Recruitment of the Nuclear Form of Uracil DNA Glycosylase into Virus Particles Participates in the Full Infectivity of HIV-1

INSERM, U1016, Institut Cochin, Paris, France.
Journal of Virology (Impact Factor: 4.44). 12/2011; 86(5):2533-44. DOI: 10.1128/JVI.05163-11
Source: PubMed


The HIV-1 Vpr protein participates in the early steps of the virus life cycle by influencing the accuracy of reverse transcription. This role of Vpr was related to the recruitment of the nuclear form of the uracil DNA glycosylase (UNG2) enzyme into virus particles, but several conflicting findings have been reported regarding the role of UNG2 encapsidation on viral infectivity. Here, we report that the catalytic activity of UNG2 was not required for influencing HIV-1 mutation, and this function of UNG2 was mapped within a 60-amino-acid domain located in the N-terminal region of the protein required for direct interaction with the p32 subunit of the replication protein A (RPA) complex. Importantly, enforced recruitment of overexpressed UNG2 into virions resulted in a net increase of virus infectivity, and this positive effect on infectivity was also independent of the UNG2 enzymatic activity. In contrast, virus infectivity and replication, as well as the efficiency of the viral DNA synthesis, were significantly reduced when viruses were produced from cells depleted of either endogenous UNG2 or RPA p32. Taken together, these results demonstrate that incorporation of UNG2 into virions has a positive impact on HIV-1 infectivity and replication and positively influences the reverse transcription process through a nonenzymatic mechanism involving the p32 subunit of the RPA complex.

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Available from: Louis M Mansky, Aug 25, 2014
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    • "In addition, Vpr is reported to be a component of the reverse transcription complex (RTC) and co-localizes with the viral nucleic acid and integrase within purified HIV-1 RTCs [20], [21]. Human uracil DNA glycosylase 2 (UNG2), which is an enzyme that is part of the DNA repair machinery [22], is the only protein that has been identified to date that may be involved along with Vpr in influencing HIV-1 reverse transcription [23]. However, the function of UNG2 remains controversial because various studies have reported that its impact on HIV-1 reverse transcription is negative, positive or even nil [24]–[26]. "
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    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Due to its specific incorporation into the viral particle by interaction with the Pr55Gag-derived p6 protein, Vpr is readily present upon entry of the virus into the cell, which speaks in favor for enrollment during early steps of viral replication (see Figure 1). In this regard, Vpr has been shown to influence the reverse transcription of HIV-1 via the interaction and recruitment of the human uracil DNA glycosylase 2, an enzyme of the DNA repair machinery (Guenzel et al., 2012). A relationship that is not without controversy since different research reports argue whether UNG2 might rather have a negative impact or even no impact on HIV-1 replication (Schrofelbauer et al., 2005; Kaiser and Emerman, 2006; Yang et al., 2007). "
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    • "Accumulating evidence indicates that UNG has a function other than U removal: (a) host UNG is required for HIV viral genome integration, in which UNG interacts with an integrase and DNA preintegration complex, and UNG's catalytic activity has recently been shown to be indispensable for this interaction (Guenzel et al., 2011); (b) although UNG is essential for vaccinia virus genome replication, its catalytic activity is not required (De Silva and Moss, 2003, 2008); and (c) the histone H3 variant CENP-A is required for chromosome segregation during mitosis. CENP-A assembly on DNA depends on UNG, but not on UNG's catalytic activity (Zeitlin et al., 2011). "
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