Schematic figure illustrating the impact of fitness and pathogenicity on virus-host outcomes. (A) Highly fit, pathogenic virus: HIV-1 in most antiretroviral-untreated humans and SIV in rhesus macaques is both highly fit (i.e., replicates at high levels) and highly pathogenic (i.e., causes T cell depletion and disease). (B) Poorly fit virus: highly pathogenic viruses may cause limited disease if replication is limited. HIV-1 under successful antiretroviral treatment and HIV-1 being controlled immunologically are examples of environments whereby HIV-1 is unable to replicate efficiently and is therefore poorly fit. Most therapeutic strategies are aimed at reducing the capacity of HIV-1 to replicate efficiently. (C) Less pathogenic virus: SIV in sooty mangabeys replicates efficiently and is therefore highly fit. This virus, however, does not consistently cause disease, suggesting that its pathogenic effect has been attenuated. There has been only a limited amount of investigation aimed at reducing the pathogenic effect of HIV-1 in humans.