scholarly journals Expansion and Diversification of Virus-Specific T Cells following Immunization of Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals with a Recombinant Modified Vaccinia Virus Ankara/HIV-1 Gag Vaccine

2006 ◽  
Vol 80 (10) ◽  
pp. 4705-4716 ◽  
Author(s):  
Lucy Dorrell ◽  
Hongbing Yang ◽  
Beatrice Ondondo ◽  
Tao Dong ◽  
Kati di Gleria ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Human Immunodeficiency Virus Type ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Affordable therapeutic strategies that induce sustained control of human immunodeficiency virus type 1 (HIV-1) replication and are tailored to the developing world are urgently needed. Since CD8+ and CD4+ T cells are crucial to HIV-1 control, stimulation of potent cellular responses by therapeutic vaccination might be exploited to reduce antiretroviral drug exposure. However, therapeutic vaccines tested to date have shown modest immunogenicity. In this study, we performed a comprehensive analysis of the changes in virus-specific CD8+ and CD4+ T-cell responses occurring after vaccination of 16 HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara-vectored vaccine expressing the consensus HIV-1 clade A Gag p24/p17 sequences and multiple CD8+ T-cell epitopes during highly active antiretroviral therapy. We observed significant amplification and broadening of CD8+ and CD4+ gamma interferon responses to vaccine-derived epitopes in the vaccinees, without rebound viremia, but not in two unvaccinated controls followed simultaneously. Vaccine-driven CD8+ T-cell expansions were also detected by tetramer reactivity, predominantly in the CD45RA− CCR7+ or CD45RA− CCR7− compartments, and persisted for at least 1 year. Expansion was associated with a marked but transient up-regulation of CD38 and perforin within days of vaccination. Gag-specific CD8+ and CD4+ T-cell proliferation also increased postvaccination. These data suggest that immunization with MVA.HIVA is a feasible strategy to enhance potentially protective T-cell responses in individuals with chronic HIV-1 infection.

scholarly journals Induction of Potent CD8+ T-Cell Responses by Novel Biodegradable Nanoparticles Carrying Human Immunodeficiency Virus Type 1 gp120

2007 ◽  
Vol 81 (18) ◽  
pp. 10009-10016 ◽  
Author(s):  
Xin Wang ◽  
Tomofumi Uto ◽  
Takami Akagi ◽  
Mitsuru Akashi ◽  
Masanori Baba
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Memory T Cells ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mainstream of recent anti-AIDS vaccines is a prime/boost approach with multiple doses of the target DNA of human immunodeficiency virus type 1 (HIV-1) and recombinant viral vectors. In this study, we have attempted to construct an efficient protein-based vaccine using biodegradable poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs), which are capable of inducing potent cellular immunity. A significant expansion of CD8+ T cells specific to the major histocompatibility complex class I-restricted gp120 epitope was observed in mice intranasally immunized once with gp120-carrying NPs but not with gp120 alone or gp120 together with the B-subunit of cholera toxin. Both the gp120-encapsulating and -immobilizing forms of NPs could induce antigen-specific spleen CD8+ T cells having a functional profile of cytotoxic T lymphocytes. Long-lived memory CD8+ T cells could also be elicited. Although a substantial decay in the effector memory T cells was observed over time in the immunized mice, the central memory T cells remained relatively constant from day 30 to day 238 after immunization. Furthermore, the memory CD8+ T cells rapidly expanded with boosting with the same immunogen. In addition, γ-PGA NPs were found to be a much stronger inducer of antigen-specific CD8+ T-cell responses than nonbiodegradable polystyrene NPs. Thus, γ-PGA NPs carrying various HIV-1 antigens may have great potential as a novel priming and/or boosting tool in current vaccination regimens for the induction of cellular immune responses.

scholarly journals Induction of Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ and CD4+ T-Cell Reactivity by Dendritic Cells Loaded with HIV-1 X4-Infected Apoptotic Cells

2002 ◽  
Vol 76 (6) ◽  
pp. 3007-3014 ◽  
Author(s):  
Xiao-Qing Zhao ◽  
Xiao-Li Huang ◽  
Phalguni Gupta ◽  
Luann Borowski ◽  
Zheng Fan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT T-cell responses to X4 strains of human immunodeficiency virus type 1 (HIV-1) are considered important in controlling progression of HIV-1 infection. We investigated the ability of dendritic cells (DC) and various forms of HIV-1 X4 antigen to induce anti-HIV-1 T-cell responses in autologous peripheral blood mononuclear cells from HIV-1-infected persons. Immature DC loaded with HIV-1 IIIB-infected, autologous, apoptotic CD8− cells and matured with CD40 ligand induced gamma interferon production in autologous CD8+ and CD4+ T cells. In contrast, mature DC loaded with HIV-1 IIIB-infected, necrotic cells or directly infected with cell-free HIV-1 IIIB were poorly immunogenic. Thus, HIV-1-infected cells undergoing apoptosis serve as a rich source of X4 antigen for CD8+ and CD4+ T cells by DC. This may be an important mechanism of HIV-1 immunogenicity and provides a strategy for immunotherapy of HIV-1-infected patients on combination antiretroviral therapy.

