Rotten to the core: antivirals targeting the HIV-1 capsid core

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The capsid core of HIV-1 is a large macromolecular assembly that surrounds the viral genome and is an essential component of the infectious virus. In addition to its multiple roles throughout the viral life cycle, the capsid interacts with multiple host factors. Owing to its indispensable nature, the HIV-1 capsid has been the target of numerous antiretrovirals, though most capsid-targeting molecules have not had clinical success until recently. Lenacapavir, a long-acting drug that targets the HIV-1 capsid, is currently undergoing phase 2/3 clinical trials, making it the most successful capsid inhibitor to-date. In this review, we detail the role of the HIV-1 capsid protein in the virus life cycle, categorize antiviral compounds based on their targeting of five sites within the HIV-1 capsid, and discuss their molecular interactions and mechanisms of action. The diverse range of inhibition mechanisms provides insight into possible new strategies for designing novel HIV-1 drugs and furthers our understanding of HIV-1 biology.

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Architecture and Secondary Structure of an Entire HIV-1 RNA Genome

Joseph M Watts, Kristen Dang, Robert J. Gorelick … (2009)

Single-stranded RNA viruses encompass broad classes of infectious agents and cause the common cold, cancer, AIDS, and other serious health threats. Viral replication is regulated at many levels, including using conserved genomic RNA structures. Most potential regulatory elements within viral RNA genomes are uncharacterized. Here we report the structure of an entire HIV-1 genome at single nucleotide resolution using SHAPE, a high-throughput RNA analysis technology. The genome encodes protein structure at two levels. In addition to the correspondence between RNA and protein primary sequences, a correlation exists between high levels of RNA structure and sequences that encode inter-domain loops in HIV proteins. This correlation suggests RNA structure modulates ribosome elongation to promote native protein folding. Some simple genome elements previously shown to be important, including the ribosomal gag-pol frameshift stem-loop, are components of larger RNA motifs. We also identify organizational principles for unstructured RNA regions. Highly used splice acceptors lie in unstructured motifs and hypervariable regions are sequestered from flanking genome regions by stable insulator helices. These results emphasize that the HIV-1 genome and, potentially, many coding RNAs are punctuated by numerous previously unrecognized regulatory motifs and that extensive RNA structure may constitute an additional level of the genetic code.

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Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.

E. A. Berger, P Murphy, J Farber (1999)

In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor for entry into target cells. The chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophage-tropic HIV-1 isolates, respectively. The updated coreceptor repertoire includes numerous members, mostly chemokine receptors and related orphans. These discoveries provide a new framework for understanding critical features of the basic biology of HIV-1, including the selective tropism of individual viral variants for different CD4+ target cells and the membrane fusion mechanism governing virus entry. The coreceptors also provide molecular perspectives on central puzzles of HIV-1 disease, including the selective transmission of macrophage-tropic variants, the appearance of T cell line-tropic variants in many infected persons during progression to AIDS, and differing susceptibilities of individuals to infection and disease progression. Genetic findings have yielded major insights into the in vivo roles of individual coreceptors and their ligands; of particular importance is the discovery of an inactivating mutation in the CCR5 gene which, in homozygous form, confers strong resistance to HIV-1 infection. Beyond providing new perspectives on fundamental aspects of HIV-1 transmission and pathogenesis, the coreceptors suggest new avenues for developing novel therapeutic and preventative strategies to combat the AIDS epidemic.

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Protein therapeutics: a summary and pharmacological classification.

Benjamin Leader, Quentin J Baca, David Golan (2008)

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

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Author and article information

Contributors

Stefan G. Sarafianos:

ORCID: http://orcid.org/0000-0002-5840-154X

stefanos.sarafianos@emory.edu

Journal

Journal ID (nlm-ta): Retrovirology

Journal ID (iso-abbrev): Retrovirology

Title: Retrovirology

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4690

Publication date (Electronic): 22 December 2021

Publication date PMC-release: 22 December 2021

Publication date Collection: 2021

Volume: 18

Electronic Location Identifier: 41

Affiliations

[1 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Laboratory of Biochemical Pharmacology, Department of Pediatrics, , Emory University School of Medicine, ; Atlanta, GA 30322 USA

[2 ]GRID grid.428158.2, ISNI 0000 0004 0371 6071, Children’s Healthcare of Atlanta, ; Atlanta, GA 30322 USA

[3 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Department of Chemistry, , Emory University, ; Atlanta, GA 30322 USA

[4 ]GRID grid.17635.36, ISNI 0000000419368657, Center for Drug Design, College of Pharmacy, , University of Minnesota, ; Minneapolis, MN 55455 USA

Author information

Stefan G. Sarafianos http://orcid.org/0000-0002-5840-154X

Article

Publisher ID: 583

DOI: 10.1186/s12977-021-00583-z

PMC ID: 8693499

PubMed ID: 33407607

SO-VID: bfb3b6a2-502c-4be1-975e-dfac7a225569

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 26 August 2021

Date accepted : 9 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, national institutes of health;

Award ID: R01 AI120860

Award ID: R35 GM133719

Award ID: U54 AI150472

Award Recipient : Monika Raj Stefan G. Sarafianos

Funded by: FundRef http://dx.doi.org/10.13039/100000001, national science foundation;

Award ID: CHE-1752654

Award Recipient : Monika Raj

Funded by: FundRef http://dx.doi.org/10.13039/100000057, national institute of general medical sciences;

Award ID: T32 726 GM135060

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ScienceOpen disciplines: Microbiology & Virology

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ScienceOpen disciplines: Microbiology & Virology

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Rotten to the core: antivirals targeting the HIV-1 capsid core

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Graphical Abstract

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Microbiology Society

Most cited references 198

Architecture and Secondary Structure of an Entire HIV-1 RNA Genome

Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.

Protein therapeutics: a summary and pharmacological classification.

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