scholarly journals Effects of Antigen and Genetic Adjuvants on Immune Responses to Human Immunodeficiency Virus DNA Vaccines in Mice

2002 ◽  
Vol 76 (1) ◽  
pp. 243-250 ◽  
Author(s):  
Anne C. Moore ◽  
Wing-pui Kong ◽  
Bimal K. Chakrabarti ◽  
Gary J. Nabel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Dna Vaccines ◽  
Interleukin 2 ◽  
Cell Mediated Immunity ◽  
Immune Reactivity ◽  
Gm Csf ◽  
Adaptive Immune ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT The effects of genetic adjuvants on humoral and cell-mediated immunity to two human immunodeficiency virus antigens, Env and Nef, have been examined in mice. Despite similar levels of gene expression and the same gene delivery vector, the immune responses to these two gene products differed following DNA immunization. Intramuscular immunization with a Nef expression vector plasmid generated a humoral response and antigen-specific gamma interferon (IFN-γ) production but little cytotoxic-T-lymphocyte (CTL) immunity. In contrast, immunization with an Env vector stimulated CTL activity but did not induce a high-titer antibody response. The ability to modify these antigen-specific immune responses was investigated by coinjection of DNA plasmids encoding cytokine and/or hematopoietic growth factors, interleukin-2 (IL-2), IL-12, IL-15, Flt3 ligand (FL), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Coadministration of these genes largely altered the immune responses quantitatively but not qualitatively. IL-12 induced the greatest increase in IFN-γ and immunoglobulin G responses to Nef, and GM-CSF induced the strongest IFN-γ and CTL responses to Env. A dual approach of expanding innate immunity by administering the FL gene, together with a cytokine that enhances adaptive immune responses, IL-2, IL-12, or IL-15, generated the most potent immune response at the lowest doses of Nef antigen. These findings suggest that intrinsic properties of the antigen determine the character of immune reactivity for this method of immunization and that specific combination of innate and adaptive immune cytokine genes can increase the magnitude of the response to DNA vaccines.

scholarly journals In Vitro Cell-Mediated Immune Responses of Human Immunodeficiency Virus-Infected and -Uninfected Individuals to Whole Cytomegalovirus Antigens and Their Subunits

2008 ◽  
Vol 15 (9) ◽  
pp. 1398-1409 ◽  
Author(s):  
A. Weinberg ◽  
J. Spritzler ◽  
M. Nokta ◽  
R. Schrier ◽  
A. Landay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Interleukin 2 ◽  
Cell Mediated Immunity ◽  
Hiv Replication ◽  
Hiv Rna ◽  
Highly Sensitive ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Cd4 Cell

ABSTRACT The aim of this study was to optimize the ability to detect cytomegalovirus (CMV)-specfic cell-mediated immunity (CMI) in human immunodeficiency virus (HIV)-infected individuals by comparing different assays (the lymphocyte proliferation assay [LPA] and assays for gamma interferon [IFN-γ] and interleukin-2 [IL-2] production) and CMV antigenic preparations. Thresholds discriminating positive from negative CMI results were developed with specimens from 36 CMV-seropositive and 21 CMV-seronegative healthy individuals. The analysis showed that the CMI elicited by any of the four CMV whole lysates tested in this study tended to be more robust and sensitive than the responses to the subunit antigens gB and pp65. LPA and inducible IFN-γ but not IL-2 were highly sensitive measures of CMV-specific CMI in HIV-infected and -uninfected individuals. The ability to detect CMV-specific LPA or IFN-γ responses in HIV-infected individuals significantly increased with higher CD4 cell numbers. Nevertheless, the proportion of HIV-infected subjects with CD4 counts of ≥500 cells/μl who had a detectable CMV-specific CMI remained significantly lower than that of healthy adults. The ability to detect CMV-specific CMI in HIV-infected individuals decreased with higher levels of HIV replication, with discriminative thresholds of 103 to 104 HIV RNA copies/ml of plasma, for LPA or inducible IFN-γ production elicited by different antigens. The LPA responses obtained with CMV whole lysate and phytohemagglutinin were significantly correlated in HIV-infected subjects but not uninfected controls, indicating a novel characteristic of the CMI defect caused by HIV. The intrasubject variabilities of the CMV-specific CMI were similar in HIV-infected and -uninfected individuals. These data show that LPA and the inducible IFN-γ production elicited by CMV whole lysates may be used to assess modifications of the immune competency of HIV-infected individuals.

