In 2016, there were more than 30 million individuals living with HIV-1, ∼1.8 million new HIV-1 infections, and ∼1 million HIV-1-related deaths according to UNAIDS (unaids.org). Hence, a preventive HIV-1 vaccine remains a global priority. The variant envelopes of HIV-1 present a significant obstacle to vaccine development and the vaccine field has realized that immunization with a single HIV-1 envelope protein will not be sufficient to generate broadly neutralizing antibodies. Here we describe two nonmutually exclusive, targeted pathways with which a multi-envelope HIV-1 vaccine may generate protective immune responses against variant HIV-1. Pathways include (i) the induction of a polyclonal immune response, comprising a plethora of antibodies with subset-reactive and cross-reactive specificities, together able to neutralize diverse HIV-1 (termed Poly-nAb in this report) and (ii) the induction of one or a few monoclonal antibodies, each with a broadly neutralizing specificity (bnAb). With each pathway in mind, we describe challenges and strategies that may ultimately support HIV-1 vaccine success.
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