The gene product Murr1 restricts HIV-1 replication in resting CD4+ 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.
Ganesh
Lakshmanan
L
Vaccine Research Center, NIAID, National Institutes of Health, Building 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Burstein
Ezra
E
Guha-Niyogi
Anuradha
A
Louder
Mark K
MK
Mascola
John R
JR
Klomp
Leo W J
LW
Wijmenga
Cisca
C
Duckett
Colin S
CS
Nabel
Gary J
GJ
D048868:Adaptor Proteins, Signal Transducing; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology*; D002352:Carrier Proteins; D002453:Cell Cycle; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D000072000:NF-KappaB Inhibitor alpha; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex