Resistance against inhibitors of HIV-1 entry into target cells

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Date: Feb. 2015
From: Future Virology(Vol. 10, Issue 2)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 12,088 words
Lexile Measure: 1860L

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Author(s): Victor G Kramer aff1 aff2 , Mark A Wainberg [*] aff1 aff2


Entry inhibitors; HIV; resistance

HAART for HIV has led to a marked decrease in morbidity and mortality. Drug candidates for HAART regimens come from the following classes: reverse transcriptase inhibitors, protease inhibitors, integrase strand-transfer inhibitors and entry inhibitors. A typical regimen includes two nucleoside/nucleotide analog reverse transcriptase inhibitors and either a non-nucleoside reverse transcription inhibitor or a protease inhibitor. A number of concerns arise as a result of lifelong HAART, including development of drug resistance, long-term toxicity and unfavorable drug-drug reactions. It is therefore vital to continue to develop and refine new drug classes in an effort to broaden the treatment options that are available. This review focuses on currently approved and candidate entry inhibitors and the development of resistance to agents in this class.

HIV enters host target cells through a complex, step-wise process that begins with virus envelope subunit gp120 binding to the CD4 receptor on the cell surface (reviewed in [1,2 ]). The gp41 and gp120 subunits are the result of furin cleavage of gp160, which is the major product of the HIV env gene, in the Golgi apparatus [3 ]. After cleavage, noncovalently associated trimers that are the result of their cleavage are transported to the cell membrane where they are incorporated into budding virions [4 ]. CD4 D1 domain binding to a conserved site on gp120 causes the latter to undergo a conformational shift that allows it to bind to one of two co-receptors at the cell surface, CCR5 or CXCR4. These co-receptors are G-protein coupled receptors that possess an extracellular N-terminus, intracellular C-terminus and six loops - equally divided into intracellular and extracellular loops. These receptors are responsible for lymphocyte chemotaxis and activation and, in the context of the immune system, are expressed on T-cells, monocytes, macrophages and dendritic cells. The conformational shift involves V1/V2 loop changes as well as exposure of the co-receptor binding site [5-8 ]. The specific co-receptor that gp120 interacts with is determined by the amino acid composition of the V3 loop [9-11 ]. Viruses that interact with CXCR4 are positively charged at amino acids 11, 24 and 25 on the V3 loop. Once gp120 binds to a co-receptor, it induces further conformational change that allows the gp41 fusion peptide to insert itself into the cell membrane. This precipitates the formation of a six-helix bundle comprised of six heptad repeat domains, three of which are termed HR1 and three others that are termed HR2 [12-14 ]. The bundle is formed when the C-terminal HR2 region binds to the N-terminal HR1 region in an opposing orientation. The formation of this bundle brings the virus and cell membrane into close proximity and culminates in fusion, allowing the viral capsid to enter the cytoplasm and begin reverse transcription (Figures 1 & 2).

Each step of the entry cascade has potential targets for inhibition. Thus, unlike other antiretroviral classes, the entry inhibitor class consists of a number of agents with diverse...

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Gale Document Number: GALE|A407934437