GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated translational inhibition

Virology. 2020 Jan 15;540:119-131. doi: 10.1016/j.virol.2019.11.010.

Mohammad Ishaq ¹, Heather Marshall ², Ven Natarajan ³

Affiliations

1 Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD, 21702, USA. Electronic address: mishaq@mail.nih.gov.
2 Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD, 21702, USA.
3 Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD, 21702, USA. Electronic address: Vnatarajan@mail.nih.gov.

PMID: 31778897 DOI: 10.1016/j.virol.2019.11.010

Abstract

Role of GADD34, a protein that is induced following cellular stress, in HIV-1 replication was investigated. GADD34 was induced during the late phase of HIV-1 Infection. siRNA-knockdown of GADD34 stimulated whereas overexpression of GADD34 inhibited HIV-1 replication. GADD34 N-terminal ER-binding-helix amino acid region 1-192 alone was found to be sufficient for the inhibition of HIV-1 replication whereas protein-phosphatase -1-binding domain and eIF-2α-phosphatase activity of GADD34 were not crucial for anti-HIV-1 activity. GADD34 did not alter the HIV-1 RNA levels but reduced the viral protein expression suggesting that GADD34 interferes in HIV protein synthesis. Studies on the effect of HIV-1-5'-UTR and its mutants on a human promoter-driven luciferase expression indicated that GADD34-inhibition was mediated by 5'-UTR/TAR RNA, probably by modulating TAR RNA structure. In summary, our data support a novel function of GADD34 as a putative anti-HIV-1 restriction factor.

Keywords

GADD34; HIV-1; HIV-1 5′-UTR; HIV-1 TAR RNA; Translation.

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