Hili Inhibits HIV Replication in Activated T Cells

Abstract

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. IMPORTANCE Piwil 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.

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…It has been reported that the expression of HERV‐R was significantly upregulated by treatment with tumor necrosis factor‐α, interleukin (IL)‐1α, and IL‐1β and downregulated by treatment with interferon (IFN)‐γ . The important role for small RNAs (such as Piwi‐interacting small RNA) in silencing ERVs via homology‐dependent mechanisms has been confirmed in mouse . However, the role of small RNAs in regulating the expression of HERVs in human needs further investigation.…”

“…70 The important role for small RNAs (such as Piwi-interacting small RNA) in silencing ERVs via homology-dependent mechanisms has been confirmed in mouse. 73,83 However, the role of small RNAs in regulating the expression of HERVs in human needs further investigation.…”

The tRNA‐associated dysregulation in immune responses and immune diseases

“…Codon usage of viral genes was reflected by the changes in polysome-associated tRNA levels, which implied the existence of local tRNA pools optimized for viral translation. 64 To demonstrate this, the researchers used an antisense oligonucleotide to specifically deplete tRNA Arg (UCU) in target cells, which inhibited HIV replication. 59 Under the catalysis of reverse transcriptase (RT), the host tRNA Lys 3 , which served as a reverse transcription primer for HIV-1, bound to the viral genomic RNA to initiate reverse transcription.…”

“…Peterlin et al discovered that P-element-induced wimpy-like 2 (Hili) protein inhibited HIV replication by binding to rare tRNAs such as tRNA Arg(UCU) and tRNA Ile(UAU) in activated CD4 + T cells. 64 To demonstrate this, the researchers used an antisense oligonucleotide to specifically deplete tRNA Arg (UCU) in target cells, which inhibited HIV replication.…”

Primate immunodeficiency virus Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex

“…To gain insight into the mechanism by which Vpx overcomes transcriptional silencing of lentiviral transgenes, a loss-of-function screen was performed focusing on genes reported to contribute to silencing of retroviruses and other transcriptional targets (Chéné et al, 2007; Peterlin et al, 2017; Tchasovnikarova et al, 2015, 2017; Wang and Goff, 2017; Weinberg and Morris, 2016; Wolf and Goff, 2007). Jurkat T cells were transduced with lentivectors that confer puromycin resistance and express shRNAs (Pertel et al, 2011b) targeting either AGO1, AGO2, AGO3, DNMT3A, HDAC1, HP1, SUV39H1, SUV39H2, PIWIL2, TRIM28, SETDB1, FAM208A, MPHOSPH8, PPHLN1, or MORC2.…”