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1.
Gregory Q. Del Prete Kelli Oswald Abigail Lara Rebecca Shoemaker Jeremy Smedley Rhonda Macallister Vicky Coalter Adam Wiles Rodney Wiles Yuan Li Randy Fast Rebecca Kiser Bing Lu Jim Zheng W. Gregory Alvord Charles M. Trubey Michael Piatak Jr. Claire Deleage Brandon F. Keele Jacob D. Estes Joseph Hesselgesser Romas Geleziunas Jeffrey D. Lifson 《Antimicrobial agents and chemotherapy》2016,60(3):1560-1572
Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4+ T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy. 相似文献
2.
《Expert review of anti-infective therapy》2013,11(10):1187-1201
Current therapy for HIV effectively suppresses viral replication and prolongs life, but the infection persists due, at least in part, to latent infection of long-lived cells. One favored strategy toward a cure targets latent virus in resting memory CD4+ T cells by stimulating viral production. However, the existence of an additional reservoir in bone marrow hematopoietic progenitor cells has been detected in some treated HIV-infected people. This review describes approaches investigators have used to reactivate latent proviral genomes in resting CD4+ T cells and hematopoietic progenitor cells. In addition, the authors review approaches for clearance of these reservoirs along with other important topics related to HIV eradication. 相似文献
3.
Guannan Geng Bingfeng Liu Cancan Chen Kang Wu Jun Liu Yijun Zhang Ting Pan Jun Li Yue Yin Junsong Zhang Feng Huang Fei Yu Jingliang Chen Xiancai Ma Jie Zhou Ersheng Kuang Chao Liu Weiping Cai Hui Zhang 《Molecular therapy》2016,24(9):1528-1537
Although combined antiretroviral therapy (cART) successfully decreases plasma viremia to undetectable levels, the complete eradication of human immunodeficiency virus type 1 (HIV-1) remains impractical because of the existence of a viral reservoir, mainly in resting memory CD4+ T cells. Various cytokines, protein kinase C activators, and histone deacetylase inhibitors (HDACi) have been used as latency-reversing agents (LRAs), but their unacceptable side effects or low efficiencies limit their clinical use. Here, by a mutation accumulation strategy, we generated an attenuated HIV-1 Tat protein named Tat-R5M4, which has significantly reduced cytotoxicity and immunogenicity, yet retaining potent transactivation and membrane-penetration activity. Combined with HDACi, Tat-R5M4 activates highly genetically diverse and replication-competent viruses from resting CD4+ T lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Thus, Tat-R5M4 has promising potential as a safe, efficient, and specific LRA in HIV-1 treatment. 相似文献
4.
Julia A.M. Sung Joy Pickeral Liqin Liu Sherry A. Stanfield-Oakley Chia-Ying Kao Lam Carolina Garrido Justin Pollara Celia LaBranche Mattia Bonsignori M. Anthony Moody Yinhua Yang Robert Parks Nancie Archin Brigitte Allard Jennifer Kirchherr JoAnn D. Kuruc Cynthia L. Gay Myron S. Cohen Christina Ochsenbauer Kelly Soderberg Hua-Xin Liao David Montefiori Paul Moore Syd Johnson Scott Koenig Barton F. Haynes Jeffrey L. Nordstrom David M. Margolis Guido Ferrari 《The Journal of clinical investigation》2015,125(11):4077-4090
Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell–mediated clearance of HIV-1–infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity–mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected–patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals. 相似文献
5.
Adam M. Spivak Alberto Bosque Alfred H. Balch David Smyth Laura Martins Vicente Planelles 《Antimicrobial agents and chemotherapy》2015,59(10):5984-5991
The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4+ T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4+ T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4+ T cells from aviremic HIV-1+ patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1+ antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4+ T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation. 相似文献
6.
