Hili Inhibits HIV Replication in Activated T Cells.
P-element-induced wimpy-like (Piwil) proteins restrict the replication of mobile genetic elements in the germ line. They are also expressed in many transformed cell lines. In this study, we discovered that the human Piwil 2 (Hili) protein can also inhibit HIV replication, especially in activated CD4+T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express Hili, its expression was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of Hili increased levels of viral proteins and new viral particles. Further studies revealed that Hili binds to tRNA. Some of the tRNAs represent rare tRNA species, whose codons are overrepresented in the viral genome. Targeting tRNAArg(UCU) with an antisense oligonucleotide replicated effects of Hili and also inhibited HIV replication. Finally, Hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, Hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements.IMPORTANCEPiwil proteins inhibit the movement of mobile genetic elements in the germ line. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small Piwi-interacting RNAs (piRNAs). However, in some species and in human somatic cells, Piwil proteins bind primarily to tRNA. In this report, we demonstrate that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of Hili in CD4+T cells. Since Hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements.
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
B Matija
BM
Peterlin
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Pingyang
P
Liu
Departments of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
Xiaoyun
X
Wang
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Daniele
D
Cary
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Wei
W
Shao
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Marie
M
Leoz
Department of Biochemistry and Cellular and Molecular Biology (BCMB), University of Tennessee, Knoxville, Knoxville, Tennessee, USA.
Tian
T
Hong
Departments of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
Tao
T
Pan
Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA koh.fujinaga@ucsf.edu.
Koh
K
Fujinaga
D060565:Argonaute Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D020077:Endogenous Retroviruses / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D012347:RNA, Transfer, Arg / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication
D060565:Argonaute Proteins; D016376:Oligonucleotides, Antisense; C486868:PIWIL2 protein, human; D034741:RNA, Small Interfering; D012347:RNA, Transfer, Arg; D012343:RNA, Transfer
HIV; Hili; IAP; inhibition; lentiviruses; rare codon; replication; tRNA; translation