The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity.

The HIV-1 envelope glycoprotein (Env) trimer contains the receptor binding sites and membrane fusion machinery that introduce the viral genome into the host cell. As the only target for broadly neutralizing antibodies (bnAbs), Env is a focus for rational vaccine design. We present a cryo-electron microscopy reconstruction and structural model of a cleaved, soluble SOSIP gp140 trimer in complex with a CD4 binding site (CD4bs) bnAb, PGV04, at 5.8 A resolution. The structure reveals the spatial arrangement of Env components, including the V1/V2, V3, HR1 and HR2 domains, and shielding glycans. The structure also provides insights into trimer assembly, gp120-gp41 interactions, and the CD4bs epitope cluster for bnAbs, which covers a more extensive area and defines a more complex site of vulnerability than previously described.

/pdf/cryo-em-structure-of-a-fully-glycosylated-soluble-cleaved-54e1e2iuuf.pdf

Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer

Exploitation of glycosylation in enveloped virus pathobiology.

To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.

https://www.pnas.org/content/pnas/118/36/e2103154118.full.pdf

SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma.

Although motor deficits are gaining attention in autism research much less attention has been paid to the physical activity patterns in this group of children. The participants in this study were a group of children with autism spectrum disorder (N = 72) between the ages of 9-18 years. This cross-sectional study explored the physical activity patterns of seventy-two children with autism spectrum disorder as they aged. Results indicated significant differences between the mean time spent in moderate to vigorous physical activity and the mean time spent in sedentary activity. Older children with autism spectrum disorder are significantly more physically inactive, compared to younger children. Physical activity programs and interventions need to address this deficit, in physical activity. Children with autism have a similar trend in physical activity patterns compared to their peers without autism; associated benefits and future research will be discussed.

/pdf/the-physical-activity-patterns-of-children-with-autism-3gm6jyfvrr.pdf

The physical activity patterns of children with autism

Glycans on the human immunodeficiency virus (HIV) envelope glycoprotein (Env) play an important role in viral infection and evasion of neutralization by antibodies. In this study, all 25 potential N-linked glycosylation sites (PNGS) on the HIV-1 CRF07_BC Env, FE, were mutated individually to study the effect of their removal on viral infectivity, virion production, and antibody-mediated neutralization. Removal of specific N-glycosylation sites has a significant effect on viral infectivity and antibody-mediated neutralization phenotype. Six of these glycosylation mutants located on the V1/V2 and C1/C2 domains lost infectivity. PNGS mutations located on V4/C4/V5 (except N392 on V4), were shown to increase viral infectivity. Furthermore, FE is much more dependent on specific glycans than clade B Env YU-2. On neutralization effect, PNGS mutations at N197 (C2), N301 (V3), N442 (C4) and N625 (gp41) rendered the virus more susceptible to neutralization by the monoclonal antibodies (MAbs) that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Furthermore, we showed that mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. We used the available structural information of HIV Env and homology modeling to provide a structural basis for the observed biological effects of these mutations. This report provides the first systematic experimental account of the biological role of the entire PNGS on an HIV-1 Env, which should provide valuable insights for understanding the function of Env in HIV infection cycle and for developing future anti-HIV strategies.

/pdf/a-systematic-study-of-the-n-glycosylation-sites-of-hiv-1-1pj8yi6b6c.pdf

A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization

Background: Although a great number of HIV-1 pseudoviruses have been generated for neutralization assays, circulating recombinant forms, such as CRF01_AE, are not included. Given the increasing prevalence of CRF01_AE, the establishment of a pool of CRF01_AE env isolates for the evaluation of potential HIV vaccines is needed. Materials and Methods: Full-length env genes were cloned from HIV-1 CRF01_AE-infected plasma samples collected in China and used to establish Env-pseudotyped viruses. The neutralization phenotypes of the pseudoviruses were characterized by testing against broadly neutralizing monoclonal antibodies, coreceptor antagonists, and 42 plasma samples that include 3 main prevalent HIV-1 subtypes in China. Results: Thirty-four genetically distinct CRF01_AE env genes were cloned and used to generate pseudotyped viruses. Of the 34 pseudoviruses, 32 used CCR5 as a coreceptor and 2 used CXCR4. The majority of pseudoviruses were resistant to the neutralizing antibodies IgG1b12 and 2G12 and susceptible to 2F5 and 4E10. There was significant variation of the neutralization susceptibility of pseudoviruses against 42 HIV-1-positive plasma samples. Based on their overall neutralization susceptibilities, the 34 CRF01_AE pseudoviruses were classified into 3 tiers: high, medium, and low. Conclusion: The CRF01_AE pseudovirus isolates should be included in the panel of pseudoviruses used to assess vaccine-elicited neutralizing antibodies.

Genotypic and phenotypic characterization of HIV-1 CRF01_AE env molecular clones from infections in China.

Comparisons of the genetic and neutralization properties of HIV-1 subtype C and CRF07/08_BC env molecular clones isolated from infections in China.

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A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization

Genotypic and phenotypic characterization of HIV-1 CRF01_AE env molecular clones from infections in China.

Comparisons of the genetic and neutralization properties of HIV-1 subtype C and CRF07/08_BC env molecular clones isolated from infections in China.