Adrienne E. Swanstrom Taina T. Immonen Kelli Oswald Cathi Pyle James A. Thomas William J. Bosche Lorna Silipino Michael Hull Laura Newman Vicky Coalter Adam Wiles Rodney Wiles Jacob Kiser David R. Morcock Rebecca Shoemaker Randy Fast Matthew W. Breed Joshua Kramer Duncan Donohue Tyler Malys Christine M. Fennessey Charles M. Trubey Claire Deleage Jacob D. Estes Jeffrey D. Lifson Brandon F. Keele Gregory Q. Del Prete 《The Journal of clinical investigation》2021,131(6)
The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound-competent HIV genomes during combination antiretroviral therapy (cART) has been limited by inefficient induction of viral protein expression. To examine antibody-mediated viral reservoir targeting without a need for viral induction, we used an anti-CD4 mAb to deplete both infected and uninfected CD4+ T cells. Ten rhesus macaques infected with barcoded SIVmac239M received cART for 93 weeks starting 4 days after infection. During cART, 5 animals received 5 to 6 anti-CD4 antibody administrations and CD4+ T cell populations were then allowed 1 year on cART to recover. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not significantly delayed in anti-CD4–treated animals compared with controls. Viral reactivation rates, determined based on rebounding SIVmac239M clonotype proportions, also were not significantly different in CD4-depleted animals. Notably, antibody-mediated depletion was limited in rectal tissue and negligible in lymphoid follicles. These results suggest that, even if robust viral reactivation can be achieved, antibody-mediated viral reservoir depletion may be limited in key tissue sites. 相似文献
7.
Shane D. Falcinelli Jackson J. Peterson Anne-Marie W. Turner David Irlbeck Jenna Read Samuel L.M. Raines Katherine S. James Cameron Sutton Anthony Sanchez Ann Emery Gavin Sampey Robert Ferris Brigitte Allard Simon Ghofrani Jennifer L. Kirchherr Caroline Baker JoAnn D. Kuruc Cynthia L. Gay Lindsey I. James Guoxin Wu Paul Zuck Inmaculada Rioja Rebecca C. Furze Rab K. Prinjha Bonnie J. Howell Ronald Swanstrom Edward P. Browne Brian D. Strahl Richard M. Dunham Nancie M. Archin David M. Margolis 《The Journal of clinical investigation》2022,132(8)
8.
Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation
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Hung-Chih Yang Sifei Xing Liang Shan Karen O’Connell Jason Dinoso Anding Shen Yan Zhou Cynthia K. Shrum Yefei Han Jun O. Liu Hao Zhang Joseph B. Margolick Robert F. Siliciano 《The Journal of clinical investigation》2009,119(11):3473-3486
The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies for reactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-κB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection. 相似文献
9.
Persaud D Pierson T Ruff C Finzi D Chadwick KR Margolick JB Ruff A Hutton N Ray S Siliciano RF 《The Journal of clinical investigation》2000,105(7):995-1003
HIV-1 persists in a latent state in resting CD4+ T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4+ T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4+ T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1–3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4+ T cells will be a major obstacle to HIV-1 eradication in children. 相似文献
10.
Amy S. Huang Victor Ramos Thiago Y. Oliveira Christian Gaebler Mila Jankovic Michel C. Nussenzweig Lillian B. Cohn 《The Journal of experimental medicine》2021,218(12)
Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain–containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion. 相似文献
11.
M. Concepción Romero-Sánchez Kawthar Machmach Alejandro Gonzalez-Serna Miguel Genebat Ildefonso Pulido María García-García Ana Isabel álvarez-Ríos Sara Ferrando-Martinez Ezequiel Ruiz-Mateos Manuel Leal 《Antimicrobial agents and chemotherapy》2012,56(11):5858-5864
The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8+ T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8+ T-cell counts and preserved CD4+ T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8+ T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients. 相似文献
12.
《Molecular therapy》2002,5(6):788-797
Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4+ and CD8+ T cells bearing a chimeric T-cell receptor (CD4ζ) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-ζ signaling chain of the CD3 T-cell receptor. CD4ζ-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4ζ gene–modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4+ T-cell counts. 相似文献
13.
14.
Brian Ferrari Amanda Cabral Da Silva Ken H. Liu Evgeniya V. Saidakova Larisa B. Korolevskaya Konstantin V. Shmagel Carey Shive Gabriela Pacheco Sanchez Mauricio Retuerto Ashish Arunkumar Sharma Khader Ghneim Laura Noel-Romas Benigno Rodriguez Mahmoud A. Ghannoum Peter P. Hunt Steven G. Deeks Adam D. Burgener Dean P. Jones Mirela A. Dobre Vincent C. Marconi Rafick-Pierre Sekaly Souheil-Antoine Younes 《The Journal of clinical investigation》2022,132(9)
People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4+ T cell count after antiretroviral therapy (ART). INRs have low CD4+ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4+ T cell cycling (Ki67+). Here, we report the findings that memory CD4+ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4+ T cell counts. In vitro PCS or IS blocked CD4+ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4+ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4+ T cell recovery during ART and may contribute to CD4+ T cell lymphopenia characteristic of INRs. 相似文献
15.
