells were polyclonally expanded from PBMC from 13 anti-retroviral naïve subjects living with HIV using CD3/CD4 bi-specific antibody. Assessment of recognition of individual peptides within a set of 1408 HIV-1 Gag, Nef, Pol and Env potential T-cell epitope peptides was achieved by sequential IFNγ ELISpot assays using peptides pooled in 3-D matrices followed by confirmation with single peptides. A Renilla reniformis luciferase viral inhibition assay assessed CD8 T-cell-mediated inhibition of replication of a cross-clade panel of 10 HIV-1 isolates, including 9 transmitted-founder isolates. Polyclonal expansion from one frozen PBMC vial provided sufficient CD8 T-cells for both ELISpot steps in 12 of 13 subjects. A median of 33 peptides in 16 epitope regions were recognised including peptides located in previously characterised HIV-1 epitope-rich regions. There was no significant difference between ELISpot magnitudes for in vitro expanded CD8 T-cells and CD8 T-cells directly isolated from PBMCs. CD8 T-cells from all subjects inhibited a median of 7 HIV-1 isolates (range 4 to 10). The breadth of CD8 T-cell mediated HIV-1 inhibition was significantly positively correlated with CD8 T-cell breadth of peptide recognition. Polyclonal CD8 T-cell expansion allowed identification of HIV-1 isolates inhibited and peptides recognised within a large peptide set spanning the major HIV-1 proteins. This approach overcomes limitations associated with obtaining sufficient cell numbers to fully characterise HIV-1-specific CD8 T-cell responses by different functional readouts within the context of extreme HIV-1 diversity. Such an approach will have useful applications in clinical development for HIV-1 and other diseases.

scholarly journals The DARC-null trait is associated with moderate modulation of NK cell profiles and unaltered cytolytic T cell profiles in black South Africans

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242448
Author(s):  
Kewreshini K. Naidoo ◽  
Zesuliwe B. Shangase ◽  
Tabassum Rashid ◽  
Ayanda Ngubane ◽  
Nasreen Ismail ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Full Blood Count ◽  
Cell Counts ◽  
Hiv 1

The Duffy Antigen Receptor for Chemokines (DARC)-null trait, common among persons of African descent and associated with lower absolute neutrophil counts (ANCs), may be linked to increased risk to certain infections including HIV-1 but the underlying causes are poorly understood. We hypothesized that DARC-null-linked neutropenia may negatively impact neutrophil immunoregulatory modulation of other immune cells such as natural killer (NK) and CD8+ T cells leading to altered phenotype, functionality and homeostatic activity of these immune cells. HIV-1 uninfected (n = 20) and HIV-1 chronically infected (n = 19) participants were assessed using multi-parametric flow cytometry to determine NK and CD8+ T cell counts, phenotypic profiles, and cytokine production and degranulation. Annexin V and carboxyfluorescein succinimidyl ester (CFSE) staining were used to examine NK cell survival and NK cell and CD8+ T cell proliferation respectively. Participants were genotyped for the DARC-null polymorphism using allelic discrimination assays and ANCs were measured by full blood count. In HIV uninfected individuals, a reduction of total NK cell counts was noted in the absence of DARC and this correlated with lower ANCs. HIV uninfected DARC-null subjects displayed a less mature NK cell phenotype. However, this did not translate to differences in NK cell activation or effector functionality by DARC state. Whilst HIV-1 infected subjects displayed NK cell profiling that is typical of HIV infection, no differences were noted upon DARC stratification. Similarly, CD8+ T cells from HIV infected individuals displayed phenotypic and functional modulation that is characteristic of HIV infection, but profiling was unaffected by the DARC-null variant irrespective of HIV status. Overall, the data suggests that the DARC-null polymorphism and lower ANCs does not impede downstream cytolytic cell priming and functionality.

scholarly journals Specificity of CD8+ T-Cell Responses Following Vaccination with Conserved Regions of HIV-1 in Nairobi, Kenya

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 260
Author(s):  
Yehia S. Mohamed ◽  
Nicola J. Borthwick ◽  
Nathifa Moyo ◽  
Hayato Murakoshi ◽  
Tomohiro Akahoshi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Cell Responses ◽  
Hiv 1

Sub-Saharan Africa carries the biggest burden of the human immunodeficiency virus type 1 (HIV-1)/AIDS epidemic and is in an urgent need of an effective vaccine. CD8+ T cells are an important component of the host immune response to HIV-1 and may need to be harnessed if a vaccine is to be effective. CD8+ T cells recognize human leukocyte antigen (HLA)-associated viral epitopes and the HLA alleles vary significantly among different ethnic groups. It follows that definition of HIV-1-derived peptides recognized by CD8+ T cells in the geographically relevant regions will critically guide vaccine development. Here, we study fine details of CD8+ T-cell responses elicited in HIV-1/2-uninfected individuals in Nairobi, Kenya, who received a candidate vaccine delivering conserved regions of HIV-1 proteins called HIVconsv. Using 10-day cell lines established by in vitro peptide restimulation of cryopreserved PBMC and stably HLA-transfected 721.221/C1R cell lines, we confirm experimentally many already defined epitopes, for a number of epitopes we define the restricting HLA molecule(s) and describe four novel HLA-epitope pairs. We also identify specific dominance patterns, a promiscuous T-cell epitope and a rescue of suboptimal T-cell epitope induction in vivo by its functional variant, which all together inform vaccine design.

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