Journal article
HIV-1 Maturation: Lessons Learned from Inhibitors
Viruses, Vol.12(9), p.940
08/26/2020
DOI: 10.3390/v12090940
PMCID: PMC7552077
PMID: 32858867
Abstract
Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.
Details
- Title: Subtitle
- HIV-1 Maturation: Lessons Learned from Inhibitors
- Creators
- Alex B. Kleinpeter - Center for Cancer ResearchEric O. Freed - Center for Cancer Research
- Resource Type
- Journal article
- Publication Details
- Viruses, Vol.12(9), p.940
- DOI
- 10.3390/v12090940
- PMID
- 32858867
- PMCID
- PMC7552077
- NLM abbreviation
- Viruses
- ISSN
- 1999-4915
- eISSN
- 1999-4915
- Publisher
- Mdpi
- Number of pages
- 32
- Grant note
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 08/26/2020
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984826361002771
Metrics
4 Record Views