APOBEC3G & HTLV-1: Inhibition without deamination

APOBEC3G is a cellular cytidine deaminase that was recently identified as the Vif-sensitive antiviral host factor responsible for the restriction of vif-defective HIV-1 in primary human cells and certain non-permissive T cell lines. Inhibition of HIV-1 replication is thought to be the result of APOBEC3G-induced hypermutation of the viral genome that occurs early during reverse transcription. Against this backdrop is a new report from the Uchiyama laboratory that proposes deaminase-independent restriction of HTLV-1 by APOBEC3G (Sasada et al. Retrovirology 2005, 2:32). These findings combined with recent reports of deaminase-independent inhibition of Hepatitis B virus as well as HIV-1 suggest that cytidine deaminase activity and antiviral activity may be separable functional properties of APOBEC3G

HIV-1 Vif, APOBEC, and Intrinsic Immunity

Members of the APOBEC family of cellular cytidine deaminases represent a recently identified group of proteins that provide immunity to infection by retroviruses and protect the cell from endogenous mobile retroelements. Yet, HIV-1 is largely immune to the intrinsic antiviral effects of APOBEC proteins because it encodes Vif (viral infectivity factor), an accessory protein that is critical for in vivo replication of HIV-1. In the absence of Vif, APOBEC proteins are encapsidated by budding virus particles and either cause extensive cytidine to uridine editing of negative sense single-stranded DNA during reverse transcription or restrict virus replication through deaminase-independent mechanisms. Thus, the primary function of Vif is to prevent encapsidation of APOBEC proteins into viral particles. This is in part accomplished by the ability of Vif to induce the ubiquitin-dependent degradation of some of the APOBEC proteins. However, Vif is also able to prevent encapsidation of APOBEC3G and APOBEC3F through degradation-independent mechanism(s). The goal of this review is to recapitulate current knowledge of the functional interaction of HIV-1 and its Vif protein with the APOBEC3 subfamily of proteins and to summarize our present understanding of the mechanism of APOBEC3-dependent retrovirus restriction

APOBEC3G encapsidation into HIV-1 virions: which RNA is it?

APOBEC3G is a cytidine deaminase with potent antiviral activity. The protein deaminates single-stranded DNA but is known to bind cellular and viral RNAs. There is increasing evidence that RNA binding of APOBEC3G is important for packaging into viral particles. However, there is no consensus yet on the type of RNA involved

Die Ausgrabungen von Tall Bderi/Dur-Aššur-ketti-lešer

The Pyviko Web User Interface Quick Start Guide, also available at [24]. This document explains the use of the Pyviko web user interface. (PDF 461 kb

Identification of Residues in the BST-2 TM Domain Important for Antagonism by HIV-1 Vpu Using a Gain-of-Function Approach

The HIV-1 Vpu protein enhances the release of viral particles from the cell-surface in a cell-type specific manner. In the absence of Vpu, nascent virions remain tethered to the cell-surface in restricted cell-types. Recently, the human host factor BST-2/CD317/tetherin was found to be responsible for the inhibition of virus release. It was also reported that HIV-1 Vpu can target human BST-2 but is unable to interfere with the function of murine or simian BST-2. We performed a gain-of-function study to determine which of the differences between human and rhesus BST-2 account for the differential sensitivity to Vpu. We transferred human BST-2 sequences into rhesus BST-2 and assessed the resulting chimeras for inhibition of HIV-1 virus release and sensitivity to Vpu. We found that rhesus BST-2 carrying the transmembrane (TM) domain of human BST-2 is susceptible to HIV-1 Vpu. Finally, a single-amino-acid change in the rhesus BST-2 TM domain was sufficient to confer Vpu sensitivity

The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu

<p>Abstract</p> <p>Background</p> <p>The Human Immunodeficiency virus type 1 (HIV-1) Vpu protein enhances virus release from infected cells and induces proteasomal degradation of CD4. Recent work identified BST-2/CD317 as a host factor that inhibits HIV-1 virus release in a Vpu sensitive manner. A current working model proposes that BST-2 inhibits virus release by tethering viral particles to the cell surface thereby triggering their subsequent endocytosis.</p> <p>Results</p> <p>Here we defined structural properties of BST-2 required for inhibition of virus release and for sensitivity to Vpu. We found that BST-2 is modified by N-linked glycosylation at two sites in the extracellular domain. However, N-linked glycosylation was not important for inhibition of HIV-1 virus release nor did it affect surface expression or sensitivity to Vpu. Rodent BST-2 was previously found to form cysteine-linked dimers. Analysis of single, double, or triple cysteine mutants revealed that any one of three cysteine residues present in the BST-2 extracellular domain was sufficient for BST-2 dimerization, for inhibition of virus release, and sensitivity to Vpu. In contrast, BST-2 lacking all three cysteines in its ectodomain was unable to inhibit release of wild type or Vpu-deficient HIV-1 virions. This defect was not caused by a gross defect in BST-2 trafficking as the mutant protein was expressed at the cell surface of transfected 293T cells and was down-modulated by Vpu similar to wild type BST-2.</p> <p>Conclusion</p> <p>While BST-2 glycosylation was functionally irrelevant, formation of cysteine-linked dimers appeared to be important for inhibition of virus release. However lack of dimerization did not prevent surface expression or Vpu sensitivity of BST-2, suggesting Vpu sensitivity and inhibition of virus release are separable properties of BST-2.</p

Antagonism of BST-2/Tetherin is a conserved function of the Env glycoprotein of primary HIV-2 isolates

Although HIV-2 does not encode a vpu gene, the ability to antagonize bone marrow stromal antigen 2 (BST-2) is conserved in some HIV-2 isolates, where it is controlled by the Env glycoprotein. We previously reported that a single-amino-acid difference between the laboratory-adapted ROD10 and ROD14 Envs controlled the enhancement of virus release (referred to here as Vpu-like) activity. Here, we investigated how conserved the Vpu-like activity is in primary HIV-2 isolates. We found that half of the 34 tested primary HIV-2 Env isolates obtained from 7 different patients enhanced virus release. Interestingly, most HIV-2 patients harbored a mixed population of viruses containing or lacking Vpu-like activity. Vpu-like activity and Envelope functionality varied significantly among Env isolates; however, there was no direct correlation between these two functions, suggesting they evolved independently. In comparing the Env sequences from one HIV-2 patient, we found that similar to the ROD10/ROD14 Envs, a single-amino-acid change (T568I) in the ectodomain of the TM subunit was sufficient to confer Vpu-like activity to an inactive Env variant. Surprisingly, however, absence of Vpu-like activity was not correlated with absence of BST-2 interaction. Taken together, our data suggest that maintaining the ability to antagonize BST-2 is of functional relevance not only to HIV-1 but also to HIV-2 as well. Our data show that as with Vpu, binding of HIV-2 Env to BST-2 is important but not sufficient for antagonism. Finally, as observed previously, the Vpu-like activity in HIV-2 Env can be controlled by single-residue changes in the TM subunit.info:eu-repo/semantics/publishedVersio