A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus and support continuing surveillance of Spike mutations to aid with development of immunological interventions.

Variable memory: Immune memory against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helps to determine protection against reinfection, disease risk, and vaccine efficacy. Using 188 human cases across the range of severity of COVID-19, Dan et al. analyzed cross-sectional data describing the dynamics of SARS-CoV-2 memory B cells, CD8 ⁺ T cells, and CD4 ⁺ T cells for more than 6 months after infection. The authors found a high degree of heterogeneity in the magnitude of adaptive immune responses that persisted into the immune memory phase to the virus. However, immune memory in three immunological compartments remained measurable in greater than 90% of subjects for more than 5 months after infection. Despite the heterogeneity of immune responses, these results show that durable immunity against secondary COVID-19 disease is a possibility for most individuals. Science , this issue p. eabf4063

We present the crystal structure at 2.7 angstrom resolution of the human antibody IgG1 b12. Antibody b12 recognizes the CD4-binding site of human immunodeficiency virus–1 (HIV-1) gp120 and is one of only two known antibodies against gp120 capable of broad and potent neutralization of primary HIV-1 isolates. A key feature of the antibody-combining site is the protruding, finger-like long CDR H3 that can penetrate the recessed CD4-binding site of gp120. A docking model of b12 and gp120 reveals severe structural constraints that explain the extraordinary challenge in eliciting effective neutralizing antibodies similar to b12. The structure, together with mutagenesis studies, provides a rationale for the extensive cross-reactivity of b12 and a valuable framework for the design of HIV-1 vaccines capable of eliciting b12-like activity.

Hexing Complement: Complement activation is an immediate and potent immune defense mechanism, but how immunoglobulin G (IgG) antibodies activate complement at the molecular level is poorly understood. Using high-resolution crystallography, Diebolder et al. (p. 1260 ) show that human IgGs form hexameric structures by interacting with neighboring IgG molecules, and the complex then activates complement. Thus, IgG molecules and the complement system can coexist in the blood because complement activation will only be triggered after IgG senses a surface antigen and starts to aggregate.

The identification and epitope mapping of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only one broadly neutralizing anti-gp41 monoclonal Ab (MAb), 2F5, has been described. Here we report on two MAbs that recognize a region immediately C-terminal of the 2F5 epitope. Both MAbs were generated from HIV-1-seropositive donors, one (Z13) from an antibody phage display library, and one (4E10) as a hybridoma. Both MAbs recognize a predominantly linear and relatively conserved epitope, compete with each other for binding to synthetic peptide derived from gp41, and bind to HIV-1 _MN virions. By flow cytometry, these MAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these MAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E). The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design.