scholarly journals Clinical experience with plasmid DNA- and modified vaccinia virus Ankara-vectored human immunodeficiency virus type 1 clade A vaccine focusing on T-cell induction

2007 ◽  
Vol 88 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Tomáš Hanke ◽  
Andrew J. McMichael ◽  
Lucy Dorrell
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Cell Induction ◽  
Hiv 1

Candidate human immunodeficiency virus type 1 (HIV-1) vaccines focusing on T-cell induction, constructed as pTHr.HIVA DNA and modified vaccinia virus Ankara (MVA).HIVA, were delivered in a heterologous prime–boost regimen. The vaccines were tested in several hundred healthy or HIV-1-infected volunteers in Europe and Africa. Whilst larger trials of hundreds of volunteers suggested induction of HIV-1-specific T-cell responses in <15 % of healthy vaccinees, a series of small, rapid trials in 12–24 volunteers at a time with a more in-depth analysis of vaccine-elicited T-cell responses proved to be highly informative and provided more encouraging results. These trials demonstrated that the pTHr.HIVA vaccine alone primed consistently weak and mainly CD4+, but also CD8+ T-cell responses, and the MVA.HIVA vaccine delivered a consistent boost to both CD4+ and CD8+ T cells, which was particularly strong in HIV-1-infected patients. Thus, whilst the search is on for ways to enhance T-cell priming, MVA is a useful boosting vector for human subunit genetic vaccines.

scholarly journals Human Immunodeficiency Virus Type 1 Escapes from Interleukin-2-Producing CD4+ T-Cell Responses without High-Frequency Fixation of Mutations

2009 ◽  
Vol 83 (17) ◽  
pp. 8722-8732 ◽  
Author(s):  
R. Brad Jones ◽  
Feng-Yun Yue ◽  
Xiao Xiao Jenny Gu ◽  
Diana V. Hunter ◽  
Shariq Mujib ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The presence of interleukin-2 (IL-2)-producing human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T-cell responses has been associated with the immunological control of HIV-1 replication; however, the causal relationship between these factors remains unclear. Here we show that IL-2-producing HIV-1-specific CD4+ T cells can be cloned from acutely HIV-1-infected individuals. Despite the early presence of these cells, each of the individuals in the present study exhibited progressive disease, with one individual showing rapid progression. In this rapid progressor, three IL-2-producing HIV-1 Gag-specific CD4+ T-cell responses were identified and mapped to the following optimal epitopes: HIVWASRELER, REPRGSDIAGT, and FRDYVDRFYKT. Responses to these epitopes in peripheral blood mononuclear cells were monitored longitudinally to >1 year postinfection, and contemporaneous circulating plasma viruses were sequenced. A variant of the FRDYVDRFYKT epitope sequence, FRDYVDQFYKT, was observed in 1/21 plasma viruses sequenced at 5 months postinfection and 1/10 viruses at 7 months postinfection. This variant failed to stimulate the corresponding CD4+ T-cell clone and thus constitutes an escape mutant. Responses to each of the three Gag epitopes were rapidly lost, and this loss was accompanied by a loss of antigen-specific cells in the periphery as measured by using an FRDYVDRFYKT-presenting major histocompatibility complex class II tetramer. Highly active antiretroviral therapy was associated with the reemergence of FRDYVDRFYKT-specific cells by tetramer. Thus, our data support that IL-2-producing HIV-1-specific CD4+ T-cell responses can exert immune pressure during early HIV-1 infection but that the inability of these responses to enforce enduring control of viral replication is related to the deletion and/or dysfunction of HIV-1-specific CD4+ T cells rather than to the fixation of escape mutations at high frequencies.

scholarly journals CD8+ T-Cell Gamma Interferon Production Specific for Human Immunodeficiency Virus Type 1 (HIV-1) in HIV-1-Infected Subjects

