Article

Evaluation of current approaches to inhibit HIV entry.

Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Current Drug Targets - Infectious Disorders 04/2002; 2(1):9-16. pp.9-16
Source: PubMed

ABSTRACT Highly active inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and protease have made it possible to dramatically reduce virus load in HIV-positive individuals. However, the presence of viral reservoirs, the emergence of drug-resistant HIV variants and the side effects of these compounds call for research into new drugs that target different stages of the viral life cycle. One attractive target is the first step in HIV replication: entry of virus into cells. HIV entry is initiated by the attachment of the virus to the host cell membrane, which is some cases involves binding to attachment factors such as DC-SIGN. Subsequent interaction of the envelope protein (Env) with the CD4 receptor causes conformational changes that enable Env to interact with a coreceptor, generally the chemokine receptors CCR5 or CXCR4. Coreceptor engagement triggers the final conformational changes in Env, which mediate lipid mixing between the viral and cellular membranes. All of these steps are potential targets for therapeutic intervention: targeting proteins that mediate viral attachment may reduce HIV transmission, while receptor blockade will inhibit virus entry. Highly conserved domains in Env which bind to CD4 and coreceptor are promising targets for broadly neutralizing antibodies, and peptide inhibitors that bind to Env and that block membrane fusion are in advanced clinical trials. These new approaches may supplement current HIV therapy and may assist in the development of an HIV vaccine.

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Keywords

active inhibitors
 
attractive target
 
block membrane fusion
 
cellular membranes
 
chemokine receptors CCR5
 
compounds call
 
envelope protein
 
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HIV-positive individuals
 
host cell membrane
 
human immunodeficiency virus
 
mediate viral attachment
 
neutralizing antibodies
 
new approaches
 
peptide inhibitors
 
steps
 
Subsequent interaction
 
target different stages
 
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virus load