scholarly journals Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 753
Author(s):  
Mohammad Haque ◽  
Fengyang Lei ◽  
Xiaofang Xiong ◽  
Yijie Ren ◽  
Hao-Yun Peng ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Viral Antigen ◽  
Peritoneal Macrophages ◽  
Hiv Replication ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
Hiv 1

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

CXCR4 engagement is required for HIV-1–induced L-selectin shedding

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1218-1221 ◽  
Author(s):  
JiangFang Wang ◽  
Susanne Marschner ◽  
Terri H. Finkel
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Signaling Cascades ◽  
T Cell Signaling ◽  
Cxcr4 Antagonist ◽  
Immunodeficiency Virus ◽  
Cxc Chemokine ◽  
Hiv 1

Abstract The chemokine receptor, CXCR4, serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus (HIV). Binding of either the CXC-chemokine, stromal-derived factor 1α (SDF-1α), or a CXCR4 antagonist, AMD3100, to CXCR4 inhibits infection of CD4+ T cells by T-tropic HIV-1, although only SDF-1α triggers T-cell signaling cascades. We have previously demonstrated that ligation of CD4 by T-cell tropic HIV-1 NL4-3 induces metalloproteinase-dependent L-selectin (CD62L) shedding on resting CD4+ T cells. However, the role of CXCR4 in HIV-induced L-selectin shedding is unclear. Here, we show that L-selectin shedding induced by HIV-1 NL4-3 is completely reversed by AMD3100, but not SDF-1α, although SDF-1α alone does not induce L-selectin shedding. These results indicate that engagement of both CD4 and CXCR4 is required for HIV-induced shedding of L-selectin on primary resting CD4+ T cells.

scholarly journals Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

2019 ◽  
Author(s):  
Birgitta Lindqvist ◽  
Sara Svensson Akusjarvi ◽  
Anders Sonnerborg ◽  
Marios Dimitriou ◽  
J. Peter Svensson
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Active Transcription ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active replication comprises only cells with intact provirus that can be reactivated. We confirmed that latently infected cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of viral latency during proviral chromatin maturation in cultures of primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.

scholarly journals Alpha Interferon Potently Enhances the Anti-Human Immunodeficiency Virus Type 1 Activity of APOBEC3G in Resting Primary CD4 T Cells

2006 ◽  
Vol 80 (15) ◽  
pp. 7645-7657 ◽  
Author(s):  
Keyang Chen ◽  
Jialing Huang ◽  
Chune Zhang ◽  
Sophia Huang ◽  
Giuseppe Nunnari ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Innate Immunity ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT The interferon (IFN) system, including various IFNs and IFN-inducible gene products, is well known for its potent innate immunity against wide-range viruses. Recently, a family of cytidine deaminases, functioning as another innate immunity against retroviral infection, has been identified. However, its regulation remains largely unknown. In this report, we demonstrate that through a regular IFN-α/β signal transduction pathway, IFN-α can significantly enhance the expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) in human primary resting but not activated CD4 T cells and the amounts of APOBEC3G associated with a low molecular mass. Interestingly, short-time treatments of newly infected resting CD4 T cells with IFN-α will significantly inactivate human immunodeficiency virus type 1 (HIV-1) at its early stage. This inhibition can be counteracted by APOBEC3G-specific short interfering RNA, indicating that IFN-α-induced APOBEC3G plays a key role in mediating this anti-HIV-1 process. Our data suggest that APOBEC3G is also a member of the IFN system, at least in resting CD4 T cells. Given that the IFN-α/APOBEC3G pathway has potent anti-HIV-1 capability in resting CD4 T cells, augmentation of this innate immunity barrier could prevent residual HIV-1 replication in its native reservoir in the post-highly active antiretroviral therapy era.

scholarly journals Productive Infection of Plasmacytoid Dendritic Cells with Human Immunodeficiency Virus Type 1 Is Triggered by CD40 Ligation

