Deakin University
Browse
mak-x4and-2010.pdf (941.33 kB)

X4 and R5 HIV-1 have distinct post-entry requirements for uracil DNA glycosylase during infection of primary cells

Download (941.33 kB)
journal contribution
posted on 2010-06-11, 00:00 authored by K Jones, M Roche, M Gantier, N Begum, T Honjo, S Caradonna, B Williams, Johnson Mak
It has been assumed that R5 and X4 HIV utilize similar strategies to support viral cDNA synthesis post viral entry. In this study, we provide evidence to show that R5 and X4 HIV have distinct requirements for host cell uracil DNA glycosylase (UNG2) during the early stage of infection. UNG2 has been previously implicated in HIV infection, but its precise role remains controversial. In this study we show that, although UNG2 is highly expressed in different cell lines, UNG2 levels are low in the natural host cells of HIV. Short interfering RNA knockdown of endogenous UNG2 in primary cells showed that UNG2 is required for R5 but not X4 HIV infection and that this requirement is bypassed when HIV enters the target cell via vesicular stomatitis virus envelope-glycoprotein-mediated endocytosis. We also show that short interfering RNA knockdown of UNG2 in virus-producing primary cells leads to defective R5 HIV virions that are unable to complete viral cDNA synthesis. Quantitative PCR analysis revealed that endogenous UNG2 levels are transiently up-regulated post HIV infection, and this increase in UNG2 mRNA is ∼10–20 times higher in R5 versus X4 HIV-infected cells. Our data show that both virion-associated UNG2 and HIV infection-induced UNG2 expression are critical for reverse transcription during R5 but not X4 HIV infection. More importantly, we have made the novel observation that R5 and X4 HIV have distinct host cell factor requirements and differential capacities to induce gene expression during the early stages of infection. These differences may result from activation of distinct signaling cascades and/or infection of divergent T-lymphocyte subpopulations.

History

Journal

Journal of biological chemistry

Volume

285

Issue

24

Pagination

18603 - 18614

Publisher

American Society for Biochemistry and Molecular Biology

Location

Bethesda, Md.

ISSN

0021-9258

eISSN

1083-351X

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2010, American Society for Biochemistry and Molecular Biology