Identifying the tissues and tissue features that define the forgiveness window for lenacapavir PrEP in pigtail macaques challenged with HIV

Pre-exposure prophylaxis (PrEP) – the use of antiretroviral drugs (ARVs) in individuals that do not have HIV-1 – can be a highly effective approach for preventing HIV-1 acquisition. However, fundamental questions about the mechanisms underlying PrEP efficacy and loss of efficacy remain unanswered, including: 1) whether effective drug concentrations must only be maintained at the mucosal site of initial virus exposure, or if effective drug levels must also be maintained at more distal sites that may also be accessible to inoculating virus; 2) whether effective PrEPmediating prevention requires complete blockade of initial viral infection events (“viral seeding”); and 3) what host tissue features contribute to breakthrough infections and PrEP failure. Adding to the uncertainty about these basic questions about PrEP activity is the recent advent of longacting (LA) PrEP agents that can be administered less often than daily agents. When used as prescribed, daily oral PrEP is highly effective for HIV-1 prevention. However, in real-world usage suboptimal regimen adherence has substantially limited the effectiveness of daily oral PrEP. Long-acting agents formulated for sustained release that require less frequent dosing represent an alternative strategy that may overcome the limitations of daily PrEP. However, while LA agents have longer dosing intervals, adherence will still largely determine their effectiveness. While ARV PrEP can be effective at preventing HIV-1 infection, the mechanisms by which it prevents systemic infection following mucosal virus exposure, and by which its protective activity initially wanes, allowing breakthrough infections, are not well understood. This proposal is designed to address fundamental questions about the mechanisms of efficacy and loss of efficacy for a promising new LA PrEP agent at the tissue level. By elucidating the tissue level mechanisms of ARV PrEP success and initial loss of efficacy, they seek to develop an improved understanding of the relationship between drug concentrations in plasma and in tissue sites relevant for the initial establishment of viral infection, which may help define more effective ARV dosing levels and intervals. In addition, this work may provide insight into key drug features and analyses to utilize for the development of future ARVs for PrEP with features that allow for more optimal in vivo distribution for infection prevention Project Number: 75N91019D00024-0-759102500016-2 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Institution: LEIDOS BIOMEDICAL RESEARCH, INC., FREDERICK, MD | Award Amount: $732,241 | Activity Code: N01 View on NIH RePORTER: https://reporter.nih.gov/project-details/11453102