An HIV fusion-inhibitory lipopeptide provides robust post-exposure prophylaxis and prevents viral reservoir seeding in macaques.

LP-98 is a lipopeptide HIV fusion inhibitor showing strong treatment and pre-exposure prophylaxis efficacies in non-human primates. In this study, we further characterized its pharmacokinetics, long-lasting antiviral activity, and post-exposure prophylaxis (PEP) efficacy using 62 macaques. In cynomolgus macaques, LP-98 achieved high concentrations (Cmax) with a half-life (T1/2) of ∼31 h, and sustained an effective therapeutic concentration for two weeks post-injection. In chronically SHIVSF162P3-infected rhesus macaques (RMs), weekly or biweekly LP-98 monotherapy efficiently suppressed virus replication. In the PEP study, early LP-98 administration (weekly for 4 weeks) provided robust protection against SHIVSF162P3 infection through intrarectal and intravenous challenges. No viral DNA or replication-competent virus was detected in tissues from protected RMs, even after CD8+ T cell depletion. Transcriptomic analyses revealed the potential immunomodulatory effects of LP-98 treatment. Collectively, our results demonstrate the importance of LP-98 for HIV prevention and treatment and facilitate its current clinical studies.