UCLA

B cells play a crucial role in humoral immunity, acting as sentinels against viral infections by using their B cell receptors (BCRs) to recognize viral proteins. This recognition typically triggers a response leading to the production of neutralizing antibodies against viral surface proteins, such as the viral envelope proteins. However, recent studies have revealed a surprising dual role for BCRs, showing that some enveloped viruses and viral vectors, such as Dengue virus and lentiviral vectors, can exploit anti-viral BCRs as their attachment and entry receptors to infect/transduce B cells. While these viruses use a simple low-pH-dependent fusion mechanism for entry, it remained unclear whether BCRs could facilitate the entry of viruses with more complex fusion requirements, such as HIV-1 and SARS-CoV-2, which rely on their cognate receptors to activate their fusion machinery. In this study, we investigated the ability of BCRs to mediate viral entry for HIV-1 and SARS-CoV-2, which require specific host receptors (CD4 and ACE2, respectively) to activate their fusion machinery. We found that while anti-HIV-1 envelope protein BCRs can mediate viral attachment, they are unable to facilitate viral fusion and entry. In contrast, anti-SARS-CoV-2 Spike (S) protein BCRs not only mediate attachment but also enable viral entry in the absence of the ACE2 receptor. Our findings demonstrate that the ability of anti-viral BCRs to mediate viral fusion/entry is not universal but depends on the specific viral envelope protein. This novel entry pathway has important implications for both viral replication and the development of B cell-mediated immunity.