The Vpr protein from HIV-1: distinct roles along the viral life cycle

Rouzic, Erwann Le; Bénichou, Serge

doi:10.1186/1742-4690-2-11

Cited by 126 publications

(49 citation statements)

References 181 publications

(179 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This, and the fact that two rounds of RT synthesis were performed in the PCR-based assay, suggests that most errors in our assays would have resulted from RT synthesis. Cellular profiles also include mutations resulting from cellular sources, most notably APOBEC3G and dUTP incorporation into DNA (64)(65)(66)(67). These cellular processes would tend to increase substitutions (particularly G to A) during reverse transcription.…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Reverse Transcriptase Displays Dramatically Higher Fidelity under Physiological Magnesium Conditions In Vitro

Achuthan

Keith

Connolly

et al. 2014

J Virol

View full text Add to dashboard Cite

The fidelity of human immunodeficiency virus (HIV) reverse transcriptase (RT) has been a subject of intensive investigation. The mutation frequencies for the purified enzyme in vitro vary widely but are typically in the 10 ؊4 range (per nucleotide addition), making the enzyme severalfold less accurate than most polymerases, including other RTs. This has often been cited as a factor in HIV's accelerated generation of genetic diversity. However, cellular experiments suggest that HIV does not have significantly lower fidelity than other retroviruses and shows a mutation frequency in the 10 ؊5 range. In this report, we reconcile, at least in part, these discrepancies by showing that HIV RT fidelity in vitro is in the same range as cellular results from experiments conducted with physiological (for lymphocytes) concentrations of free Mg 2؉ (ϳ0.25 mM) and is comparable to Moloney murine leukemia virus (MuLV) RT fidelity. The physiological conditions produced mutation rates that were 5 to 10 times lower than those obtained under typically employed in vitro conditions optimized for RT activity (5 to 10 mM Mg 2؉ ). These results were consistent in both commonly used lacZ␣ complementation and steady-state fidelity assays. Interestingly, although HIV RT showed severalfold-lower fidelity under high-Mg 2؉ (6 mM) conditions, MuLV RT fidelity was insensitive to Mg 2؉ . Overall, the results indicate that the fidelity of HIV replication in cells is compatible with findings of experiments carried out in vitro with purified HIV RT, providing more physiological conditions are used. IMPORTANCEHuman immunodeficiency virus rapidly evolves through the generation and subsequent selection of mutants that can circumvent the immune response and escape drug therapy. This process is fueled, in part, by the presumably highly error-prone HIV polymerase reverse transcriptase (RT). Paradoxically, results of studies examining HIV replication in cells indicate an error frequency that is ϳ10 times lower than the rate for RT in the test tube, which invokes the possibility of factors that make RT more accurate in cells. This study brings the cellular and test tube results in closer agreement by showing that HIV RT is not more error prone than other RTs and, when assayed under physiological magnesium conditions, has a much lower error rate than in typical assays conducted using conditions optimized for enzyme activity. R everse transcriptase (RT), the DNA polymerase of retroviruses, is a key target for highly active antiretroviral therapy (HAART) directed against human immunodeficiency virus (HIV) (for a recent review, see reference 1). HIV RT is a heterodimer with p66 and p51 subunits and, like other RTs, possesses both DNA polymerase and RNase H activities (2). Both activities are divalent cation dependent, and the polymerase active site contains two divalent cation binding sites. Models for one or two cation binding sites have also been proposed for .Much of what is known about the biochemical properties of HIV RT is based on in vitro assay...

show abstract

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Reverse Transcriptase Displays Dramatically Higher Fidelity under Physiological Magnesium Conditions In Vitro

Achuthan

Keith

Connolly

et al. 2014

J Virol

View full text Add to dashboard Cite

show abstract

“…Vpr accessory proteins are multifunctional regulators located in the nuclei of the infected cells (6). Although Vpr is not required for lentivirus replication in cultured cells, its conservation in HIV-1, HIV-2, and simian immunodeficiency viruses (SIV) indicates that a strong selective pressure to preserve these proteins must operate in vivo.…”

mentioning

confidence: 99%

Lentiviral Vpr usurps Cul4–DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle

Hrecka

Gierszewska

Srivastava

et al. 2007

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

207

234

View full text Add to dashboard Cite

The replication of viruses depends on the cell cycle status of the infected cells. Viruses have evolved functions that alleviate restrictions imposed on their replication by the host. Vpr, an accessory factor of primate lentiviruses, arrests cells at the DNA damage checkpoint in G 2 phase of the cell cycle, but the mechanism underlying this effect has remained elusive. Here we report that Vpr proteins of both the human (HIV-1) and the distantly related simian (

show abstract

“…Although both RT and Vpr are colocalized in the RTC, the PIC, and the viral core (153,154), a direct interaction between RT and Vpr has not been reported to our knowledge. Based on HIV-host protein interactions, cellular primer tRNA Lys3 physically interacts with RT (155)(156)(157)(158) and Vpr (159).…”

Section: Rt-trna Lys3 -Vpr Associationmentioning

confidence: 90%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

show abstract

The Vpr protein from HIV-1: distinct roles along the viral life cycle

Cited by 126 publications

References 181 publications

Human Immunodeficiency Virus Reverse Transcriptase Displays Dramatically Higher Fidelity under Physiological Magnesium Conditions In Vitro

Human Immunodeficiency Virus Reverse Transcriptase Displays Dramatically Higher Fidelity under Physiological Magnesium Conditions In Vitro

Lentiviral Vpr usurps Cul4–DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Contact Info

Product

Resources

About