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The development of an HIV-1 vaccine that would be effective against all existing subtypes and circulating recombinant forms remains one of the great scientific and public health challenges of our generation. One of the major barriers to HIV-1 vaccine development is a lack of understanding of the correlates of protective immunity against the virus. In this context, research has focused on the rare phenomenon of spontaneous control of HIV-1 infection, in groups referred to as 'long-term nonprogressors' and 'elite controllers', together with models of nonprogressive sooty mangabey simian immunodeficiency (SIV) infection in African nonhuman primate hosts such as sooty mangabeys and African green monkeys, in which the majority of animals tolerate high levels of viral replication without development of immunodeficiency or disease. Much less attention has been given to humans infected with the nonpandemic strain HIV-2, derived from the SIV in West Africa, most of whom behave as long-term nonprogressors or viral controllers, while a minority develop disease clinically indistinguishable from AIDS caused by HIV-1. This apparent dichotomous outcome is, based on the evidence accumulated to date, more clearly related to the host immune response than the good clinical outcome of HIV-1 controllers. We propose that complementing research into HIV-1 controllers and nonpathogenic SIV models with the prioritization of HIV-2 research could enhance the HIV-1 vaccine research effort. The absence of disease progression or detectable plasma viral replication in the presence of an effective immune response in most patients living with HIV-2 represents an opportunity to unravel the virus' evolutionary adaptation in human hosts and to establish the correlates of such a protective response. © 2011 Expert Reviews Ltd.