HIV-1 and AIDS are threats not only to the health of individuals but to societies and nations. While a vaccine that induces broadly neutralizing antibodies (bNAbs) against HIV could be transformative for intervening in the HIV-1 pandemic, no vaccine has been shown to induce HIV-1 bNAbs and while the somatic evolution of bNAb development has been mapped, we do not yet understand the origins of bNAb responses and why they arise infrequently. To be effective, HIV-1 vaccine antigens must carry neutralizing epitopes recognized by bnAb lineage founders. In addition, it may also be necessary to activate B cells that escape from limiting mechanisms of immune control. Indeed, atypical characteristics of bNAbs, including high frequencies of somatic mutations and frequent poly- or autoreactivity, suggest that the induction of bNAb responses may be problematic even with ideal immunogens. Consequently, we have begun to characterize – on a single-cell basis - humoral immune responses elicited in rhesus macaques (RMs) by novel SHIV strains that establish chronic and high viral-load infections. We have focused on the germinal center and memory B-cell compartments and established high-throughput methods capable of detailing even complex humoral responses. In this way, we hope to overcome a major limitation in our knowledge of HIV-1 bNAb responses, namely that we entirely rely on rare natural histories, observational and correlational data, of B-cell populations that arise in individual patients infected in different ways by different viruses. The primary question that we are asking is straightforward: how similar are humoral responses of individual RMs to identical SHIV infections? The answer to this simple, but neglected question is crucial to the design of effective vaccine strategies.