2002 ◽  
Vol 76 (21) ◽  
pp. 11033-11041 ◽  
Author(s):  
Lawrence Fong ◽  
Manuela Mengozzi ◽  
Nancy W. Abbey ◽  
Brian G. Herndier ◽  
Edgar G. Engleman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
Cd40 Ligand ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Immature plasmacytoid dendritic cells are the principal alpha interferon-producing cells (IPC), responsible for primary antiviral immunity. IPC express surface molecules CD4, CCR5, and CXCR4, which are known coreceptors required for human immunodeficiency virus (HIV) infection. Here we show that IPC are susceptible to and replicate HIV type 1 (HIV-1). Importantly, viral replication is triggered upon activation of IPC with CD40 ligand, a signal physiologically delivered by CD4 T cells. Immunohistochemical staining of tonsil from HIV-infected individuals reveals HIV p24+ IPC, consistent with in vivo infection of these cells. IPC exposed in vitro to HIV produce alpha interferon, which partially inhibits viral replication. Nevertheless, IPC efficiently transmit HIV-1 to CD4 T-cells, and such transmission is also augmented by CD40 ligand activation. IPC produce RANTES/CCL5 and MIP-1α/CCL3 when exposed to HIV in vitro. IPC also induce naïve CD4 T cells to proliferate and would therefore preferentially infect these cells. These results indicate that IPC may play an important role in the dissemination of HIV.

scholarly journals TRIM5α Restriction Affects Clinical Outcome and Disease Progression in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2014 ◽  
Vol 89 (4) ◽  
pp. 2233-2240 ◽  
Author(s):  
Fan Wu ◽  
Ilnour Ourmanov ◽  
Nadeene Riddick ◽  
Kenta Matsuda ◽  
Sonya Whitted ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Survival Rate ◽  
Disease Progression ◽  
Gene Modification ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTTripartite motif-containing protein 5α (TRIM5α) is considered to be a potential target for cell-based gene modification therapy against human immunodeficiency virus type 1 (HIV-1) infection. In the present study, we used a relevant rhesus macaque model of infection with simian immunodeficiency virus from sooty mangabey (SIVsm) to evaluate the effect of TRIM5α restriction on clinical outcome. For macaques expressing a restrictive TRIM5 genotype, the disease outcomes of those infected with the wild-type TRIM-sensitive SIVsm strain and those infected with a virus with escape mutations in the capsid were compared. We found that TRIM5α restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, supporting the feasibility of exploiting TRIM5α as a target for gene therapy against HIV-1. Furthermore, we also found that preservation of memory CD4 T cells was associated with protection by TRIM5α restriction, suggesting memory CD4 T cells or their progenitor cells as an ideal target for gene modification. Despite the significant effect of TRIM5α restriction on survival, SIV escape from TRIM5α restriction was also observed; therefore, this may not be an effective stand-alone strategy and may require combination with other targets.IMPORTANCERecent studies suggest that it may be feasible not only to suppress viral replication with antiviral drugs but also potentially to eliminate or “cure” human immunodeficiency virus (HIV) infection. One approach being explored is the use of gene therapy to introduce genes that can restrict HIV replication, including a restrictive version of the host factor TRIM5α. TRIM5 was identified as a factor that restricts HIV replication in macaque cells. The rhesus gene is polymorphic, and some alleles are restrictive for primary SIVsm isolates, although escape mutations arise late in infection. Introduction of these escape mutations into the parental virus conferred resistance to TRIM5 on macaques. The present study evaluated these animals for long-term outcomes and found that TRIM5α restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, suggesting that this could be a valid gene therapy approach that could be adapted for HIV.

scholarly journals Naive CD4+ T Cells Harbor a Large Inducible Reservoir of Latent, Replication-competent Human Immunodeficiency Virus Type 1

