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1.
Virology ; 364(2): 245-55, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17428516

ABSTRACT

An effective HIV vaccine will likely need to induce broad and potent CTL responses. Epitope-based vaccines offer significant potential for inducing multi-specific CTL, but often require conjugation to T helper epitopes or carrier moieties to induce significant responses. We tested hybrid DNA vaccines encoding one or more HIV or SIV CTL epitopes fused to a hepatitis B core antigen (HBcAg) carrier gene as a means to improve the immunogenicity of epitope-based DNA vaccines. Immunization of mice with a HBcAg-HIV epitope DNA vaccine induced CD8(+) T cell responses that significantly exceeded levels induced with DNA encoding either the whole HIV antigen or the epitope alone. In rhesus macaques, a multi-epitope hybrid HBcAg-SIV DNA vaccine induced CTL responses to 13 different epitopes, including 3 epitopes that were previously not detected in SIV-infected macaques. These data demonstrate that immunization with hybrid HBcAg-epitope DNA vaccines is an effective strategy to increase the magnitude and breadth of HIV-specific CTL responses.


Subject(s)
HIV Antigens/genetics , HIV Antigens/immunology , Hepatitis B Core Antigens/genetics , Hepatitis B Core Antigens/immunology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Vaccines, DNA/genetics , Vaccines, DNA/immunology , AIDS Vaccines/genetics , AIDS Vaccines/immunology , Amino Acid Sequence , Animals , Chlorocebus aethiops , Epitopes/genetics , Genetic Vectors , Humans , In Vitro Techniques , Macaca mulatta , Mice , Mice, Inbred BALB C , Plasmids/genetics , SAIDS Vaccines/genetics , SAIDS Vaccines/immunology , T-Lymphocytes, Cytotoxic/immunology , Vero Cells
2.
Virology ; 348(1): 200-15, 2006 Apr 25.
Article in English | MEDLINE | ID: mdl-16439000

ABSTRACT

DNA immunization in conjunction with antiretroviral therapy was evaluated in SIV-infected rhesus macaques treated with [R]-9-[2-phosphonylmethoxypropyl]adenine (PMPA). Macaques were immunized monthly with DNA vaccines expressing either SIV gag/tat or SIV gag/tat and 19 CD8+ T cell epitopes during 7 months of therapy. Half the animals from each group were additionally immunized before infection. Only 60% of the animals (4 controls, 20 vaccinated) responded to PMPA (ART responders). All 4 ART responder controls demonstrated viral rebound or CD4 decline after PMPA was withdrawn. In contrast, 17 of 20 vaccinated ART responders contained viral rebound for over 7 months after PMPA was withdrawn. Viral control correlated with stable CD4 counts, higher lymphoproliferation and an increase in the magnitude and breadth of the CD8+ T cell response. Immunizing before infection or with multi-epitopes enhanced these effects. These results demonstrate that DNA immunization during antiretroviral therapy may be an effective strategy to treat HIV infection.


Subject(s)
Adenine/analogs & derivatives , Organophosphonates/administration & dosage , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/immunology , Vaccines, DNA/administration & dosage , Viremia/prevention & control , Adenine/administration & dosage , Adenine/therapeutic use , Animals , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Disease Progression , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Gene Products, gag/genetics , Gene Products, gag/immunology , Gene Products, tat/genetics , Gene Products, tat/immunology , Immunotherapy, Active/methods , Macaca mulatta , Organophosphonates/therapeutic use , RNA, Viral/blood , Simian Immunodeficiency Virus/drug effects , Statistics as Topic , Tenofovir , Vaccines, DNA/immunology , Withholding Treatment
3.
J Virol ; 76(9): 4536-46, 2002 May.
Article in English | MEDLINE | ID: mdl-11932419

