HIV entry

Mflnch J, Standker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, Pdhlmann S, Chaipan C, Biet T, Peters T et al. (2007) Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129 263-275 Nisole S, Stoye JP, Saib A (2005). TRIM family proteins retroviral restriction and antiviral defence. Nat Rev Microbiol 3 799-808... 

Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral hfe cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression. 

This chapter is intended to provide an overview of HIV-1 entry inhibitors, focusing on the mechanism of action, development, and knowledge of viral resistance to the currently available entry inhibitors, enfuvirtide and maraviroc. Although reversed relative to their order in the entry process, enfuvirtide is discussed first due to the greater clinical experience with this drug. 

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Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996 381 667-673. 

Farzan M, Mirzabekov T, Kolchinsky P, et al. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 1999 96 667-76. 

Farzan M, Babcock GJ, Vasilieva N, et al. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1 alpha association and HIV-1 entry. J Biol Chem 2002 277 29484-9. 

Sabroe I, Peck MJ, Van Keulen BJ, et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000 275(34) 25985-25992. 

Cooperation and Interactions of Multiple Receptors During HIV-1 Entry Process... 

Clustering of a certain number of CD4 and coreceptor molecules is presumed to be necessary for the efficient HIV-1 Env-mediated fusion pore formation. It has been proposed that four to six CCR5 molecules (91) and three CD4 binding events are needed to induce fusion between the viral and host cell membranes (92). Both CD4 (93) and chemokine receptors can form functional dimers (94) in the plasma membrane. It was proposed that formation of CD4 dimers, mediated by a disulfide bond between the cysteine residues of the D2 domain, might enhance HIV-1 entry and infection (95,96). In contrast, others have provided... 

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