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The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes

Abstract

Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4+ lymphocytes, the virus replicates poorly in resting T cells1,2,3,4,5,6. Factors that block viral replication in these cells might help to prolong the asymptomatic phase of HIV infection7; however, the molecular mechanisms that control this process are not fully understood. Here we show that Murr1, a gene product known previously for its involvement in copper regulation8,9, inhibits HIV-1 growth in unstimulated CD4+ T cells. This inhibition was mediated in part through its ability to inhibit basal and cytokine-stimulated nuclear factor (NF)-κB activity. Knockdown of Murr1 increased NF-κB activity and decreased IκB-α concentrations by facilitating phospho-IκB-α degradation by the proteasome. Murr1 was detected in CD4+ T cells, and RNA-mediated interference of Murr1 in primary resting CD4+ lymphocytes increased HIV-1 replication. Through its effects on the proteasome, Murr1 acts as a genetic restriction factor that inhibits HIV-1 replication in lymphocytes, which could contribute to the regulation of asymptomatic HIV infection and the progression of AIDS.

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Figure 1: Murr1 suppresses NF-κB-dependent activity from independent stimuli by acting downstream of IκB kinase.
Figure 2: Murr1 associates with the NF-κB–IκB-α complex.
Figure 3: Murr1 regulates IκB-α turnover through effects on proteasomal degradation.
Figure 4: Murr1 inhibits productive HIV-1 infection in CD4+ lymphocytes.

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Acknowledgements

We thank K. Leung for preparation of the Murr1 mutants; S. Majeed for helping with protein purifications; M. Roederer for advice in interpretation of flow cytometry data and statistical analysis; A. Tislerics, A. Gooch and T. Suhana for manuscript preparation; and K. Stroud and T. Miller for the preparation of figures. This work was supported in part by the Michigan Gastrointestinal Hormone Research Core Center (E.B.).

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Correspondence to Gary J. Nabel.

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Ganesh, L., Burstein, E., Guha-Niyogi, A. et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426, 853–857 (2003). https://doi.org/10.1038/nature02171

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