Hatziioannou’s research is guided by the premise that understanding the mechanisms by which lentiviruses avoid and/or counteract inhibitors in their natural host is fundamental to determining the primate lentivirus host range. To successfully colonize a species, lentiviruses have to adapt to optimally use key host factors critical for virus replication. Equally importantly, viruses have to overcome host proteins, known as restriction factors, that inhibit virus replication in a species-specific manner. Hatziioannou has shown that although such restriction factors are generally beneficial, as they protect humans from viruses infecting other primates, they may also account for our inability to generate optimal animal models for research on HIV and AIDS. Understanding how host protein variation drives lentivirus adaptation provides important insights into the evolutionary history of lentiviruses and, moreover, suggests paths toward the development of novel animal models for HIV-1 to facilitate the evaluation of clinical therapies, prevention strategies, and other interventions.