Elevated glycolysis imparts functional ability to CD8+ T cells in HIV infection.
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ABSTRACT:
SUBMITTER: Rahman AN
PROVIDER: S-EPMC8473722 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:HIV frequently escapes CD8 T cell responses, leading to the accumulation of viral adaptations. We recently demonstrated that during chronic HIV infection, adapted epitopes can promote maturation of dendritic cells (DCs) through direct CD8 T cell interactions and lead to enhanced HIV trans-infection of CD4 T cells. Here, we sought to determine the role of such adaptations following HIV MRKAd5 vaccination. We observed that vaccine-induced adapted epitope-specific CD8 T cells promoted higher levels of DC maturation than nonadapted ones and that these matured DCs significantly enhanced HIV trans-infection. These matured DCs were associated with higher levels of interleukin 5 (IL-5) and IL-13 and a lower level of CXCL5, which have been shown to impact DC maturation, as well as a lower level of CXCL16. Finally, we observed that vaccine recipients with high HLA-I-associated adaptation became HIV infected more quickly. Our results offer another possible mechanism for enhanced infection among MRKAd5 vaccinees. IMPORTANCE Despite the well-established contribution of CD8 T cells in HIV control, prior CD8 T cell-based HIV vaccines have failed to demonstrate any efficacy in preventing viral infection. One such vaccine, known as the MRKAd5 vaccine, showed a potential increased risk of viral infection among vaccine recipients. However, the underlying mechanism(s) remains unclear. In this study, we observed that vaccine recipients with high adaptation to their HLA-I alleles were associated with an increased HIV infection risk in comparison to the others. Similar to what we observed in HIV infection in the prior study, adapted epitope-specific CD8 T cells obtained from vaccine recipients exhibit a greater capacity in facilitating viral infection by promoting dendritic cell maturation. Our findings provide a possible explanation for the enhanced viral acquisition risk among MRKAd5 vaccine recipients and highlight the importance of optimizing vaccine design with consideration of HLA-I-associated HIV adaptation.
| S-EPMC8312883 | biostudies-literature
Project description:Immediate-early host-virus interactions that occur during the first weeks after HIV infection have a major impact on disease progression. The mechanisms underlying the failure of HIV-specific CD8 T-cell response to persist and control viral replication early in infection are yet to be characterized. In this study, we performed a thorough phenotypic, gene expression and functional analysis to compare HIV-specific CD8 T cells in acutely and chronically infected subjects. We showed that HIV-specific CD8 T cells in primary infection can be distinguished by their metabolic state, rate of proliferation, and susceptibility to apoptosis. HIV-specific CD8 T cells in acute/early HIV infection secreted less IFN-? but were more cytotoxic than their counterparts in chronic infection. Importantly, we showed that the levels of IL-7R expression and the capacity of HIV-specific CD8 T cells to secrete IL-2 on antigenic restimulation during primary infection were inversely correlated with the viral set-point. Altogether, these data suggest an altered metabolic state of HIV-specific CD8 T cells in primary infection resulting from hyperproliferation and stress induced signals, demonstrate the discordant function of HIV-specific CD8 T cells during early/acute infection, and highlight the importance of T-cell maintenance for viral control.
| S-EPMC3743465 | biostudies-literature
Project description:CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1hiEOMEShiT-betlowTIGIT+ phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited via mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.
| S-EPMC9295450 | biostudies-literature
Project description:HIV-specific CD8+ T cells are known to play a key role in viral control during acute and chronic HIV infection. Although many studies have demonstrated the importance of HIV-specific CD8+ T cells in viral control, its correlation with protection against HIV infection remains incompletely understood. To better understand the nature of the immune response that contributes to the early control of HIV infection, we analyzed the phenotype, distribution and function of anti-viral CD8+ T cells in a cohort of HIV-exposed seronegative (HESN) women, and compared them with healthy controls and HIV-infected individuals. Further, we evaluated the in vitro viral inhibition activity of CD8+ T cells against diverse HIV-1 strains. We found that the HESN group had significantly higher levels of CD8+ T cells that express T-stem cell-like (TSCM) and follicular homing (CXCR5+) phenotype with more effector like characteristics as compared to healthy controls. Further, we observed that the HESN population had a higher frequency of HIV-specific poly-functional CD8+ T cells with robust in vitro virus inhibiting capacity against different clades of HIV. Overall, our results demonstrate that the HESN population has elevated levels of HIV-specific poly-functional CD8+ T cells with robust virus inhibiting ability and express elevated levels of markers pertaining to TSCM and follicular homing phenotype. These results demonstrate that future vaccine and therapeutic strategies should focus on eliciting these critical CD8+ T cell subsets.
