1. Vaccine Research Center, NIAID, National Institutes of Health, Building 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, Maryland 20892-3005, USA
2. University of Michigan, Medical Science I, Room 5315, 1301 Catherine Street, Ann Arbor, Michigan 48109-0602, USA
3. University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands

Correspondence to: Gary J. Nabel¹ Email: gnabel@nih.gov

Abstract

Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4⁺ lymphocytes, the virus replicates poorly in resting T cells^{1, 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 regulation^{8, 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)-B activity. Knockdown of Murr1 increased NF-B activity and decreased IB- concentrations by facilitating phospho-IB- 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.