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ADAPTATION, CO-EVOLUTION, AND HUMAN SUSCEPTIBILITY TO HIV-1 INFECTION Amalio Telenti «The closer you look at life, the more rapid and intense the rate of evolutionary change.» Jonathan Weiner, The Beak of the Finch Darwin believed evolution occurred over very long periods of time and generally moved in a set direction toward fitness, in the same direction the environment was heading. HIV-1, by means of its inherent capacity to mutate, and thus evade and adapt, serves to assess co-evolution with humans over the short period that elapsed since the estimated entry of HIV-1 into the human population during the first half of the last century (Korber, 2000). In this paper, I review the selective pressures exerted by humans on the virus, and potential evolutionary influences exerted by the virus on the human population under the weight of the current pandemic. I will pay special attention to the growing knowledge on the elaborate in- nate defense mechanisms against retroviruses, and on the potential role of human genetic variants of antiviral genes and of host proteins needed for the viral life cycle in modulating human susceptibility to HIV-1 infection. Adaptation of HIV-1 to the human population Humans exert powerful selective pressures on HIV-1. Some are exoge- nous in nature, such as the pressure exerted by antiretroviral drugs lead- ing to the selection of drug resistance, and others are of endogenous nature, such as the pressure generated by the adaptive immune system, leading to selection of immune escape mutants. These two processes shape the virus in a fashion that may lead to population-specific HIV-1 variants, and that generally result in diminished viral fitness. In popu- lation biology, fitness is defined by the relative reproductive capacity of an individual based on its contribution to the next generation. In viro- 16