Gregory Q. Del Prete Rebecca Shoemaker Kelli Oswald Abigail Lara Charles M. Trubey Randy Fast Douglas K. Schneider Rebecca Kiser Vicky Coalter Adam Wiles Rodney Wiles Brandi Freemire Brandon F. Keele Jacob D. Estes Octavio A. Qui?ones Jeremy Smedley Rhonda Macallister Rosa I. Sanchez John S. Wai Christopher M. Tan W. Gregory Alvord Daria J. Hazuda Michael Piatak Jr. Jeffrey D. Lifson 《Antimicrobial agents and chemotherapy》2014,58(11):6790-6806
16.
Yoshiaki Nishimura Olivia K. Donau Joana Dias Sara Ferrando-Martinez Eric Jesteadt Reza Sadjadpour Rajeev Gautam Alicia Buckler-White Romas Geleziunas Richard A. Koup Michel C. Nussenzweig Malcolm A. Martin 《The Journal of experimental medicine》2021,218(1)
We report that combination bNAb immunotherapy initiated on day 3 post-infection (PI) maintained durable CD8+ T cell–mediated suppression of SHIVAD8 viremia and preinoculation levels of CD4+ T cells in 9 of 13 treated monkeys during nearly 6 yr of observation, as assessed by successive CD8+ T cell–depletion experiments. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs) beginning on week 2 PI were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8+ cells. However, the median time to suppression of plasma viremia following intervention on week 2 was markedly delayed (85 wk) compared with combination bNAb immunotherapy initiated on day 3 (39 wk). In both cases, the principal correlate of virus control was the induction of CD8+ T cellular immunity. 相似文献
17.
Carly M. Harro Jairo Perez-Sanz Tara Lee Costich Kyle K. Payne Carmen M. Anadon Ricardo A. Chaurio Subir Biswas Gunjan Mandal Kristen E. Rigolizzo Kimberly B. Sprenger Jessica A. Mine Louise C. Showe Xiaoqing Yu Kebin Liu Paulo C. Rodriguez Javier Pinilla-Ibarz Lubomir Sokol Jose R. Conejo-Garcia 《The Journal of clinical investigation》2021,131(3)
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence–binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases. 相似文献
18.
Daniel J Hui Etiena Basner-Tschakarjan Yifeng Chen Robert J Davidson George Buchlis Mustafa Yazicioglu Gary C Pien Jonathan D Finn Virginia Haurigot Alex Tai David W Scott Leslie P Cousens Shangzhen Zhou Anne S De Groot Federico Mingozzi 《Molecular therapy》2013,21(9):1727-1737
Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro. We showed that incubation of peripheral blood mononuclear cells with these epitopes triggers proliferation of CD4+CD25+FoxP3+ T cells that suppress killing of target cells loaded with MHC class I antigens in an antigen-specific fashion, through a mechanism that seems to require cell-to-cell contact. Expression of a construct encoding for the AAV capsid structural protein fused to Tregitopes resulted in reduction of CD8+ T cell reactivity against the AAV capsid following immunization with an adenoviral vector expressing capsid. This was accompanied by an increase in frequency of CD4+CD25+FoxP3+ T cells in spleens and lower levels of inflammatory infiltrates in injected tissues. This proof-of-concept study demonstrates modulation of CD8+ T cell reactivity to an antigen using regulatory T cell epitopes is possible. 相似文献
19.
Catherine Riou Elsa du Bruyn Cari Stek Remy Daroowala Rene T. Goliath Fatima Abrahams Qonita Said-Hartley Brian W. Allwood Nei-Yuan Hsiao Katalin A. Wilkinson Cecilia S. Lindestam Arlehamn Alessandro Sette Sean Wasserman Robert J. Wilkinson 《The Journal of clinical investigation》2021,131(12)
T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis–specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease. 相似文献
20.
Induction of HIV-1 Replication in Latently Infected
CD4+ T Cells Using a Combination of Cytokines
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Tae-Wook Chun Delphine Engel Stephanie B. Mizell Linda A. Ehler Anthony S. Fauci 《The Journal of experimental medicine》1998,188(1):83-91
Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1–infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4+ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4+ T cells derived from HIV-infected individuals who are antiretroviral therapy–naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-α, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART. 相似文献