Lv2, a Novel Postentry Restriction, Is Mediated by both Capsid and Envelope

Schmitz, Christian; Marchant, David; Neil, Stuart J. D.; Aubin, Keith; Reuter, Sandra; Dittmar, Matthias T.; McKnight, Áine

doi:10.1128/jvi.78.4.2006-2016.2004

Cited by 56 publications

(101 citation statements)

References 43 publications

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“…A restriction of this kind is not limited to mouse viruses. Many primates express Fv1-like activities toward a variety of retroviruses (94,95), and it has been speculated that some of the responsible inhibitors are expressed by endogenous retroviral sequences analogous to Fv1. Recently, however, the activity that blocks HIV-1 in rhesus monkey cells at the postentry, preintegration stage has been identified as the cellular protein TRIM5␣ (96).…”

Section: Biological Implications Of Retroelement Inheritancementioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

465

423

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Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

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Section: Biological Implications Of Retroelement Inheritancementioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

465

423

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“…In this paper, we examine whether the susceptibility of human immunodeficiency virus types 1 and 2 (HIV-1/2) to the Lv2 restriction factor is dependent on the route of virus delivery into the cell as previously postulated by us (33).…”

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confidence: 99%

An Envelope-Determined, pH-Independent Endocytic Route of Viral Entry Determines the Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 to Lv2 Restriction

Marchant¹,

Neil²,

Aubin³

et al. 2005

J Virol

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We identified a postentry restriction, termed Lv2, which determines the cellular tropism of two related human immunodeficiency virus type 2 (HIV-2) isolates and is dependent on the sequence of the capsid (CA) and envelope (Env) proteins. To explain the reliance on both CA and Env, we proposed that restrictive Envs deliver susceptible capsids to a compartment where Lv2 is active whereas nonrestrictive Envs deliver capsids into a compartment where Lv2 is either absent or less active. To test this model, we used compounds that affect endocytic pathways (ammonium chloride, bafilomycin A1, hypertonic sucrose) or lipid rafts (methyl-␤-cyclodextrin) to treat restrictive cells and show that restricted virus can be rescued from Lv2 if a lipid-raftdependent, pH-independent endocytic pathway is inhibited. Furthermore, viral entry into HeLa/CD4 cells containing a tailless CD4 receptor, located outside lipid rafts, was fully permissive. Finally, we show that a variety of primary HIV-1 and HIV-2 viruses are susceptible to Lv2. Thus, we show that the route of entry, determined by the viral envelope, can influence cellular tropism by avoiding intracellular blocks to infection.

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“…Involvement of cellular lipids in the post-entry restriction of HIV has been reported as Lv2 activity, where a yet-to-be-identified restriction factor determines the cellular tropism of two related HIV type 2 (HIV-2) isolates (66 -68). Lv2 restriction is determined by the viral capsid and envelope protein sequences, and Lv2 lentiviral restriction activity is determined by the route of viral entry; the restriction is only prominent after the restriction-sensitive viral core reached a subcellular compartment where Lv2 activity is accessible (67,68). Although Lv2 restriction appears to be independent of human TRIM5␣-mediated post-entry restriction (66), these observations indicate the involvement of cellular lipids in the post-entry restriction of lentiviruses.…”

Section: Discussionmentioning

confidence: 91%

Cytoplasmic Body Component TRIM5α Requires Lipid-enriched Microdomains for Efficient HIV-1 Restriction

Ohmine

Sakuma

et al. 2010

Journal of Biological Chemistry

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TRIM5␣ is a member of the tripartite motif (TRIM) family of proteins and affects both early and late phases of the retroviral life cycle. Although TRIM5␣ multimerizes to form cytoplasmic bodies, which are thought to play an important role in viral restriction, the identity of TRIM5␣-containing cytoplasmic bodies remains elusive. To better understand TRIM5␣ cytoplasmic body constituents and the cellular proteins that could be involved in the TRIM5␣-mediated antiviral activities, we sought TRIM5␣-binding factors. We identified a lipid microdomain protein flotillin-1/Reggie-2 as an interacting partner of TRIM5␣ via co-immunoprecipitation. Immunohistochemistry studies confirmed the co-localization of rhesus monkey TRIM5␣ (TRIM5␣rh) cytoplasmic bodies with flotillin-1/Reggie-2. Caveolin-1, another lipid microdomain-associated protein, also co-localized with TRIM5␣ cytoplasmic bodies. Intriguingly, disruption of cellular cholesterol by cyclodextrin perturbed TRIM5␣ cytoplasmic body formation. Furthermore, lipid starvation partially relieved the endogenous post-entry restriction of HIV-1 infection, which could be subsequently restored by lipid repletion. These observations indicate the involvement of cellular lipids in TRIM5␣-mediated antiviral activities. Given that many viruses utilize cellular lipid microdomains for viral entry and assembly, it is plausible that lipid-enriched domains provide microenvironments where TRIM5␣ recognizes retroviral components.

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Lv2, a Novel Postentry Restriction, Is Mediated by both Capsid and Envelope

Cited by 56 publications

References 43 publications

Retroelements and the human genome: New perspectives on an old relation

Retroelements and the human genome: New perspectives on an old relation

An Envelope-Determined, pH-Independent Endocytic Route of Viral Entry Determines the Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 to Lv2 Restriction

Cytoplasmic Body Component TRIM5α Requires Lipid-enriched Microdomains for Efficient HIV-1 Restriction

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