Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc

Abstract

Sustained inhibition of HIV-1, the goal of antiretroviral therapy, is often impeded by the emergence of viral drug resistance. For patients infected with HIV-1 resistant to conventional drugs from the viral reverse transcriptase and protease inhibitor classes, the recently approved entry and integration inhibitors effectively suppress HIV-1 and offer additional therapeutic options. Entry inhibitors are particularly attractive because, unlike conventional antiretrovirals, they target HIV-1 extracellularly, thereby sparing cells from both viral- and drug-induced toxicities. The fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc are the first entry inhibitors licensed for patients with drug-resistant HIV-1, with maraviroc restricted to those infected with CCR5-tropic HIV-1 (R5 HIV-1) only. Vicriviroc (another CCR5 antagonist) is in Phase III clinical trials, whereas the CCR5 antibodies PRO 140 and HGS 004 are in early stages of clinical development. Potent antiviral synergy between maraviroc and CCR5 antibodies, coupled with distinct patterns of resistance, suggest their combinations might be particularly effective in patients. In addition, given that oral administration of maraviroc achieves high drug levels in cervicovaginal fluid, combinations of maraviroc and other CCR5 inhibitors could be effective in preventing HIV-1 transmission. Moreover, since CCR5 antagonists prevent rejection of transplanted organs, maraviroc could both suppress HIV-1 and prolong organ survival for the growing number of HIV-1 patients with kidney or liver failure necessitating organ transplantation. Thus, maraviroc offers an important treatment option for patients with drug-resistant R5 HIV-1, who presently account for >50% of drug-resistance cases.

Figure 1. Therapeutic opportunities for inhibition of HIV-1 entry

HIV-1 entry is mediated by the viral Env protein, which comprises the glycoproteins gp120 and gp41 arranged in trimeric spikes on the viral surface. Entry encompasses three steps: CD4 binding, coreceptor binding and fusion. The viral gp120 first binds to CD4, causing a repositioning of the variable loops V1/V2 and V3 and thereby exposing the bridging sheet and forming a coreceptor binding site. Upon coreceptor binding, conformational changes in gp120 and gp41 lead to the insertion of gp41 fusion peptide into the cell membrane. Subsequent conformational changes result in the formation of a six-helix bundle, with the HR2 domains folding back and packing into grooves on the outside of the triple-stranded HR1 domains. This brings the fusion peptide and transmembrane region of gp41 in close proximity, forming a fusion pore that allows transfer of the viral core into the cell. Each step on HIV-1 entry can be targeted by inhibitors currently approved or in clinical development. CD4 binding is targeted by ibalizumab (formerly TNX-355), a humanized monoclonal antibody that binds to CD4. Coreceptor binding is blocked by small-molecule CCR5 antagonists (maraviroc and vicriviroc) and by CCR5 antibodies (PRO-140 and HGS-004). Finally, the formation of a six-helix bundle, and thereby fusion, is prevented by enfuvirtide.

Figure 2. Model for maraviroc mechanism of action

Binding of HIV-1 gp120 to CD4 exposes the bridging sheet and creates a coreceptor binding site. In the absence of maraviroc, the bridging sheet and the base of V3 interact with the N-terminus of CCR5, while more distal regions of V3 interact with extracellular loops (mainly ECL2). Binding of maraviroc to the transmembrane region of CCR5 locks CCR5 in a conformation that does not recognize the distal regions of V3.

Figure 3. Model for maraviroc mechanism of resistance

Maraviroc binds to the transmembrane region of CCR5, thereby inducing confomational changes that cannot be recognized by R5 HIV-1 gp120. One mechanism of resistance involves changes in HIV-1 Env that permit recognition of maraviroc-bound CCR5. As such, resistant viruses are not blocked by increasing maraviroc doses.