| S-EPMC8056154 | biostudies-literature
Project description: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 1beta (MIP-1beta) 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.
| S-EPMC2863846 | biostudies-other
Project description:Sema4D, also known as CD100, is a constitutively expressed immune semaphorin on T cells and NK cells. CD100 has important immune regulatory functions that improve antigen-specific priming by antigen-presenting cells, and can also act as a costimulatory molecule on T cells. We investigated the consequence of HIV-1 infection on CD100 expression by T cells, and whether CD100 expression signifies functionally competent effector cells. CD100 expression on T cells from healthy individuals was compared with HIV-1-infected subjects including elite controllers, noncontrollers, and patients receiving antiretroviral therapy. The frequency and fluorescence intensity of CD100 on CD8(+) and CD4(+) T cells were decreased during HIV-1 infection. Furthermore, the absolute number of CD100-expressing CD8(+) T cells was positively associated with the magnitude of HIV-1-specific T-cell responses. CD8(+) T cells lacking CD100 expression were functionally impaired and present in increased numbers in HIV-1-infected individuals. The number of CD100(-)CD8(+) T cells positively correlated with T-cell immunosenescence, immune activation, and viral load. Loss of CD100 expression appears to result from direct antigen stimulation, as in vitro cytokine exposure and viral replication did not significantly impact CD100 expression. These data suggest that loss of CD100 expression probably plays an important role in dysfunctional immunity in HIV-1 infection.
| S-EPMC3265199 | biostudies-literature
Project description:During HIV infection, specific responses exhibited by CD8+ T cells are crucial to establish an early, effective, and sustained viral control, preventing severe immune alterations and organ dysfunction. Several CD8+ T cells subsets have been identified, exhibiting differences in terms of activation, functional profile, and ability to limit HIV replication. Some of the most important CD8+ T cells subsets associated with viral control, production of potent antiviral molecules, and strong polyfunctional responses include Th1-like cytokine pattern and Tc17 cells. In addition, the expression of specific activation markers has been also associated with a more effective response of CD8+ T cells, as evidenced in HLA-DR+ CD38- cells. CD8+ T cells in both, peripheral blood and gut mucosa, are particularly important in individuals with a resistant phenotype, including HIV-exposed seronegative individuals (HESNs), long-term non-progressors (LTNPs) and HIV-controllers. Although the role of CD8+ T cells has been extensively explored in the context of an established HIV-1 infection, the presence of HIV-specific cells with effector abilities and a defined functional profile in HESNs, remain poorly understood. Here, we reviewed studies carried out on different subpopulations of CD8+ T cells in relation with natural resistance to HIV infection and progression.
| S-EPMC5545716 | biostudies-other
Project description:BackgroundExpression of the cellular karyopherin TNPO3/transportin-SR2/Tnp3 is necessary for HIV-1 infection. Depletion of TNPO3 expression in mammalian cells inhibits HIV-1 infection after reverse transcription but prior to integration.ResultsThis work explores the role of cleavage and polyadenylation specificity factor subunit 6 (CPSF6) in the ability of TNPO3-depleted cells to inhibit HIV-1 infection. Our findings showed that depletion of TNPO3 expression inhibits HIV-1 infection, while the simultaneous depletion of TNPO3 and CPSF6 expression rescues HIV-1 infection. Several experiments to understand the rescue of infectivity by CPSF6 were performed. Our experiments revealed that the HIV-1 capsid binding ability of the endogenously expressed CPSF6 from TNPO3-depleted cells does not change when compared to CPSF6 from wild type cells. In agreement with our previous results, depletion of TNPO3 did not change the nuclear localization of CPSF6. Studies on the formation of 2-LRT circles during HIV-1 infection revealed that TNPO3-depleted cells are impaired in the integration process or exhibit a defect in the formation of 2-LTR circles. To understand whether the cytosolic fraction of CPSF6 is responsible for the inhibition of HIV-1 in TNPO3-depleted cells, we tested the ability of a cytosolic full-length CPSF6 to block HIV-1 infection. These results demonstrated that overexpression of a cytosolic full-length CPSF6 blocks HIV-1 infection at the nuclear import step. Fate of the capsid assays revealed that cytosolic expression of CPSF6 enhances stability of the HIV-1 core during infection.ConclusionsThese results suggested that inhibition of HIV-1 by TNPO3-depleted cells requires CPSF6.
| S-EPMC3695788 | biostudies-literature
Project description:Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-?-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.
| S-EPMC3105047 | biostudies-literature
Project description:In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1?-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants.
| S-EPMC3037354 | biostudies-literature