2000 ◽  
Vol 7 (2) ◽  
pp. 279-287 ◽  
Author(s):  
Xiao-Li Huang ◽  
Zheng Fan ◽  
Christine Kalinyak ◽  
John W. Mellors ◽  
Charles R. Rinaldo
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Single Cell ◽  
Human Immunodeficiency Virus Type ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT The CD8+-T-cell response to human immunodeficiency virus type 1 (HIV-1) is considered to be important in host control of infection and prevention of AIDS. We have developed a single-cell enzyme immunoassay (enzyme-linked immunospot assay) specific for gamma interferon (IFN-γ) production stimulated by either autologous B-lymphoblastoid cell lines (B-LCL) infected with vaccinia virus vectors expressing HIV-1 proteins or synthetic peptides representing known HIV-1 CD8+ cytotoxic T-lymphocyte (CTL) epitopes. Single-cell IFN-γ production stimulated by HIV-1 Gag-, Pol-, and Env-expressing B-LCL was a reliable measure of HIV-1-specific T-cell immunity in peripheral blood CD8+ T cells from HIV-1 infected individuals. This method was more sensitive than stimulation of IFN-γ by direct infection of the cultures with HIV-1–vaccinia virus vectors. Comparable results were found for IFN-γ production in CD8+ T cells from HIV-1-negative, cytomegalovirus (CMV)-seropositive, healthy donors stimulated with B-LCL expressing the CMV pp65 lower matrix protein. HIV-1 peptides were immunodominant for both CD8+ single-cell IFN-γ production and CTL precursor frequencies. The number of cells producing IFN-γ decreased in individuals with late-stage HIV-1 infection and was temporally enhanced during combination antiretroviral therapy with two reverse transcriptase nucleoside inhibitors and a protease inhibitor.

scholarly journals Enhanced immunogenicity using an alphavirus replicon DNA vaccine against human immunodeficiency virus type 1

2005 ◽  
Vol 86 (2) ◽  
pp. 349-354 ◽  
Author(s):  
Eva K. L. Nordström ◽  
Mattias N. E. Forsell ◽  
Christina Barnfield ◽  
Eivor Bonin ◽  
Tomas Hanke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Dna Vaccine ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Semliki Forest Virus ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

With the human immunodeficiency virus type 1 (HIV-1) epidemic expanding at increasing speed, development of a safe and effective vaccine remains a high priority. One of the most central vaccine platforms considered is plasmid DNA. However, high doses of DNA and several immunizations are typically needed to achieve detectable T-cell responses. In this study, a Semliki Forest virus replicon DNA vaccine designed for human clinical trials, DREP.HIVA, encoding an antigen that is currently being used in human trials in the context of a conventional DNA plasmid, pTHr.HIVA, was generated. It was shown that a single immunization of DREP.HIVA stimulated HIV-1-specific T-cell responses in mice, suggesting that the poor immunogenicity of conventional DNA vaccines may be enhanced by using viral replicon-based plasmid systems. The results presented here support the evaluation of Semliki Forest virus replicon DNA vaccines in non-human primates and in clinical studies.

scholarly journals Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
CB Baumler ◽  
T Bohler ◽  
I Herr ◽  
A Benner ◽  
PH Krammer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

scholarly journals Human Immunodeficiency Virus Type 1 Derived from Cocultures of Immature Dendritic Cells with Autologous T Cells Carries T-Cell-Specific Molecules on Its Surface and Is Highly Infectious

1999 ◽  
Vol 73 (4) ◽  
pp. 3449-3454 ◽  
Author(s):  
Ines Frank ◽  
Laco Kacani ◽  
Heribert Stoiber ◽  
Hella Stössel ◽  
Martin Spruth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT During the budding process, human immunodeficiency virus type 1 (HIV-1) acquires cell surface molecules; thus, the viral surface of HIV-1 reflects the antigenic pattern of the host cell. To determine the source of HIV-1 released from cocultures of dendritic cells (DC) with T cells, immature DC (imDC), mature DC (mDC), T cells, and their cocultures were infected with different HIV-1 isolates. The macrophage-tropic HIV-1 isolate Ba-L allowed viral replication in both imDC and mDC, whereas the T-cell-line-tropic primary isolate PI21 replicated in mDC only. By a virus capture assay, HIV-1 was shown to carry a T-cell- or DC-specific cell surface pattern after production by T cells or DC, respectively. Upon cocultivation of HIV-1-pulsed DC with T cells, HIV-1 exclusively displayed a typical T-cell pattern. Additionally, functional analysis revealed that HIV-1 released from imDC–T-cell cocultures was more infectious than HIV-1 derived from mDC–T-cell cocultures and from cultures of DC, T cells, or peripheral blood mononuclear cells alone. Therefore, we conclude that the interaction of HIV-1-pulsed imDC with T cells in vivo might generate highly infectious virus which primarily originates from T cells.

