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

Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, Klomp LW, Wijmenga C, Duckett CS and Nabel GJ
Source: Nature
Publication Date: (2003)
Issue: 426: 853-857
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
The authors studied the effect of Murr1 on HIV-1 replication in primary human CD4+ lymphocytes. Murr1 is a highly conserved 190-amino-acid protein which was known previously for its involvement in copper regulation. To reveal the role Murr1 on HIV-1 replication, stimulated CD4+ T cells were nucleofected with Murr1 or IkappaB super-repressor. Subsequently, transfected cells were infected with HIV-1 and rate of HIV-1 capsid protein (p24 Gag) positive cells was measured. Murr1 inhibited HIV-1 replication similar to IkappaB. The negative regulatory effect on HIV-1 was further confirmed by transfecting CD4+ lymphocytes with an siRNA construct targeted to Murr1. Cells transfected with the siRNA construct showed increased HIV-1 replication (% p24 Gag positive cells). The authors conclude that Murr1 acts as a genetic restriction factor that inhibits HIV-1 replication in lymphocytes.
Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4+ lymphocytes, the virus replicates poorly in resting T cells. Factors that block viral replication in these cells might help to prolong the asymptomatic phase of HIV infection; 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, 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)-kappaB activity. Knockdown of Murr1 increased NF-kappaB activity and decreased IkappaB-alpha concentrations by facilitating phospho-IkappaB-alpha 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.