A randomized trial using in situ viral imaging and mass spectrometry reports that first-line dolutegravir/lamivudine can penetrate lymph node tissue and coincides with a rapid decline in HIV-1–infected cells. The study’s approach focuses on where HIV hides—lymph node reservoirs—rather than only blood-based readouts. By tying pharmacologic penetration to viral cell declines in tissue, the work strengthens the case that simplified regimens can still achieve compartment-level impact. For developers of next-generation long-acting and simplified antiretrovirals, the imaging-plus-mass-spectrometry framework provides a sharper benchmark for “real reservoir biology,” not just plasma suppression.