MLV-derived retroviral vectors selective for CD4-expressing cells and resistant to neutralization by sera from HIV-infected patients.
Retroviral vectors derived from amphotropic murine leukemia viruses (MLV) mediate gene transfer into almost all human cells and are thus not suitable for in vivo applications in gene therapy in which cell-specific gene delivery is required. We and others recently reported the generation of MLV-derived vectors pseudotyped by variants of the envelope glycoproteins (Env) of human immunodeficiency virus type 1 (HIV-1), thus displaying the CD4-dependent tropism of the parental lentivirus (Mammano et al., 1997, J. Virol. 71, 3341-3345; Schnierle et al., 1997, Proc. Natl. Acad. Sci. USA 76, 8640-8645). However, because of their HIV-1-derived envelopes these vectors are neutralized by HIV-specific antibodies present in some infected patients. To circumvent this problem, we pseudotyped MLV capsid particles with variants of Env proteins derived from the apathogenic simian immunodeficiency virus (SIVagm) of African green monkeys (AGM; Chlorocebus pygerythrus). Truncation of the C-terminal domain of the transmembrane protein was found to be necessary to allow formation of infectious pseudotype vectors. These [MLV(SIVagm)] vectors efficiently transduced various human CD4-expressing cell lines using the coreceptors CCR5 and Bonzo to enter target cells. Moreover, they were resistant to neutralization by antibodies directed against HIV-1. Therefore, [MLV(SIVagm)] vectors will be useful to study the mechanisms of SIVagm cell entry and for the selective gene transfer into CD4+ T-cells of AIDS patients.
Stitz
J
J
Department of Medical Biotechnology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, Langen, D-63225, Germany.
Steidl
S
S
Merget-Millitzer
H
H
König
R
R
Müller
P
P
Nocken
F
F
Engelstädter
M
M
Bobkova
M
M
Schmitt
I
I
Kurth
R
R
Buchholz
C J
CJ
Cichutek
K
K
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004274:DNA, Recombinant; D004279:DNA, Viral / Q000235:genetics; D005786:Gene Expression Regulation; D015752:Genes, env / Q000235:genetics; D014644:Genetic Variation; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D015726:Giant Cells / Q000821:virology; D015658:HIV Infections / Q000097:blood*; D006367:HeLa Cells; D006801:Humans; D007106:Immune Sera / Q000276:immunology*; D019169:Jurkat Cells; D009052:Leukemia Virus, Murine / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000502:physiology; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D011991:Receptors, Virus / Q000502:physiology; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D014407:Tumor Cells, Cultured
C106330:CXCR6 protein, human; D004274:DNA, Recombinant; D004279:DNA, Viral; D007106:Immune Sera; D019713:Receptors, CCR5; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D043562:Receptors, G-Protein-Coupled; D011991:Receptors, Virus