In light of HIV’s propensity to mutate and thereby to ever ramify viral populations, could it be that providing sufficient protection against global diversity is an insurmountable problem? We propose an alternative HIV-1 vaccine design that deliberately includes viral segments conserved across the entire main group (or M group) of HIV-1 strains and excludes variable segments. We describe a prototype conserved elements (CE) vaccine constituted of 45 viral segments at least eight amino acids long that fulfill stringent conservation criteria. Our paradigm contends that the best way to cope with HIV-1 diversity may be to avoid it altogether. We argue that a successful vaccine must elicit responses against conserved regions of the viral proteome in which mutations would severely compromise the viability of the virus. Simultaneously, it must not elicit responses against variable,‘‘decoy’’elements of the virus, ie, features that can mutate while retaining function, and that can absorb much of the adaptive host immune response. Coping with HIV-1! s extensive diversity is a major challenge for vaccine design strategies. Centralized (consensus and ancestral) immunogens [1–3] have in some cases improved the breadth of responses, and recent designs seek to compress the more common variant features among circulating strains into immunogens [4–6]. However, there is a practical limit to antigenic complexity that may prevent inclusion of all escape pathways in realistically sized immunogens. Besides, HIV’s propensity to mutate has been shown to provide means for HIV to escape from antiretrovirals and antibody and cytotoxic T lymphocyte (CTL) pressures.

The foregoing considerations led us to propose a vaccine exclusively composed of viral segments strictly conserved in all HIV-1 M group proteins and specifically devoid of mutable segments. The presence of segments that are nearly invariant in all HIV-1 M group proteomes strongly suggests that those CE are both obligatory for viral viability and are the Achilles’ heels of the virus. Additionally, considering that variable segments can readily escape CTL pressures and can be highly immunogenic epitopes, we propose that mutable segments may act as immunologic decoys, subverting responses away from conserved elements.