scholarly journals Human Immunodeficiency Virus Type 1 Controllers but Not Noncontrollers Maintain CD4 T Cells Coexpressing Three Cytokines

2007 ◽  
Vol 81 (21) ◽  
pp. 12071-12076 ◽  
Author(s):  
Sunil Kannanganat ◽  
Bill G. Kapogiannis ◽  
Chris Ibegbu ◽  
Lakshmi Chennareddi ◽  
Paul Goepfert ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd4 T Cells ◽  
Strong Association ◽  
Interleukin 2 ◽  
Inverse Correlation ◽  
Necrosis Factor Alpha ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
And Control

ABSTRACT Here, we evaluate the cytokine coexpression profiles of human immunodeficiency virus (HIV)-specific CD4 T cells for the expression of the cytokines gamma interferon (IFN-γ), interleukin-2, and tumor necrosis factor alpha. In controllers, CD4 T cells producing three or two cytokines (triple producers and double producers, respectively) represented >50% of the total response. In contrast, in noncontrollers ∼75% of responding cells produced only one cytokine (single producers), mostly IFN-γ. Cells producing three cytokines were functionally superior to those producing single cytokines and showed an inverse correlation (P < 0.001) with viral load. These results demonstrate a strong association between the maintenance of highly functional CD4 T cells producing three cytokines and control of HIV-1.

scholarly journals Comparison of Human and Rhesus Macaque T-Cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens

2009 ◽  
Vol 83 (11) ◽  
pp. 5881-5889 ◽  
Author(s):  
Petra Mooij ◽  
Sunita S. Balla-Jhagjhoorsingh ◽  
Niels Beenhakker ◽  
Patricia van Haaften ◽  
Ilona Baak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Effector Memory ◽  
Data Set ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-γ) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4+ and CD8+ T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-γ, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-γ T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

scholarly journals Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus

2007 ◽  
Vol 204 (11) ◽  
pp. 2733-2746 ◽  
Author(s):  
Marcin Kwissa ◽  
Rama R. Amara ◽  
Harriet L. Robinson ◽  
Bernard Moss ◽  
Sefik Alkan ◽  
...  
Keyword(s):  
T Cells ◽  
Dna Vaccine ◽  
Dna Vaccines ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
Flt3 Ligand ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Ifn Γ

DNA vaccines offer promising strategies for immunization against infections. However, their clinical use requires improvements in immunogenicity. We explored the efficacy of Toll-like receptor (TLR) ligands (TLR-Ls) on augmenting the immunogenicity of a DNA prime–modified vaccinia virus Ankara (MVA) boost vaccine against SIV. Rhesus macaques were injected with Fms-like tyrosine kinase 3 (Flt3)–ligand (FL) to expand dendritic cells (DCs) and were primed with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7/8. Subsequently, the animals were boosted with DNA and twice with recombinant MVA expressing the same antigens. TLR9-L (CpG DNA) mediated activation of DCs in vivo and enhanced the magnitude of antigen-specific CD8+ interferon (IFN) γ+ T cells and polyfunctional CD8+ T cells producing IFN-γ, tumor necrosis factor α, and interleukin 2. Although this trial was designed primarily as an immunogenicity study, we challenged the animals with pathogenic SIVmac251 and observed a reduction in peak viremia and cumulative viral loads in the TLR9-L plus FL-adjuvanted group relative to the unvaccinated group; however, the study design precluded comparisons between the adjuvanted groups and the group vaccinated with DNA/MVA alone. Viral loads were inversely correlated with the magnitude and quality of the immune response. Thus, the immunogenicity of DNA vaccines can be augmented with TLR9-L plus FL.

