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Chapter 2 : Entry Inhibitors of Human Immunodeficiency Virus
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
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Highly active antiretroviral therapy (HAART) based on the combination of different classes of inhibitors has dramatically improved the prognosis of human immunodeficiency virus type 1 (HIV-1) infection after its establishment. This chapter focuses on the viral entry processes that play crucial roles in HIV-1 replication and describes inhibitors thereof. It talks about three kinds of inhibitor named as fusion inhibitors, coreceptor inhibitors and viral attachment inhibitors. Maraviroc was approved for use in combination with other antiretroviral medications for the treatment of R5 HIV-1 in adults whose viral loads remain detectable despite existing antiretroviral treatment or who have multidrug-resistant HIV-1. HIV-1 variants resistant to Cyanovirin-N (CV-N) or cross-resistant to additional carbohydrate-binding agents were generated and examined for their biological properties. A study on resistance to CV-N demonstrated that the resistant variants had increased susceptibility to immunoglobulins and sera obtained from HIV-1-infected patients and particularly to V3-loop-directed monoclonal antibodies. The maraviroc-resistant R5 HIV-1 retained full susceptibility to SCH-C and aplaviroc, suggesting that although the CCR5 binding sites for these agents are similar, their impacts on the surface conformation of the receptor are different. The results of the study also suggest that the envelope proteins of maraviroc-resistant viruses are able to recognize and utilize inhibitor-bound CCR5, which involves the ordered accumulation of mutations in the viral envelope, both in the V3 loop and elsewhere within gp120. In addition to the inhibitors described in the chapter, several antibodies have been shown to interact with the molecules essential for HIV-1 entry to the host cells.
Key Concept Ranking
- Viral Entry Via Membrane Fusion
A schematic presentation of HIV-1 entry. (a) The first step of HIV-1 entry to the host cells is gp120 binding to the primary receptor CD4. (b) After binding, the conformation of gp120 changes, which induces exposure of the coreceptor binding domain. Consequently, gp120 binds to a coreceptor, either CCR5 or CXCR4. (c) The binding of gp120 to a coreceptor leads to conformational changes of gp41 that allow insertion of its fusion peptide into the target cell membrane. (d) Then, the heptad repeat (HR-1 and HR-2) regions of gp41 fold into a six-helix bundle (hairpin structure). (e) The bundle formation brings viral envelope and cell membrane closer together and facilitates their fusion. The closed arrows indicate the molecules or steps that entry inhibitors interact with.
Chemical structures of viral attachment inhibitors. (a) BMS-378806; (b) BMS-488043.
Chemical structures of CXCR4 inhibitors. (a) AMD3100; (b) KRH-1636.
Chemical structures of CCR5 inhibitors. (a) TAK-779; (b) SCH-C (SCH 351125); (c) maraviroc (UK-427,857); (d) vicriviroc (SCH-D); (e) aplaviroc (GW873140/ONO4128); (f) TAK-220; (g) TAK-652; (h) CMPD167; (i) AMD3451.
A schematic presentation of gp41 and enfuvirtide structure. gp41 consists of the fusion peptide (FP), two regions of the hydrophobic heptad repeat (HR-1 and HR-2), the transmembrane segment (TM), and the cytoplasmic region (not drawn in this schema). Enfuvirtide is a synthetic 36-amino-acid peptide corresponding to residues 643 to 678 in HR-2.
Entry inhibitors approved for clinical use or in clinical studies a