FUSION INHIBITORS

The most recent class of anti-HIV medications to reach the market is fusion inhibitors, so called because they interfere with the last stage of virion binding and entry processes.

HIV cell entry requires active conformational changes by gp41, triggered by co-receptor binding, that lead to so-called prehairpin intermediate formations (coiled-coil helical arrangements) among trimers of gp41. These prehairpin structures then drive into and anchor in the cell membrane before folding back at their middle into the hairpin structure. This action of gp41—its amino and carboxyl termini self-attracting- are what draw cell and virion membranes into contact. Although the gp41 trimers are arranged in the “prehairpin intermediate formation,” they are vulnerable to interference.^85,86 Enfuvirtide, a 36-amino acid peptide homologous to particular repeat regions of HIV-1 gp41,⁸⁷ was designed to competitively bind to the hydrophobic grooves of the gp41 carboxy terminus, preventing association with the gp41 amino-terminal region.

This type of interference, at the last stages of entry, might not have been expected to affect cellular apoptosis, but interestingly, Barretina et al. reported that not only was ex vivo treatment of CD4 lymphocytes with T-20 able to completely prevent syncytium formation but T-20 treatment also fully abrogated death of bystander cells with an IC50 of only 40 ng/ml.⁸⁸ As mutant virus resistant to T-20 demonstrated the ability to induce bystander cell death in the presence of the drug,

FIGURE 25.2 Apoptotic influences of Protease Inhibitors (PIs).

this suggests that gp41 is involved in mediating single-cell death. This also suggests that any anti- apoptotic property of T-20 may be indirect, through interference with gp120 signaling.

Conversely, others have reported that interfering with HIV binding to either CD4 or co-receptors CXCR4 and CCR5 successfully inhibits bystander apoptosis, whereas T-20 fusion inhibitor dis­played no effect.⁸⁹ In this system, Holm et al. produced molecularly cloned viruses that differed only in specific Env amino acids and tested them for their ability to induce apoptosis in herpesvirus saimiri-immortalized primary CD4 T cells. They observed that amino acid changes resulting in increased Env affinity for either CD4 or one of the co-receptors lead to increased abilities to induce bystander apoptosis. Furthermore, the enhanced apoptosis in bystander cells by these mutants could be inhibited by antibodies to CD4, CXCR4, or CCR5, or by the CXCR4 inhibitor AMD3100, but not by T-20.⁸⁹ Such results argue that bystander apoptosis is due largely to co-receptor cross-linking; however, further investigations are needed. It should be noted that any compound able to enhance bystander lymphocyte survival in the context of HIV infection will be welcomed.

Future generation fusion inhibitors already are being tested. T-1249 is a current example of a compound that, although apparently more potent, seems to remain—as its forerunner—well tol­erated.² Two-week monotherapy studies in patients with advanced disease indicate that doses greater than 25 mg once per day significantly raise CD4 cell counts from baseline.⁹⁰ Whether this increase results simply from decreased viral load or whether further research indicates these fusion inhibitors can directly prevent bystander apoptosis remains to be seen.

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