A doxycycline-dependent human immunodeficiency virus type 1 replicates in vivo without inducing CD4+ T-cell depletion

• Published in: Journal of general virology Vol. 93; no. Pt 9; pp. 2017 - 2027
• Main Authors: LEGRAND, Nicolas, VAN DER VELDEN, Gisela J, HO TSONG FANG, Raphaël, DOUAISI, Marc, WEIJER, Kees, DAS, Atze T, BLOM, Bianca, UITTENBOGAART, Christel H, BERKHOUT, Ben, CENTLIVRE, Mireille
• Format: Journal Article
• Language: English
• Published: Reading Society for General Microbiology 01.09.2012
• Subjects: Animal; Animals; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cells, Cultured; Doxycycline - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Viral; HIV Infections - immunology; HIV Infections - virology; HIV-1 - genetics; HIV-1 - physiology; Humans; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Knockout; Microbiology; Miscellaneous; Virology; Virus Replication; Virus; Antibiotic; CD4 T lymphocyte; HIV-1 virus; Doxycycline; Retroviridae; Human immunodeficiency virus; Antibacterial agent; Lentivirus
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.042796-0

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.