Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis

William M McFadden; Mia Faerch; Karen A Kirby; Robert A Dick; Bruce E Torbett; Stefan G Sarafianos

doi:10.1016/j.molmed.2025.01.013

Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis

Trends Mol Med. 2025 Feb 27:S1471-4914(25)00013-9. doi: 10.1016/j.molmed.2025.01.013. Online ahead of print.

Authors

William M McFadden¹, Mia Faerch², Karen A Kirby¹, Robert A Dick¹, Bruce E Torbett³, Stefan G Sarafianos⁴

Affiliations

¹ Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
² Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
³ Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98101, USA; Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98101, USA.
⁴ Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. Electronic address: stefanos.sarafianos@emory.edu.

PMID: 40021388
DOI: 10.1016/j.molmed.2025.01.013

Abstract

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.

Keywords: acquired immunodeficiency syndrome (AIDS); antiretroviral therapy (ART); capsid protein (CA); human immunodeficiency virus (HIV); lenacapavir (LEN); pre-exposure prophylaxis (PrEP).

Publication types

Review