AIDSWEEKLY Plus; Monday, April 13 & 20, 1998
Daniel J. DeNoon, Senior Editor
Feline immunodeficiency virus (FIV) is a scourge of pet cats, possibly infecting up to one out of five of the domestic animals (Felis catus). FIV is transmitted by bites, but never to humans: an extensive history of human exposure has never led to an infection.
This history could save lengthy and expensive primate and human tests if an FIV vector could be used in vaccines, gene therapies, or human-cell-line production of bioactive molecules.
Such a vector has been created.
"Promoter substitution enabled an env-deleted, three-plasmid, human cell-FIV lentiviral vector system to express high levels of FIV proteins and FIV vectors in human cells," announced Eric M. Poeschla and colleagues of the University of California San Diego.
Poeschla et al. reported their findings in the journal Nature Medicine ("Efficient Transduction of Nondividing Human Cells by Feline Immunodeficiency Virus Lentiviral Vectors," Nature Med, 1998:4(3):354- 357).
FIV is only a distant cousin of HIV, having diverged from the HIV evolutionary tree long before the human pathogen split off from primate lentiviruses. It is incapable of infecting human cells; and if artificially introduced into human cells it cannot replicate or even express its genetic material.
However, Poeschla et al. showed that the inability of FIV to express its genome in human cells depends entirely on the U3 element within the 5' long terminal repeat element (LTR) of FIV. Replacement of U3 with the cytomegalovirus (CMV) immediate early gene promoter sequence yielded the plasmid CT5b, which could infect human cells.
"CT5b was used as the starting point for constructing retroviral vectors containing internally promoted marker gene cassettes that replace pol, env, and the accessory genes as well as a portion of gag," they wrote. "Vesicular stomatitis virus glycoprotein G (VSV-G)- pseudotyped vectors were produced."
Various pseudotyped FIV vectors were capable of transfecting human cells that were dividing, growth-arrested, or postmitotic. Transduction could be achieved in primary human monocyte-derived macrophages and postmitotic human neurons. No FIV structural gene sequences could be detected.
Poeschla et al. suggested that FIV vectors have unique advantages over primate lentiviruses, even HIV vectors with nonstructural protein genes deleted.
"For eventual human clinical use, FIV vectors may have advantages," they wrote. "The determinants of HIV pathogenicity are incompletely understood. Primate lentiviruses deleted in multiple nonstructural genes have been shown to cause disease in infant primates and more recently even in adult animals. Given the extensive, safe human exposure to FIV, vectors derived from this lentivirus may represent a safer alternative to HIV vectors, even those deleted in nonstructural proteins."
Final questions about FIV safety easily can be addressed in nonhuman primates, Poeschla et al. noted.
This work was supported by grants 3K12-DK01408-10S1, 1U19 AI3661203 (SPIRAT), AND 2P30AI3621404 (CFAR).
The corresponding author for this study is Eric M. Poeschla, Department of Medicine, 0655, University of California San Diego, La Jolla, California 92093-0655. Email: <epoeschla@ucsd.edu>.
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