Abstract
Despite the success of protease and reverse transcriptase inhibitors, new drugs to suppress HIV-1 replication are still needed. Several other early events in the viral life cycle (stages before the viral genome is inserted into host cell DNA) are susceptible to drugs, including virus attachment to target cells, membrane fusion and post-entry events such as integration, accessory-gene function and assembly of viral particles. Among these, inhibitors of virus?cell fusion and integration are the most promising candidates.
Key Points
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So far, inhibitors against HIV-1 have been designed to antagonize the viral reverse transcriptase and protease enzymes. However, there are concerns about both the long-term effects of the protease inhibitors and the ability of HIV-1 to evolve resistance to these drugs.
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New attempts to block HIV-1 infection have diversifed to consider many steps in the viral life cycle of HIV-1 that are crucial to infection. These include virus?cell attachment, virus entry and virus uncoating. The reverse transcription of viral cDNA, nuclear import and integration into the host cell's genome are also potential sites of inhibition.
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Antagonists of viral entry are now in, or approaching, human clinical trials; these inhibitors are directed against both the viral glycoproteins that interact with receptors and co-receptors on the host cell membrane. The design of post-entry inhibitors remains problematic; the more advanced inhibitors include agonists of the integrase enzyme, which mediates viral cDNA integration into the host cell's genome.
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Design of new viral-entry inhibitors also considers the escape pathways adopted by the evolving HIV-1 virus in response to inhibition of its normal entry route. It is predicted that the most successful therapeutic approach will be a ?cocktail? of inhibitors, which block infection at several points, including the potential escape pathways.
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Acknowledgements
The authors thank B. Mellor for preparing the illustrations, and T. P. Sakmar, R. W. Doms, M. S. Dimitrov, S. Durell and M. Lu for making scientific contributions to the figures. The authors' work in this area is funded by NIH grants and by the Pediatric AIDS Foundation (J.P.M.).
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Glossary of HIV-1 related terms
Protease inhibitors and new classes of drugs
ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- BIOAVAILABILITY
-
The rate/extent to which a drug is absorbed and becomes available at its site of action.
- VIRION
-
A complete viral particle, comprising the nucleic-acid core and protein capsid, enclosed by a glycoprotein-containing membrane envelope in some species.
- CHEMOKINES
-
Cytokines involved in specific inflammatory responses. They are differentiated into CC or CXC chemokines on the basis of their primary sequence.
- D-PEPTIDES
-
Peptides comprising d-amino acids, rather than the naturally occurring L isomer.
- CAPSID PROTEIN
-
The main constituent of the viral core.
- PLUS- AND MINUS-STRAND RNA
-
The polarity of each RNA molecule contained in the virion.
- LONG TERMINAL REPEAT
-
A repeated sequence, several hundred base pairs long, found at the two ends of the retroviral genome.
- PRIMARY CELLS
-
Cells taken directly from an organism, rather than from a cell culture.
- DC-SIGN
-
(?DC-specific ICAM-3 grabbing nonintegrin?. Host cell-surface lectin, with which glycan moieties on the viral envelope glycoprotein can interact during initial attachment.
- ICAM-1
-
?Intercellular adhesion molecule-1?. Cell-associated adhesion factor that can facilitate initial binding of HIV-1 to target cells.
- LFA-1
-
?Leukocyte cell-surface antigen-1?. Virion-associated adhesion factor that can facilitate initial binding of HIV-1 to target cells.
- CD4
-
A cell-surface antigen found on T helper cells. Interacts with viral gp120, allowing entry of the virus into host cells.
- gp120
-
Surface glycoprotein found in membrane of HIV-1. Interacts with host-cell CD4.
- V3 loop
-
A region of viral gp120 that can influences tropism and coreceptor interactions.
- CCR5
-
Chemokine receptor. Facilitates the entry of macrophage-tropic, non syncytium-inducing (R5) isolates of HIV-1 into host cells.
- CXCR4
-
Chemokine receptor. Facilitates the entry of T-cell-line-tropic, syncytium-inducing (X4) isolates of HIV-1 into host cells.
- R5
-
Abbreviation for viral strains that use CCR5 to enter host cells.
- X4
-
Abbreviation for viral strains that use CXCR4 to enter host cells.
- SDF-α
-
?Stromal-derived factor-1α?. A CXC chemokine that binds to CXCR4, so can block replication of HIV-1 strains that use this co-receptor.
- MIP-1α/MIP-1β
-
?Macrophage-inflammatory protein-1?/-1b?. Endogenous CC chemokines that bind to CCR5, so can block replication of HIV-1 strains that use this co-receptor.
- RANTES
-
?Regulated upon activation, normal T-cell expressed and secreted chemokine?. Endogenous CC chemokine that binds to CCR5, so can block replication of HIV-1 in strains that use this co-receptor.
- T22
-
A highly cationic, peptidic inhibitor of CXCR4.
- ALX40-4C
-
A highly cationic, peptidic inhibitor of CXCR4.
- AMD3100
-
A highly cationic, small molecule inhibitor of CXCR4.
- TAK-779
-
A small-molecule inhibitor of CCR5.
- gp41
-
HIV-1 transmembrane glycoprotein, which undergoes conformational changes to drive the final stages of fusion.
- T20
-
Peptide that inhibits gp41-mediated fusion by substituting for one or more components of the gp41 trimeric complex.
- RPR103611
-
Inhibits gp41-mediated fusion by an unknown mechanism.
- Cyclophilin A
-
A cellular protein thought to be involved in viral uncoating.
- Cyclosporine A
-
An immunosuppressive drug that binds to cyclophilin A.
- Ribonuclease H
-
An intrinsic component of reverse transcriptase, RNAse H degrades the RNA component of the RNA/DNA hybrid.
- Delavirdine
-
A non-nucleoside reverse transcriptase inhibitor.
- Nucleocapsid protein
-
The product of the viral gag gene, it promotes the packaging of genomic viral RNA during virion assembly.
- NF-ATc
-
A transcription factor that is thought to promote reverse transcription of HIV.
- Viral integrase
-
Catalyses integration of viral complementary DNA into a host chromosome.
- Vif
-
Virion infectivity factor; essential for HIV replication, probably by blocking a cellular factor.
- Sch-C
-
A small molecule inhibitor of CCR5.
- T1249
-
Peptide that inhibits gp41-mediated fusion by substituting for one or more components of the gp41 trimeric complex.
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Moore, J., Stevenson, M. New targets for inhibitors of HIV-1 replication. Nat Rev Mol Cell Biol 1, 40–49 (2000). https://doi.org/10.1038/35036060
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DOI: https://doi.org/10.1038/35036060
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