Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis

Antiretroviral therapy (ART) impairs viral replication in people living with HIV (PLWH) by suppressing infection or spread. However, not all treatment strategies apply to preventive applications like pre-exposure prophylaxis (PrEP) for uninfected individuals. To prevent the establishment of HIV infection, PrEP must block viral replication either before, or at the stage of integration into the host genome. A promising PrEP approach under investigation utilizes lenacapavir (LEN), which targets the HIV-1 capsid protein (CA) potently before integration. LEN, a first-in-class antiretroviral, has shown high protective efficacy in the ongoing PURPOSE trials thus far. Here, we discuss clinical investigations of LEN, theoretical suitability of preclinical CA-binding antivirals in PrEP, and other key considerations for preventing HIV-1 infection by targeting the capsid.