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lutionary pressures of the virus on the host because of the recent nature of the epidemic. However, this topic can be revisited if what is describ- ed is the adaptation of humans to retroviruses. To approach this topic, I will focus on the determinants of human susceptibility to HIV, and the genetic basis of inter-individual differences in susceptibility to disease progression. Interindividual levels of permissiveness. The genetic make-up of an individual plays a role in his or her susceptibility to HIV-1 infection and progression of disease. Some of the observed variation has been attri- buted to immunogenetic diversity (MHC homozygocity, specific HLA types), polymorphism in chemokines, chemokine receptors and in cy– tokine genes (CCR5, CCR2, CX3CR1, SDF1, MIP1a, RANTES, IL-10, IL-4) (Carrington, 2001, Telenti, 2002, O’Brien, 2004). Isolated pri- mary human cells from different individuals also vary in their permis- siveness – the ability of purified cells to be infected and to sustain repli- cation of HIV-1 (Williams, 1991, Spira, 1995, Eisert, 2001, Ciuffi, 2004). Infection of macrophages derived from pairs of identical twins displays a high concordance in the kinetics of HIV-1 replication (Chang, 1996, Naif, 1999), underscoring the role of genetic factors in determining susceptibility to infection. The HIV-1 life cycle is characterized by numerous interactions with host cellular proteins (Greene, 2002, Peterlin, 2003) (Figure 1). Restriction at entry plays a key role in determining infection kinetics (Reeves, 2002, Butticaz, 2003). However, host proteins involved in later steps of the viral life cycle also contribute to interindividual susceptibility to HIV-1 infection (Ciuffi, 2004). Genetic polymorphism in host genes participating in the viral life cycle could result in diffe- rences in the levels of expression or in functional differences of protein variants that may lead to differences in permissiveness to HIV-1 infec- tion. The cell would thus constitute an “environment of evolution”, whereby differences among individuals or inter-species, lead to viral variants adapted to different host partner proteins. Eventually, escape mutants with potential fitness deficits or increase pathogenicity may contribute to shape the epidemic. One of the main focuses of the research in my laboratory has been to understand interindividual differences in 19