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A proposal for a new HIV-1 DLS structural model.

ABSTRACT: The dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome is suggested to play essential roles at various stages of the viral life cycle. Through a novel assay we had recently developed, we reported on the necessary and sufficient region for RNA dimerization in the HIV-1 virion. Using this system, we performed further detailed mapping of the functional base pairs necessary for HIV-1 DLS structure. Interestingly, the study revealed a previously unnoticed stem formation between two distantly positioned regions. Based on this and other findings on functional base pairing in vivo, we propose new 3D models of the HIV-1 DLS which contain a unique pseudoknot-like conformation. Since this pseudoknot-like conformation appears to be thermodynamically stable, forms a foundational skeleton for the DLS and sterically restricts the spontaneous diversification of DLS conformations, its unique shape may contribute to the viral life cycle and potentially serve as a novel target for anti-HIV-1 therapies.

SUBMITTER: Sakuragi J

PROVIDER: S-EPMC3367192 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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A proposal for a new HIV-1 DLS structural model.

Sakuragi Jun-ichi J Ode Hirotaka H Sakuragi Sayuri S Shioda Tatsuo T Sato Hironori H

Nucleic acids research 20120210 11

The dimer initiation site/dimer linkage sequence (DIS/DLS) region of the human immunodeficiency virus type 1 (HIV-1) RNA genome is suggested to play essential roles at various stages of the viral life cycle. Through a novel assay we had recently developed, we reported on the necessary and sufficient region for RNA dimerization in the HIV-1 virion. Using this system, we performed further detailed mapping of the functional base pairs necessary for HIV-1 DLS structure. Interestingly, the study reve ...[more]

PMID: 22328732

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Project description:BackgroundThe HIV epidemic imposes a heavy burden on societal development. Protection of susceptible populations is the most feasible method for eliminating the spread of HIV. In the absence of a biological vaccine, the definitive solution is enabling susceptible populations to recognize and avoid high-risk sexual behavior.ObjectiveThe objective of this study is to use specific technologies and strategies to establish a system by which high-HIV-risk individuals can determine the HIV infection status of one another anonymously, conveniently, and credibly.MethodsThis study proposes an HIV digital vaccine (HDV) strategy, a decentralized application (Dapp) based on blockchain for use by individuals with a high risk of HIV and accredited testing agencies (ATAs). Following testing, only the HIV-negative results (or linked information) are uploaded to the blockchain, which results in high-risk individuals being able to determine the HIV-negative status of each other anonymously, conveniently, and credibly.ResultsFuture work includes the following: (1) a survey of the willingness to use Dapps among high-HIV-risk populations, (2) a larger framework containing both HDV and people living with HIV (PLH) and discussing the influence of HDV on PLH and its possible solutions, and (3) coordinating with the blockchain development team, ATAs, community-based organizations, and third-party organizations to raise funds, develop the Dapp, formulate detailed plans, and publicize and promote it. The exact timeline for achieving these objectives cannot be determined at present.ConclusionsThe HDV strategy may reduce the occurrence of high-risk sexual behavior and effectively protect susceptible populations; combined with current strategies, it is a promising solution to prevent the spread of HIV. The included concepts of decentralized surveillance and surveillance as intervention may spark a change in current infectious disease prevention and control modes to introduce beneficial innovations in public health systems globally.International registered report identifier (irrid)PRR1-10.2196/37133.

Project description:ObjectivesAntiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies.MethodsThree key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model.ResultsMutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition.ConclusionThis study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.

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A proposal for a new HIV-1 DLS structural model.

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A proposal for a new HIV-1 DLS structural model.

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