The uracil base plays a central role in intrinsic immunity against HIV-1 when it is found in DNA rather than RNA.  A well-known uracil-centric innate immune response involves the host enzyme cytidine deaminase APOBEC3G, which selectively deaminates cytosine residues during HIV-1 first strand DNA synthesis thereby rendering the viral genome nonfunctional by hypermutation.  We have uncovered another uracil-dependent HIV-1 restriction pathway that involves incorporation of dUTP into viral DNA by reverse transcriptase to produce non-mutagenic U/A base pairs (�uracilation�).  Notably, U/A pairs are �invisible� to normal DNA sequencing methods and their presence, persistence and ultimate fate in proviral DNA of infected cells is an important aspect of viral infection that is largely unknown.  Our findings show that if an infected immune cell expresses the nuclear UBER enzyme uracil DNA glycosylase (hUNG2), heavily uracilated viral DNA products will be destroyed and viral DNA integration will be blocked.  Alternatively, if a cell expresses little or no hUNG2 (such as resting CD4+ T cells and tissue macrophages), then uracilated viral DNA products will integrate efficiently, but these uracilated proviruses will persist with severely attenuated viral gene expression. Since gene silencing is the hallmark of viral latency, our results suggest that non-mutagenic uracils present within proviruses in resting cells may contribute to latency, or alternatively, may result in viral genome destruction after cell reactivation.

Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration

247th National Meeting (2014)

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