# B Cell Receptor’s function in virus entry: Anti-SARS-CoV-2 B cell receptors can mediate viral entry in an ACE2-independent mechanism

## TL;DR

This study shows that B cell receptors can help SARS-CoV-2 enter B cells without needing the ACE2 receptor, revealing a new way the virus infects immune cells.

## Contribution

The study reveals a novel ACE2-independent mechanism by which anti-SARS-CoV-2 BCRs can mediate viral entry into B cells.

## Key findings

- Anti-HIV-1 BCRs can mediate viral attachment but not fusion or entry.
- Anti-SARS-CoV-2 BCRs enable viral attachment and entry without ACE2.
- The ability of BCRs to mediate viral entry depends on the specific viral envelope protein.

## Abstract

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.

We investigated a surprising function of B cell receptors (BCR) in viral infection. While antiviral BCR is recognized for their critical roles in producing humoral immunity against viruses, recent evidence suggests that some viruses, like Dengue, can exploit the antiviral BCR as a receptor for viral entry into B cells. This led us to question whether this mechanism, previously seen with viruses that have simple entry requirements, could also apply to more complex mechanisms of viral entry used by viruses such as HIV-1 and SARS-CoV-2. Our research revealed a distinct difference between these two viruses. We found that anti-HIV-1 BCRs, even when specifically recognizing the HIV-1 envelope, were not enough to allow the virus to enter the cell. However, we discovered that BCRs recognizing the SARS-CoV-2 Spike protein could successfully enable the virus to attach and enter B cells, even without the support of cognate SARS-CoV-2 receptor, ACE2. This discovery uncovers a novel pathway for SARS-CoV-2 infection of B cells. This has significant implications for understanding virus-immune system interactions and could inform the development of new strategies to preserve or enhance the antiviral immune response by preventing B cell infection.