How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses?

•Despite considerable similarities in genomic organization and sequence, the natural history of infection with HIV-2 is quite distinct from HIV-1, with low rates of transmission and a surprisingly high proportion of long-term non-progressors.•Unlike HIV-1, most HIV-2-infected subjects generate high titers of broadly neutralizing antibodies that neutralize primary HIV-2 isolates.•The V3 and V4 loops of HIV-2 envelope have fewer glycosylation sites than HIV-1, which may lead to increased exposure to neutralizing antibody.•Despite high rates of intra-patient envelope diversity, HIV-2 variants that are resistant to neutralization do not appear to accumulate to fixation.•A better understanding of the factors that lead to such a potent broadly neutralizing antibody response in HIV-2 infection could provide important clues for HIV vaccine design.