Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants

Kinetics of early innate immune activation during HIV-1 infection of humanized mice

Human immunodeficiency virus type-1(HIV-1) infectionis associated with aberrant immune activation, however, most model systems for HIV-1have been used during established infection. Here, we utilizeultra-sensitive HIV-1quantification to delineate early events during the HIV-1eclipse,burstand chronicphases ofHIV-1infection in humanized mice. We show that veryearlyin infection, HIV-1suppresses peripheral type I interferon(IFN)and interferon-stimulated gene (ISG) responses,including the HIV-1restriction factorIFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1infection differentially affects peripheral and lymphoid TLR expression profiles in T cells and macrophages. This resultsin a trend towardsanaltered activation of NFkB, TBK1 and IRF3. The subsequenttype I and III IFN responsesresult in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of theHIV-1restriction factorSAMHD1returnsto levels below those observed in uninfected mice, suggesting that HIV-1interferes with their basal expression. However, peripheralcells, still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISG in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1infection and suggests that blocks to the induction of HIV-1restriction factors contribute to theestablishment of viral persistence