Cytotoxic T lymphocyte and antibody responses generated in rhesus monkeys immunized with retroviral vector-transduced fibroblasts expressing human immunodeficiency virus type-1 IIIB ENV/REV proteins.
The immune response against human immunodeficiency virus type-1 (HIV-1) is believed to play a role in controlling the early stages of disease progression. The cellular immune response, in particular cytotoxic T lymphocyte (CTL) activity, may be important for eliminating virally infected cells in HIV-1-infected individuals. Genetic immunization using retroviral vectors provides an effective means of introducing antigens into the antigen presentation pathways for T cell stimulation. A nonreplicating, amphotropic murine retroviral vector containing the HIV-1 IIIB env gene has been used to transduce primary rhesus monkey fibroblasts for the expression of HIV-1 antigenic determinants. Rhesus monkeys were immunized with four doses of either vector-transduced autologous fibroblasts (VTAF) expressing the HIV-1 IIIB ENV/REV proteins or nontransduced autologous fibroblasts (NTAF) administered at 2-week intervals. The animals were evaluated for both the induction of HIV-1-specific immune responses and potential toxicity associated with this ex vivo treatment. The VTAF-immunized monkeys generated CTL responses specific for HIV-1 ENV/REV expressing autologous target cells, whereas, NTAF-immunized monkeys showed negligible CTL activity. The cytotoxic activity was mediated by CD8+, major histocompatibility complex (MHC)-restricted CTL. In addition, antibody responses directed against the HIV-1 gp120 protein were also detected in the sera of VTAF-immunized monkeys. Clinical and histopathological evaluation of immunized monkeys showed no evidence of significant adverse events. Several animals that received either VTAF or NTAF had detectable anti-cytoplasmic antibodies, but were not positive for anti-nuclear antibodies or rheumatoid factor. Subsequent evaluation of renal, synovial, and hepatic tissue samples from these monkeys revealed no autoimmune disease-associated lesions. This study demonstrates the safety and ability of autologous retroviral vector-transduced cells expressing HIV-1 IIIB ENV/REV proteins to stimulate immune responses in a non-human primate model, and provides a basis for this form of genetic immunization in HIV-infected humans.
Laube
L S
LS
Viagene, Inc., San Diego, CA 92121.
Burrascano
M
M
Dejesus
C E
CE
Howard
B D
BD
Johnson
M A
MA
Lee
W T
WT
Lynn
A E
AE
Peters
G
G
Ronlov
G S
GS
Townsend
K S
KS
D016915:AIDS Vaccines; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001327:Autoimmune Diseases / Q000209:etiology; D001402:B-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D003429:Cross Reactions; D003587:Cytomegalovirus / Q000235:genetics; D003593:Cytoplasm / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology*; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D015694:Gene Products, rev / Q000235:genetics / Q000276:immunology*; D005813:Genes, Synthetic; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000096:biosynthesis*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000009:adverse effects / Q000379:methods*; D008107:Liver Diseases / Q000209:etiology; D008253:Macaca mulatta / Q000276:immunology; D008979:Moloney murine leukemia virus / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D012217:Rheumatoid Factor / Q000032:analysis; D012449:Safety; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic; D054321:rev Gene Products, Human Immunodeficiency Virus
D016915:AIDS Vaccines; D000974:Antibodies, Antinuclear; D015686:Gene Products, env; D015694:Gene Products, rev; D015483:HIV Antibodies; D011993:Recombinant Fusion Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus; D012217:Rheumatoid Factor