Abstract
The human immunodeficiency virus (HIV) enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under development. Unfortunately, as is the case for other classes of antiretroviral drugs that target later steps in the viral life cycle, HIV can become resistant to entry inhibitors. In contrast to inhibitors that block viral enzymes in intracellular compartments, entry inhibitors interfere with the function of the highly variable envelope glycoprotein as it continuously adapts to changing immune pressure and available target cells in the extracellular environment. Consequently, pathways and mechanisms of resistance for entry inhibitors are varied and often involve mutations across the envelope gene. This review provides a broad overview of entry inhibitor resistance mechanisms that inform our understanding of HIV entry and the design of new inhibitors and vaccines.
Highlights
Since zidovudine (AZT) was approved in 1987 as the first drug for treating human immunodeficiency virus (HIV) infection, more than twenty drugs representing antiretroviral classes that inhibit five different steps in the viral lifecycle have reached the clinic [1,2]
This finding suggests that these resistant envelope glycoprotein (Env) are able to side-step saturating levels of monoclonal antibody (mAb) bound to CD4 using non-competitive mechanisms, similar to the mechanism seen for resistance to CCR5 inhibitors [94,96]
Resistance mutations in and around the CD4bs may directly or indirectly interfere with inhibitor binding (Table 1, mechanism A (I)) or they may alter how Env undergoes conformational changes to preserve Env function, whether or not the inhibitor remains bound to its target (Table 1, mechanism B (I))
Summary
The class of entry inhibitors targets the fusion activity of gp. After gp120 engages receptors, a series of still poorly defined refolding events frees the hydrophobic fusion peptide at the N terminus of gp so that it can insert into the target cell membrane (forming the prehairpin intermediate) [98]. As discussed in more detail in the sections below, lead inhibitors in this class are peptides corresponding to residues in HR1 and HR2 (Figure 3A) that appear to inhibit Env after receptor activation and before formation of the gp41 6HB in a dominant negative manner [202,203,204]. According to this mechanism of inhibition, the HR peptide inhibitors bind to a fusion-intermediate conformation of gp to form peptide-gp41 6HB-like structure (inhibitor bundle) (Figure 3B). New types of fusion inhibitors targeting gp, including small molecules, are under development, and they can be used as additional tools for deciphering how gp120 and gp coordinate conformational changes to mediate virus entry [10]
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