A doxycycline-dependent human immunodeficiency virus type 1 replicates in vivo without inducing CD4+ T-cell depletion.
A novel genetic approach for the control of virus replication was used for the design of a conditionally replicating human immunodeficiency virus (HIV) variant, HIV-rtTA. HIV-rtTA gene expression and virus replication are strictly dependent on the presence of a non-toxic effector molecule, doxycycline (dox), and thus can be turned on and off at will in a graded and reversible manner. The in vivo replication capacity, pathogenicity and genetic stability of this HIV-rtTA variant were evaluated in a humanized mouse model of haematopoiesis that harbours lymphoid and myeloid components of the human immune system (HIS). Infection of dox-fed BALB Rag/γc HIS (BRG-HIS) mice with HIV-rtTA led to the establishment of a productive infection without CD4(+) T-cell depletion. The virus did not show any sign of escape from dox control for up to 10 weeks after the onset of infection. No reversion towards a functional Tat-transactivating responsive (TAR) RNA element axis was observed, confirming the genetic stability of the HIV-rtTA variant in vivo. These results demonstrate the proof of concept that HIV-rtTA replicates efficiently in vivo. HIV-rtTA is a promising tool for fundamental research to study virus-host interactions in vivo in a controlled fashion.
Department of Cell Biology and Histology, Center for Immunology of Amsterdam (CIA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Nicolas
N
Legrand
Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Gisela J
GJ
van der Velden
Microbiology, Immunology and Molecular Genetics, and Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
Raphaël Ho Tsong
RHT
Fang
Microbiology, Immunology and Molecular Genetics, and Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
Marc
M
Douaisi
Department of Cell Biology and Histology, Center for Immunology of Amsterdam (CIA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Kees
K
Weijer
Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Atze T
AT
Das
Department of Cell Biology and Histology, Center for Immunology of Amsterdam (CIA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Bianca
B
Blom
Microbiology, Immunology and Molecular Genetics, and Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
Christel H
CH
Uittenbogaart
Department of Cell Biology and Histology, Center for Immunology of Amsterdam (CIA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Ben
B
Berkhout
Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Mireille
M
Centlivre
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002478:Cells, Cultured; D004318:Doxycycline / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014779:Virus Replication
D004318:Doxycycline