Evidence for Host-Driven Selection of the HIV Type 1<i>vpr</i>Gene<i>in Vivo</i>during HIV Disease Progression in a Transfusion-Acquired Cohort

Cali, Leon; Wang, Bin; Mikhail, Meriet; Gill, M John; Beckthold, Brenda; Salemi, Marco; Jans, David A.; Piller, Sabine C.; Saksena, Nitin K.

doi:10.1089/aid.2005.21.728

Cited by 14 publications

(26 citation statements)

References 24 publications

(22 reference statements)

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“…The analysis revealed that other amino acid substitutions such as R90G and R90S are present, but at a cumulative frequency not exceeding 1.3%. Reports of the R90K substitution were found by a manual search of the literature [26], [29] and in both cases this mutation was isolated from a patient exhibiting an LTNP phenotype. It is therefore possible to envision that strains of HIV encoding R90K have lower virulence.…”

Section: Discussionmentioning

confidence: 99%

The Immunosuppressive Properties of the HIV Vpr Protein Are Linked to a Single Highly Conserved Residue, R90

et al. 2009

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BackgroundA hallmark of AIDS progression is a switch of cytokines from Th1 to Th2 in the plasma of patients. IL-12, a critical Th1 cytokine secreted by antigen presenting cells (APCs) is suppressed by Vpr, implicating it as an important virulence factor. We hypothesize that Vpr protein packaged in the virion may be required for disabling APCs of the first infected mucosal tissues. Consistent with this idea are reports that defects in the C-terminus of Vpr are associated with long-term non-progression.Principal FindingsVpr RNA amplified from various sources was electroporated into monocyte-derived DC and IL-12 levels in supernatants were analyzed. The analysis of previously reported C-terminal Vpr mutations demonstrate that they do not alleviate the block of IL-12 secretion. However, a novel single conservative amino acid substitution, R90K, reverses the IL-12 suppression. Analysis of 1226 Vpr protein sequences demonstrated arginine (R) present at position 90 in 98.8%, with other substitutions at low frequency. Furthermore, none of sequences report lysine (K) in position 90. Vpr clones harboring the reported substitutions in position 90 were studied for their ability to suppress IL-12. Our data demonstrates that none of tested substitutions other than K relieve IL-12 suppression. This suggests a natural selection for sequences which suppress IL-12 secretion by DC and against mutations which relieve such suppression. Further analyses demonstrated that the R90K, as well as deletion of the C-terminus, directs the Vpr protein for rapid degradation.ConclusionThis study supports Vpr as an HIV virulence factor during HIV infection and for the first time provides a link between evolutionary conservation of Vpr and its ability to suppress IL-12 secretion by DC. DC activated in the presence of Vpr would be defective in the production of IL-12, thus contributing to the prevailing Th2 cytokine profile associated with progressive HIV disease. These findings should be considered in the design of future immunotherapies that incorporate Vpr as an antigen.

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Section: Discussionmentioning

confidence: 99%

The Immunosuppressive Properties of the HIV Vpr Protein Are Linked to a Single Highly Conserved Residue, R90

et al. 2009

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“…The results of this study suggest that Vpr mutations contributed to alterations in the set-point viral load (SPVL) in this donor/recipient pair (Wang et al , 1996). However, recent cohort studies suggest that host factors play roles in driving the selection of Vpr variants associated with long-term non-progression (Cali et al , 2005). However, the specific viral and host factors that drive Vpr selection are still largely unknown and need to be examined further.…”

Section: Clinical Consequences Of Vpr Sequence Variationmentioning

confidence: 99%

“…In a study involving a non-progressor who carried a mutation at position S90R in the nonstructural C-terminus of Vpr, the virus was followed in two recipients who exhibited normal disease progression. Sequence analyses of the recipients' quasispecies demonstrated that the S90R mutation had reverted to the wild type sequence (Cali et al , 2005). Although position 90 in Vpr has been suggested to be a phosphorylation site, its function is unknown (Guenzel et al , 2014; Schuler et al , 1999).…”

Section: Clinical Consequences Of Vpr Sequence Variationmentioning

confidence: 99%

Defining the roles for Vpr in HIV-1-associated neuropathogenesis

et al. 2016

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It is increasingly evident that the human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) has a unique role in neuropathogenesis. Its ability to induce G2/M arrest coupled with its capacity to increase viral gene transcription gives it a unique role in sustaining viral replication and aiding in the establishment and maintenance of a systemic infection. The requirement of Vpr for HIV-1 infection and replication in cells of monocytic origin (a key lineage of cells involved in HIV-1 neuroinvasion) suggests an important role in establishing and sustaining infection in the central nervous system (CNS). Contributions of Vpr to neuropathogenesis can be expanded further through (i) naturally occurring HIV-1 sequence variation that results in functionally divergent Vpr variants; (ii) the dual activities of Vpr as a intracellular protein delivered and expressed during HIV-1 infection and as an extracellular protein that can act on neighboring, uninfected cells; (iii) cell type-dependent consequences of Vpr expression and exposure, including cell cycle arrest, metabolic dysregulation, and cytotoxicity; and (iv) the effects of Vpr on exosome-based intercellular communication in the CNS. Revealing the effects of this pleiotropic viral protein is an essential part of a greater understanding of HIV-1-associated pathogenesis and potential approaches to treating and preventing disease caused by HIV-1 infection.

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“…Interestingly, they found that another Vpr mutation localized at the C‐terminal, R90K, completely reverted IL‐12 suppression, restoring the levels of this interleukin in DCs . Reports of R90K substitution have also been associated with LTNP patients , and therefore, it is possible that virus encoding Vpr R90K may relieve the blockade of IL‐12 secretion. This finding reinforces Vpr protein as a virulence factor during HIV‐infection and the importance that should be given to the preservation or restoration of IL‐12 secretion.…”

Section: Vpr Mutations‐dependent Phenotypesmentioning

confidence: 99%

HIV1‐viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies

Soares

Rocha

Meliço-Silvestre

et al. 2016

Reviews in Medical Virology

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Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd.

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Evidence for Host-Driven Selection of the HIV Type 1vprGenein Vivoduring HIV Disease Progression in a Transfusion-Acquired Cohort

Cited by 14 publications

References 24 publications

The Immunosuppressive Properties of the HIV Vpr Protein Are Linked to a Single Highly Conserved Residue, R90

The Immunosuppressive Properties of the HIV Vpr Protein Are Linked to a Single Highly Conserved Residue, R90

Defining the roles for Vpr in HIV-1-associated neuropathogenesis

HIV1‐viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies

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