2 National Hospital Organization Nagoya Med. Center, Clinical Res. Center, Dept. of Infectious Diseases and Immunology. 3 Div. of Molecular Virology and Genetics, Joint Res. Center for Human Retrovirus Infection, Kumamoto Univ.1 Dept. of Microbiology, Faculty of Life Sci., Kumamoto Univ. 4 Dept. of Veterinary Med., Univ. of Miyazaki.LENACAPAVIR INHIBITS VIRAL FORMATION AT THE LATE STAGE Lenacapavir (LEN) inhibits the formation of the viral CA core after viral release and nuclear translocation in the early stage of HIV-1 cycle. However, the mechanisms of how LEN inhibits viral particle formation at the late stage of HIV-1 replication are not precise. In this study, HIV-1 release was inhibited by LEN (IC50：7.2nM) using p24 ELISA analysis as previously reported. However, the release inhibition effect by LEN was diminished (IC50：>100nM) using RT-qPCR and particle assays based on Vpr-HiBiT. This discrepancy was due to the inability of p24 antibodies to react with the p24 epitope, as LEN tightly masked the p24 epitope. These results indicate that virus release is not inhibited by LEN. We also observed large Gag punctates at the cell membrane in the presence of LEN. Using Mass Photometry analysis and transmission electron microscopy (TEM), we predominantly observed the giant size of LEN-induced viral-like particles (LENiVLP) (200-500nm) in the cell supernatant from pNL43-transfected 293T. Moreover, we detected the mature Gag protein and Gp120 in the LENiVLP having the ability of membrane fusion at the early stage of viral infection however inhibited at the post-entry. We propose that LEN binds to the precursor HIV-1 Gag protein within HIV-1-infected cells, potentially preventing particle formation due to aberrant precursor Gag protein polymerization at the plasma membrane.OF THE HIV-1 LIFE CYCLE ○Wright Andrews Ofotsu Amesimeku1 Yoshihiro Nakata2 Hirotaka Ode2 Nami Monde1Hiromi Terasawa1 Perpetual Nyame1 Md Jakir Hossain1 Terumasa Ikeda3 Akatsuki Saito4 Tomohiro Sawa1 Yosuke Maeda1 Yasumasa Iwatani2 Kazuaki Monde148P 018
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