2019 ◽  
Vol 69 (11) ◽  
pp. 1919-1925 ◽  
Author(s):  
Jennifer M Zerbato ◽  
Deborah K McMahon ◽  
Michelle D Sobolewski ◽  
John W Mellors ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Virus Production ◽  
Major Barrier ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Background The latent human immunodeficiency virus type 1 (HIV-1) reservoir represents a major barrier to a cure. Based on the levels of HIV-1 DNA in naive (TN) vs resting memory CD4+ T cells, it is widely hypothesized that this reservoir resides primarily within memory cells. Here, we compared virus production from TN and central memory (TCM) CD4+ T cells isolated from HIV-1–infected individuals on suppressive therapy. Methods CD4+ TN and TCM cells were purified from the blood of 7 HIV-1–infected individuals. We quantified total HIV-1 DNA in the CD4+ TN and TCM cells. Extracellular virion-associated HIV-1 RNA or viral outgrowth assays were used to assess latency reversal following treatment with anti-CD3/CD28 monoclonal antibodies (mAbs), phytohaemagglutinin/interleukin-2, phorbol 12-myristate 13-acetate/ionomycin, prostratin, panobinostat, or romidepsin. Results HIV-1 DNA was significantly higher in TCM compared to TN cells (2179 vs 684 copies/106 cells, respectively). Following exposure to anti-CD3/CD28 mAbs, virion-associated HIV-1 RNA levels were similar between TCM and TN cells (15 135 vs 18 290 copies/mL, respectively). In 4/7 donors, virus production was higher for TN cells independent of the latency reversing agent used. Replication-competent virus was recovered from both TN and TCM cells. Conclusions Although the frequency of HIV-1 infection is lower in TN compared to TCM cells, as much virus is produced from the TN population after latency reversal. This finding suggests that quantifying HIV-1 DNA alone may not predict the size of the inducible latent reservoir and that TN cells may be an important reservoir of latent HIV-1.

scholarly journals Preferential Infection of α4β7+ Memory CD4+ T Cells During Early Acute Human Immunodeficiency Virus Type 1 Infection

2020 ◽  
Vol 71 (11) ◽  
pp. e735-e743 ◽  
Author(s):  
Andrey Tokarev ◽  
Lyle R McKinnon ◽  
Amélie Pagliuzza ◽  
Aida Sivro ◽  
Tosin E Omole ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Immunodeficiency Virus ◽  
Memory Cd4 T Cells ◽  
Hiv 1

Abstract Background Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection. Methods Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I–III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls. Results In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation. Conclusions β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells.

scholarly journals C–C Chemokines Released by Lipopolysaccharide (LPS)-stimulated Human Macrophages Suppress HIV-1 Infection in Both Macrophages and T Cells

1997 ◽  
Vol 185 (5) ◽  
pp. 805-816 ◽  
Author(s):  
Alessia Verani ◽  
Gabriella Scarlatti ◽  
Manola Comar ◽  
Eleonora Tresoldi ◽  
Simona Polo ◽  
...  
Keyword(s):  
T Cells ◽  
Inhibitory Effect ◽  
Hiv Replication ◽  
Soluble Factors ◽  
Human Macrophages ◽  
Immunodeficiency Virus ◽  
Releasing Factors ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C–C chemokines (RANTES, MIP-1α, and MIP-1β) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C–C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C–C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

HIV-1–specific CTLs effectively suppress replication of HIV-1 in HIV-1–infected macrophages

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4832-4838 ◽  
Author(s):  
Mamoru Fujiwara ◽  
Masafumi Takiguchi
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Hla Class I ◽  
The Other ◽  
Class I ◽  
Cytolytic T Lymphocytes ◽  
Down Regulation ◽  
Specific Ctls ◽  
Hiv 1

AbstractBoth CD4+ T cells and macrophages are major reservoirs of HIV-1. Previous study showed that HIV-1–specific cytolytic T lymphocytes (CTLs) hardly recognize HIV-1–infected CD4+ T cells because of Nef-mediated HLA class I down-regulation, suggesting that HIV-1 escapes from HIV-1–specific CTLs and continues to replicate in HIV-1–infected donors. On the other hand, the CTL recognition of HIV-1–infected macrophages and the effect of Nef-mediated HLA class I down-regulation on this recognition still remain unclear. We show a strong HIV-1 antigen presentation by HIV-1–infected macrophages. HIV-1–specific CTLs had strong abilities to suppress HIV-1R5 virus replication in HIV-1–infected macrophages and to kill HIV-1R5–infected macrophages. Nef-mediated HLA class I down-regulation minimally influenced the recognition of HIV-1–infected macrophages by HIV-1–specific CTLs. In addition, HIV-1–infected macrophages had a stronger ability to stimulate the proliferation of HIV-1–specific CTLs than HIV-1–infected CD4+ T cells. Thus, the effect of Nef-mediated HLA class I down-regulation was less critical with respect to the recognition by HIV-1–specific CTLs of HIV-infected macrophages than that of HIV-1–infected CD4+ T cells. These findings support the idea that the strong HIV-1 antigen presentation by HIV-1–infected macrophages is one of the mechanisms mediating effective induction of HIV-1–specific CTLs in the acute and early chronic phases of HIV-1 infection.

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