A previously described Moloney-based vector expressing a double copy anti-tat antisense tRNA (DC-tRNA-AT) (Biasolo et al., 1996. J. Virol. 70, 2154-2161) was modified to increase the copy number of the antisense molecule and to target the intra-cytoplasmic localization of the HIV genome. To this end, an anti-U5 hammerhead ribozyme, engineered as a hybrid small adenoviral VAI RNA (VAIalpha), was inserted into the vector as a single molecule or in combination with the double copy anti-tat sequence. The retroviral vector expressing only VAIalpha (DC-VAIalpha) inhibited HIV-1 replication to an extent comparable to that of DC-tRNA-AT. A more effective inhibition was produced by the vector expressing multiple copies of the anti-tat antisense (DC-6tRNA-AT). This higher effectiveness correlated with anti-tat stochiometry, i.e. with the absolute number of therapeutic molecules being produced on a per cell basis at the steady state. Surprisingly, when the tRNA-AT and VAIalpha genes were combined in the same vector (DC-AT-VAIalpha), an enhancement of viral replication was noticed. This study indicates that it is possible to potentiate the antiviral activity of a retroviral vector by increasing the steady-state level of the therapeutic molecule. Results also show that the combined expression of two singularly active therapeutic RNAs can have antagonistic rather than synergistic effects.

Additive and antagonist effects of therapeutic gene combinations for suppression of HIV-1 infection / Francesca Gennari, Maria Angela Biasolo, Enrico Cancellotti, Antonia Radaelli, Carlo De Giuli Morghen, Irene Bozzoni, Paolo Martino Cereda, Carlo Mengoli, Giorgio Palù, Cristina Parolin. - In: ANTIVIRAL RESEARCH. - ISSN 0166-3542. - 55:1(2002 Jul), pp. 77-90.

Additive and antagonist effects of therapeutic gene combinations for suppression of HIV-1 infection

Antonia Radaelli;Carlo De Giuli Morghen;
2002

Abstract

A previously described Moloney-based vector expressing a double copy anti-tat antisense tRNA (DC-tRNA-AT) (Biasolo et al., 1996. J. Virol. 70, 2154-2161) was modified to increase the copy number of the antisense molecule and to target the intra-cytoplasmic localization of the HIV genome. To this end, an anti-U5 hammerhead ribozyme, engineered as a hybrid small adenoviral VAI RNA (VAIalpha), was inserted into the vector as a single molecule or in combination with the double copy anti-tat sequence. The retroviral vector expressing only VAIalpha (DC-VAIalpha) inhibited HIV-1 replication to an extent comparable to that of DC-tRNA-AT. A more effective inhibition was produced by the vector expressing multiple copies of the anti-tat antisense (DC-6tRNA-AT). This higher effectiveness correlated with anti-tat stochiometry, i.e. with the absolute number of therapeutic molecules being produced on a per cell basis at the steady state. Surprisingly, when the tRNA-AT and VAIalpha genes were combined in the same vector (DC-AT-VAIalpha), an enhancement of viral replication was noticed. This study indicates that it is possible to potentiate the antiviral activity of a retroviral vector by increasing the steady-state level of the therapeutic molecule. Results also show that the combined expression of two singularly active therapeutic RNAs can have antagonistic rather than synergistic effects.
Settore BIO/19 - Microbiologia Generale
lug-2002
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/27997
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