Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G

Darja Pollpeter, Maddy Parsons, Andrew Sobala, Sashika Coxhead, Rupert D. Lang, Annie M. Bruns, Stelios Papaioannou, James M. McDonnell, Luis Apolonia, Jamil A. Chowdhury, Curt M. Horvath, Michael Malim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)
213 Downloads (Pure)


Following cell entry, the RNA genome of HIV-1 is reverse transcribed into double-stranded DNA that ultimately integrates into the host-cell genome to establish the provirus. These early phases of infection are notably vulnerable to suppression by a collection of cellular antiviral effectors, called restriction or resistance factors. The host antiviral protein APOBEC3G (A3G) antagonizes the early steps of HIV-1 infection through the combined effects of inhibiting viral cDNA production and cytidine-to-uridine-driven hypermutation of this cDNA. In seeking to address the underlying molecular mechanism for inhibited cDNA synthesis, we developed a deep sequencing strategy to characterize nascent reverse transcription products and their precise 3′-termini in HIV-1 infected T cells. Our results demonstrate site- and sequence-independent interference with reverse transcription, which requires the specific interaction of A3G with reverse transcriptase itself. This approach also established, contrary to current ideas, that cellular uracil base excision repair (UBER) enzymes target and cleave A3G-edited uridine-containing viral cDNA. Together, these findings yield further insights into the regulatory interplay between reverse transcriptase, A3G and cellular DNA repair machinery, and identify the suppression of HIV-1 reverse transcriptase by a directly interacting host protein as a new cell-mediated antiviral mechanism.

Original languageEnglish
Pages (from-to)220-233
Number of pages14
JournalNature Microbiology
Issue number2
Early online date20 Nov 2017
Publication statusPublished - 1 Feb 2018


Dive into the research topics of 'Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G'. Together they form a unique fingerprint.

Cite this