Background:  Cytidine deaminase APOBEC3G (A3G) has broad antiviral activity against diverse retroviruses and retrotransposons and its antiviral functions rely on its virion encapsidation in a RNA-dependent fashion. However, the co-factors of A3G have not yet been identified.

Methods:  We examined RNA-dependent A3G packaging by immunoprecipitating A3G and identifying cellular partners and using real-time polymerase chain reaction (PCR) to assess RNA interaction. In addition we constructed A3G mutants and overexpressed SRP in order to inhibit A3G function.

Results:  Here we demonstrate that A3G selectively interacts with certain Pol-III-derived RNA including Y and 7SL RNA. Among A3G-binding Pol-III-derived RNA, 7SL RNA was preferentially packaged into HIV-1 particles and interacted with A3G in released virions. Efficient packaging of 7SL RNA, as well as A3G was mediated by the RNA-binding nucleocapsid domain of HIV-1 Gag. A3G mutants that had reduced 7SL RNA binding, but maintained wild type level of mRNA and tRNA binding, were packaged poorly and had impaired antiviral activity. Reducing 7SL RNA packaging by overexpression SRP19 proteins inhibited 7SL RNA and A3G virion packaging and impaired its antiviral function.

Conclusions:  Thus, 7SL RNA, which is encapsidated into diverse retroviruses, is a key co-factor of the antiviral A3G. Selective interaction of A3G with certain Pol-III-derived RNA raises the question of whether A3G and its co-factors may have yet-unidentified cellular functions.