Delaying Reverse Transcription Does Not Increase Sensitivity of HIV-1 to Human TRIM5 alpha

作者：Battivelli Emilie; Lecossier Denise; Clavel Francois; Hance Allan J^*

来源：PLos One, 2013, 8(1): e52434.

DOI：10.1371/journal.pone.0052434

Background: Because uncoating of the capsid is linked to reverse transcription, modifications that delay this process lead to the persistence in the cytoplasm of capsids susceptible to recognition by the human restriction factor TRIM5 alpha (hTRIM5 alpha). It is unknown, however, if increasing the time available for capsid-hTRIM5 alpha interactions would actually render viruses more sensitive to hTRIM5 alpha. %26lt;br%26gt;Results: Viral sensitivity to hTRIM5 alpha was evaluated by comparing their replication in human U373-X4 cells in which hTRIM5 alpha activity had or had not been inhibited by overexpression of human TRIM5 gamma. No differences were observed comparing wildtype HIV-1 and variants carrying mutations in reverse transcriptase or the central polypurine tract that delayed the completion of reverse transcription. In addition, the effect of delaying the onset of reverse transcription for several hours by treating target cells with nevirapine was evaluated using viral isolates with different sensitivities to hTRIM5 alpha. Delaying reverse transcription led to a time-dependent loss in viral infectivity that was increased by inhibiting capsid-cyclophilin A interactions, but did not result in increased viral sensitivity to hTRIM5 alpha, regardless of their intrinsic sensitivity to this restriction factor. %26lt;br%26gt;Conclusions: Consistent with prior studies, the HIV-1 capsid can be targeted for destruction by hTRIM5 alpha, but different strains display considerable variability in their sensitivity to this restriction factor. Capsids can also be lost more slowly through a TRIM5 alpha-independent process that is accelerated when capsid-cyclophilin A interactions are inhibited, an effect that may reflect changes in the intrinsic stability of the capsid. Blocking the onset or delaying reverse transcription does not, however, increase viral sensitivity to hTRIM5 alpha, indicating that the recognition of the capsids by hTRIM5 alpha is completed rapidly following entry into the cytoplasm, as previously observed for the simian restriction factors TRIM-Cyp and rhesus TRIM5 alpha.

• 出版日期2013-1-8