scholarly journals Control of Viremia and Prevention of Simian-Human Immunodeficiency Virus-Induced Disease in Rhesus Macaques Immunized with Recombinant Vaccinia Viruses plus Inactivated Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Particles

2003 ◽  
Vol 77 (2) ◽  
pp. 1163-1174 ◽  
Author(s):  
Ronald L. Willey ◽  
Russ Byrum ◽  
Michael Piatak ◽  
Young B. Kim ◽  
Michael W. Cho ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Recombinant Vaccinia ◽  
Immunodeficiency Virus ◽  
Vaccinia Viruses ◽  
Hiv 1

ABSTRACT An effective vaccine against the human immunodeficiency virus type 1 (HIV-1) will very likely have to elicit both cellular and humoral immune responses to control HIV-1 strains of diverse geographic and genetic origins. We have utilized a pathogenic chimeric simian-human immunodeficiency virus (SHIV) rhesus macaque animal model system to evaluate the protective efficacy of a vaccine regimen that uses recombinant vaccinia viruses expressing simian immunodeficiency virus (SIV) and HIV-1 structural proteins in combination with intact inactivated SIV and HIV-1 particles. Following virus challenge, control animals experienced a rapid and complete loss of CD4+ T cells, sustained high viral loads, and developed clinical disease by 17 to 21 weeks. Although all of the vaccinated monkeys became infected, they displayed reduced postpeak viremia, had no significant loss of CD4+ T cells, and have remained healthy for more than 15 months postinfection. CD8+ T-cell and neutralizing antibody responses in vaccinated animals following challenge were demonstrable. Despite the control of disease, virus was readily isolated from the circulating peripheral blood mononuclear cells of all vaccinees at 22 weeks postchallenge, indicating that immunologic control was incomplete. Virus recovered from the animal with the lowest postchallenge viremia generated high virus loads and an irreversible loss of CD4+ T-cell loss following its inoculation into a naïve animal. These results indicate that despite the protection from SHIV-induced disease, the vaccinated animals still harbored replication-competent and pathogenic virus.

scholarly journals Production of a Dendritic Cell-Based Vaccine Containing Inactivated Autologous Virus for Therapy of Patients with Chronic Human Immunodeficiency Virus Type 1 Infection

2008 ◽  
Vol 16 (2) ◽  
pp. 233-240 ◽  
Author(s):  
Theresa L. Whiteside ◽  
Paolo Piazza ◽  
Amanda Reiter ◽  
Joanna Stanson ◽  
Nancy C. Connolly ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Human Immunodeficiency Virus Type ◽  
Endogenous Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In preparation for a pilot clinical trial in patients with chronic human immunodeficiency virus type 1 (HIV-1) infection, a novel dendritic cell (DC)-based vaccine is being manufactured. The trial will test the hypothesis that isolated endogenous virus presented by DCs serves as a potent immunogen for activation of CD8+ and CD4+ T cells specific for a broad range of autologous HIV-1 antigens. Production of the vaccine under good manufacture practice conditions involves (i) autologous virus isolation; (ii) superinfection of CD4+ T cells with the virus; (iii) inactivation of the virus in CD4+ T cells, T-cell apoptosis, and coincubation of T cells with autologous DCs; and (iv) product testing and release. Endogenous virus was isolated from peripheral blood-derived CD4+ T cells of three HIV-1-positive subjects by coincubation with autologous OKT-3-stimulated CD4+ T cells. CD4+ T-cell supernatants were tested for p24 levels by enzyme-linked immunosorbent assay (>25 ng/ml) and for the 50% tissue culture infective doses (TCID50; which ranged from 4,642 to 46,416/ml on day 19 of culture). Autologous CD4+ T cells that were separated on immunobeads (>95% purity) and superinfected with virus-expressed p24 (28 to 54%) had TCID50 of >400/ml on days 5 to 10. Virus inactivation with psoralen (20 μg/ml) and UVB irradiation (312 nm) reduced the TCID50 of the supernatants from 199,986 to 11/ml (>99%). 7-Amino-actinomycin D-positive, annexin V-positive CD4+ T cells were fed to autologous DCs generated by using the Elutra cell separation system and the Aastrom system. Flow analysis showed that DC loading was complete in 24 h. On the basis of these translational results and experience with the generation of DCs from HIV-1-infected patients in a previous clinical trial, the Investigational New Drug application for clinical vaccination was submitted and approved by the FDA (application no. BB-IND-13137).

Sign in / Sign up

Export Citation Format

Share Document