Purpose of review: To provide an overview of HIV-1 entry inhibitors, with a focus on chemokine receptor antagonists.
Recent findings: Entry of HIV-1 into target cells is an ordered multistep process involving attachment, co-receptor binding, and fusion. Inhibitors of each step have been identified and shown to have antiviral activity in clinical trials. Phase 1–2 trials of monoclonal antibodies and small-molecule attachment inhibitors have demonstrated activity in HIV-1-infected patients, but none has progressed to later-phase clinical trials. The postattachment inhibitor ibalizumab has shown activity in phase 1 and 2 trials; further studies are anticipated. The CCR5 antagonists maraviroc (now been approved for clinical use) and vicriviroc (in phase 3 trials) have shown significant benefit in controlled trials in treatment-experienced patients; additional CCR5 antagonists are in various stages of clinical development. Targeting CXCR4 has proven to be more challenging. Although proof of concept has been demonstrated in phase 1–2 trials of two compounds, neither proved suitable for chronic administration. Little progress has been reported in developing longer acting or orally bioavailable fusion inhibitors.
Summary: A CCR5 antagonist and a fusion inhibitor are approved for use as HIV-1 entry inhibitors. Development of drugs targeting other steps in HIV-1 entry is ongoing.