ABSTRACT

Two plasmid vectors encoding the A and B subunits of cholera toxin (CT) and two additional vectors encoding the A and B subunits of the Escherichia coli heat-labile enterotoxin (LT) were evaluated for their ability to serve as genetic adjuvants for particle-mediated DNA vaccines administered to the epidermis of laboratory animals. Both the CT and the LT vectors strongly augmented Th1 cytokine responses (gamma interferon [IFN-gamma]) to multiple viral antigens when codelivered with DNA vaccines. In addition, Th2 cytokine responses (interleukin 4 [IL-4]) were also augmented by both sets of vectors, with the effects of the LT vectors on IL-4 responses being more antigen dependent. The activities of both sets of vectors on antibody responses were antigen dependent and ranged from no effect to sharp reductions in the immunoglobulin G1 (IgG1)-to-IgG2a ratios. Overall, the LT vectors exhibited stronger adjuvant effects in terms of T-cell responses than did the CT vectors, and this was correlated with the induction of greater levels of cyclic AMP by the LT vectors following vector transfection into cultured cells. The adjuvant effects observed in vivo were due to the biological effects of the encoded proteins and not due to CpG motifs in the bacterial genes. Interestingly, the individual LT A and B subunit vectors exhibited partial adjuvant activity that was strongly influenced by the presence or absence of signal peptide coding sequences directing the encoded subunit to either intracellular or extracellular locations. Particle-mediated delivery of either the CT or LT adjuvant vectors in rodents and domestic pigs was well tolerated, suggesting that bacterial toxin-based genetic adjuvants may be a safe and effective strategy to enhance the potency of both prophylactic and therapeutic DNA vaccines for the induction of strong cellular immunity.


Subject(s)
Adjuvants, Immunologic , Bacterial Toxins/genetics , Cholera Toxin/genetics , Enterotoxins/genetics , Escherichia coli Proteins , Genetic Vectors/administration & dosage , Vaccines, DNA/immunology , AIDS Vaccines/genetics , AIDS Vaccines/immunology , Animals , Antibodies, Viral/blood , Bacterial Toxins/administration & dosage , Caco-2 Cells , Cholera Toxin/administration & dosage , Enterotoxins/administration & dosage , HIV Envelope Protein gp120/genetics , HIV Envelope Protein gp120/immunology , Humans , Immunization , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Mice , Plasmids/genetics , Swine , T-Lymphocytes/immunology , Transfection , Vaccines, DNA/administration & dosage , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology
4.
J Virol ; 76(7): 3309-17, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11884556

ABSTRACT

An effective vaccine against human immunodeficiency virus (HIV) should protect against mucosal transmission of genetically divergent isolates. As a safe alternative to live attenuated vaccines, the immunogenicity and protective efficacy of a DNA vaccine containing simian immunodeficiency virus (SIV) strain 17E-Fr (SIV/17E-Fr) gag-pol-env was analyzed in rhesus macaques. Significant levels of cytotoxic T lymphocytes (CTL), but low to undetectable serum antibody responses, were observed following multiple immunizations. SIV-specific mucosal antibodies and CTL were also detected in rectal washes and gut-associated lymphoid tissues, respectively. Vaccinated and naive control monkeys were challenged intrarectally with SIV strain DeltaB670 (SIV/DeltaB670), a primary isolate whose env is 15% dissimilar to that of the vaccine strain. Four of seven vaccinees were protected from infection as determined by the inability to identify viral RNA or DNA sequences in the peripheral blood and the absence of anamnestic antibody responses postchallenge. This is the first report of mucosal protection against a primary pathogenic, heterologous isolate of SIV by using a commercially viable vaccine approach. These results support further development of a DNA vaccine for protection against HIV.


Subject(s)
Immunity, Mucosal , Membrane Glycoproteins , SAIDS Vaccines/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/immunology , Vaccination , Viral Envelope Proteins , Amino Acid Sequence , Animals , Antibodies, Viral/analysis , Gene Products, env/genetics , HIV Envelope Protein gp120/chemistry , HIV Envelope Protein gp120/genetics , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Intestines/immunology , Lymphoid Tissue/immunology , Macaca mulatta , Molecular Sequence Data , Rectum/immunology , Sequence Alignment , Simian Immunodeficiency Virus/genetics , T-Lymphocytes, Cytotoxic/immunology , Vaccines, DNA/administration & dosage
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