Significance Most HIV antiretrovirals target viral proteins. Unfortunately, HIV mutates under drug pressure, which can lead to drug resistance. Targeting cellular proteins that HIV necessitates in its lifecycle may help overcome HIV drug resistance because cellular proteins have lower mutations rates than do HIV proteins. Mammalian target of rapamycin (mTOR) is a cellular kinase that forms two complexes (mTORC-1 and -2), regulating protein translation and transduction signaling. We demonstrate that dual targeting of mTORC-1/2 with the catalytic inhibitor INK128 blocks HIV by interfering with entry and with transcription (basal and induced). Importantly, INK128 suppressed HIV in a preclinical animal model, suggesting that mTORC-1/2 catalytic inhibitors may help control HIV in patients, particularly in those with drug-resistant HIV.