Recent developments in antiretroviral therapy (ART) have reduced human immunodeficiency virus type-1 (HIV-1) infection from a potent killer to a chronic illness. However, HIV-1 major drug resistance mutations (DRMs) hamper the efficacy of ART. While screening for major DRMs is routine in most areas, low-resource regions cannot search for major DRMs due to poor infrastructure and high testing costs. We propose using Specific High-sensitivity Enzymatic Reporter unLOCKing (SHERLOCK) in order to diagnose HIV-1 major DRMs point-of-care and present an in-silico proof-of-concept using HIV-1 protease. SHERLOCK employs Loop-mediated isothermal AMPlification (LAMP) and a Cas12b-guide RNA (gRNA) complex to isothermally amplify protease sequences and detect any amplified DRM targets, respectively. To accommodate for HIV-1 variability, LAMP primers and gRNAs were developed against patient-derived variants rather than a simple reference sequence. Primers were scored by their target diversity and thermodynamic characteristics to select the most sensitive primer set. The sequences that could not be targeted by this set were re-inputted into the pipeline. The best sets from three iterations were combined into a sensitive (70.5%) package. Next, gRNAs were ranked, and the top specific gRNAs for each major DRM were considered. gRNAs would be added to DRM-specific packages based on their additional sensitivity (AS) until the AS was <1%. All packages were specific (92.2%±4.3%) with a majority (21/24) displaying high sensitivity (≥90%). Packages were then combined into highly-sensitive drug-specific meta-packages. Thus, SHERLOCK is suitable for major HIV-1 DRM detection, and we will validate our results in vitro.