scholarly journals Induction of Potent Immune Responses by Cationic Microparticles with Adsorbed Human Immunodeficiency Virus DNA Vaccines

2001 ◽  
Vol 75 (19) ◽  
pp. 9037-9043 ◽  
Author(s):  
Derek O'Hagan ◽  
Manmohan Singh ◽  
Mildred Ugozzoli ◽  
Carl Wild ◽  
Susan Barnett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Guinea Pigs ◽  
Dna Vaccines ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Combination Vaccine ◽  
Enzyme Linked Immunosorbent Assay ◽  
Naked Dna ◽  
Immunodeficiency Virus

ABSTRACT The effectiveness of cationic microparticles with adsorbed DNA at inducing immune responses was investigated in mice, guinea pigs, and rhesus macaques. Plasmid DNA vaccines encoding human immunodeficiency virus (HIV) Gag and Env adsorbed onto the surface of cationic poly(lactide-coglycolide) (PLG) microparticles were shown to be substantially more potent than corresponding naked DNA vaccines. In mice immunized with HIV gag DNA, adsorption onto PLG increased CD8+ T-cell and antibody responses by ∼100- and ∼1,000-fold, respectively. In guinea pigs immunized with HIV env DNA adsorbed onto PLG, antibody responses showed a more rapid onset and achieved markedly higher enzyme-linked immunosorbent assay and neutralizing titers than in animals immunized with naked DNA. Further enhancement of antibody responses was observed in animals vaccinated with PLG/DNA microparticles formulated with aluminum phosphate. The magnitude of anti-Env antibody responses induced by PLG/DNA particles was equivalent to that induced by recombinant gp120 protein formulated with a strong adjuvant, MF-59. In guinea pigs immunized with a combination vaccine containing HIVenv and HIV gag DNA plasmids on PLG microparticles, substantially superior antibody responses were induced against both components, as measured by onset, duration, and titer. Furthermore, PLG formulation overcame an apparent hyporesponsiveness of the env DNA component in the combination vaccine. Finally, preliminary data in rhesus macaques demonstrated a substantial enhancement of immune responses afforded by PLG/DNA. Therefore, formulation of DNA vaccines by adsorption onto PLG microparticles is a powerful means of increasing vaccine potency.

scholarly journals Human Immunodeficiency Virus Type 1-Specific Immune Responses in Primates upon Sequential Immunization with Adenoviral Vaccine Carriers of Human and Simian Serotypes

2004 ◽  
Vol 78 (14) ◽  
pp. 7392-7399 ◽  
Author(s):  
A. Reyes-Sandoval ◽  
J. C. Fitzgerald ◽  
R. Grant ◽  
S. Roy ◽  
Z. Q. Xiang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Immune Responses ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Immunodeficiency Virus ◽  
Adenoviral Vaccine

ABSTRACT Two triple immunization vaccine regimens with adenoviral vectors with E1 deleted expressing Gag of human immunodeficiency virus type 1 were tested for induction of T- and B-cell-mediated-immune responses in mice and in nonhuman primates. The vaccine carriers were derived from distinct serotypes of human and simian adenoviruses that fail to elicit cross-neutralizing antibodies expected to dampen the effect of booster immunizations. Both triple immunization regimens induced unprecedented frequencies of gamma interferon-producing CD8+ T cells to Gag in mice and monkeys that remained remarkably stable over time. In addition, monkeys developed Gag-specific interleukin-2-secreting T cells, presumably belonging to the CD4+ T-cell subset, and antibodies to both Gag and the adenoviral vaccine carriers.

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