Soon thereafter infection is established, hosts strive for an efficient eradication of microorganisms, with as limited tissue damage as possible, and durable immunological protection against re-infection. On the other hand, pathogens have developed countermeasures to escape host surveillance and to warrant diffusion to other hosts. In this molecular arms race the final results relies on multiple variables, including the genetic and immunologic e correlates of protection available for the host. In the field of HIV-infection, natural protection has been repeatedly associated to the presence of an immune activation state, at least in some cohorts of HESN (HIV-exposed seronegative). Indeed, these subjects, who naturally resist HIV-infection despite repeated exposure to the virus, are characterized by an increased expression of activation markers on circulating cells and greater production of immunological effector molecules both in basal condition and upon specific-stimulation. Although these results are not univocally shared, several publications emphasize the existence of a correlation between polymorphisms in genes associated with increased immune activation and the HESN phenotype. In this review, we will describe some of the genetic variants associated with protection against HIV infection. Understanding the basis of HIV resistance in HESN is mandatory to develop new preventative and therapeutic interventions.