Cryo-EM structures of prefusion SIV envelope trimer

Gorman, Jason; Wang, Chunyan; Mason, Rosemarie D.; Nazzari, Alexandra; Welles, Hugh C.; Zhou, Tongqing; Bess, Julian W.; Bylund, Tatsiana; Lee, Myungjin; Tsybovsky, Yaroslav; Verardi, Raffaello; Wang, Shuishu; Yang, Yongping; Zhang, Baoshan; Rawi, Reda; Keele, Brandon F.; Lifson, Jeffrey D.; Liu, Jun; Kwong, Peter D.

doi:10.1038/s41594-022-00852-1

Cited by 11 publications

(17 citation statements)

References 117 publications

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“…B41 and JRFL Env constructs exhibited fairly modest ~2-fold increases in yield, whereas fold increases for CAM13K, T250-4, and CH505 Env constructs could not be reliably calculated due to an inability to purify the non-2P-stabilized construct. During the review of the manuscript, a report from Gorman et al, was published describing the cryo-EM structure of an Env trimer from rhesus macaque SIV ( 34 ). In an effort to reliably express this trimer in the prefusion conformation, Gorman et al also independently identified the T569P mutation, which reportedly aided in their purification of SIV mac Env.…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Stabilization of SOSIP Env Enhances Recombinant Ectodomain Durability and Yield

Wrapp

Thakur

et al. 2023

J Virol

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Recent estimates have placed the number of new human immunodeficiency virus type 1 (HIV-1) infections at approximately 1.5 million per year, emphasizing the ongoing and urgent need for an effective vaccine. The envelope (Env) glycoprotein is the main focus of HIV-1 vaccine development, but, due to its inherent metastability, many Env variants are difficult to recombinantly express in the relatively large quantities that are required for biochemical studies and animal trials.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Stabilization of SOSIP Env Enhances Recombinant Ectodomain Durability and Yield

Wrapp

Thakur

et al. 2023

J Virol

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“…Two cryo-electron microscopy structures of the SIV mac 239 Env trimer were recently solved [37, 40], one of which was determined for PGT145 in complex with an Env variant (SIV mac 239 Env:K180T) with a lysine-to-threonine (K180T) substitution that stabilizes the binding of this antibody to SIV Env similar to our K180S substitution [32, 40]. This structure reveals extensive asymmetric contacts between PGT145 and the N171 glycans on each of the three gp120 protomers, primarily involving the complementarity determining region 3 and 1 of the heavy and light chain, respectively (CDRH3 and CDRL1) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…M325 is located in the V3 loop within the core of the Env trimer where it contacts a sulfated tyrosine residue (Y100f) of the PGT145 CDRH3 ( Fig. 5B ) [40]. M325 and Y100f form a characteristic methionine-aromatic interaction that is predicted to contribute an additional 1-1.5 kcal/mol of energy to protein stability beyond a purely hydrophobic interaction [41].…”

Section: Resultsmentioning

confidence: 99%

Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge

Grunst,

Gil,

Grandea

et al. 2023

Preprint

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Fc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 Env trimer (PGT145) that potently directs the lysis of SIV-infected cells by NK cells but poorly neutralizes SIV infectivity. To determine if ADCC is sufficient for protection, separate groups of six rhesus macaques were treated with PGT145 or a control antibody (DEN3) by intravenous infusion followed five days later by intrarectal challenge with SIVmac239. Despite high concentrations of PGT145 and potent ADCC activity in plasma on the day of challenge, all animals became infected and viral loads did not differ between the PGT145- and DEN3-treated animals. To determine if PGT145 can protect against a neutralization-sensitive virus, two additional groups of six macaques were treated with PGT145 and DEN3 and challenged with an SIVmac239 variant with a single amino acid change in Env (K180S) that increases PGT145 binding and renders the virus susceptible to neutralization by this antibody. Although there was no difference in virus acquisition, peak and chronic phase viral loads were significantly lower and time to peak viremia was significantly delayed in the PGT145-treated animals compared to the DEN3-treated control animals. Env changes were also selected in the PGT145-treated animals that confer resistance to both neutralization and ADCC. These results show that ADCC is not sufficient for protection by this V2-specific antibody. However, protection may be achieved by increasing the affinity of antibody binding to Env above the threshold required for detectable viral neutralization.Author SummaryAntibodies that bind to the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) on virions can neutralize viral infectivity. Antibodies may also bind to Env on the surface of virus-infected cells and recruit immune cells to eliminate the productively infected cells through a process known as antibody dependent cellular cytotoxicity (ADCC). In rare instances, certain antibodies are capable of mediating ADCC despite negligible neutralizing activity. Such antibodies are thought to have contributed to the modest protection observed in the RV144 HIV-1 vaccine trial and in some nonhuman primate studies. One antibody, PGT145, was found to cross-react with simian immunodeficiency virus (SIV) and to mediate potent ADCC against SIV-infected cells despite weak neutralization of viral infectivity. We therefore tested if the potent ADCC activity of PGT145 could protect rhesus macaques against mucosal challenge with pathogenic SIV. PGT145 did not protect against wild-type SIVmac239, but did protect against an SIVmac239 variant with a single amino acid substitution in Env (K180S) that increases antibody binding to Env and makes the virus susceptible to neutralization. Thus, while ADCC may contribute to protection against immunodeficiency viruses through the elimination of productively infected cells, the higher affinity of Env binding necessary for potent neutralization is a critical determinant of antibody-mediated protection.

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“…As shown in Figure C and Table S2, the cross-reactivities for the flu virus (massive sulfation and nitrosylation of the envelope glycans), RV (only two glycosylation sites on the envelope G protein), and Ad5 (without envelope) were 2.76%, 3.88%, and 0.95%, respectively, indicating that GINPs were highly specific toward HIV-1. For HIV-2 and SIV, the cross-reactivity of the GINPs were 41.36% and 31.27%, respectively, due to the glycans on their Env proteins being highly mannose-type, which partly overlapped with HIV-1. − A competitive binding assay was designed to demonstrate the binding sites between GINPs and HIV-1 Env glycans. Briefly, GINPs or NINPs were first incubated with Env glycoproteins to block the imprinted cavities (GINPs@glycan or NINPs@glycan) prior to binding to HIV-1.…”

Section: Binding Performance and Specificity Of Ginps In Vitromentioning

confidence: 99%

Glycan-Imprinted Nanoparticle as Artificial Neutralizing Antibody for Efficient HIV-1 Recognition and Inhibition

Zhou,

Wang,

Liu

et al. 2024

Nano Lett.

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The HIV-1 envelope is a heavily glycosylated class 1 trimeric fusion protein responsible for viral entry into CD4 + immune cells. Developing neutralizing antibodies against the specific envelope glycans is an alternative method for antiviral therapies. This work presents the first-ever development and characterization of artificial neutralizing antibodies using molecular imprinting technology to recognize and bind to the envelope protein of HIV-1. The prepared envelope glycan-imprinted nanoparticles (GINPs) can successfully prevent HIV-1 from infecting target cells by shielding the glycans on the envelope protein. In vitro experiments showed that GINPs have strong affinity toward HIV-1 (K d = 36.7 ± 2.2 nM) and possess high anti-interference and specificity. GINPs demonstrate broad inhibition activity against both tier 1 and tier 2 HIV-1 strains with a pM-level IC 50 and exhibit a significant inhibitory effect on long-term viral replication by more than 95%. The strategy provides a promising method for the inhibition and therapy of HIV-1 infection.

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Cryo-EM structures of prefusion SIV envelope trimer

Cited by 11 publications

References 117 publications

Structure-Based Stabilization of SOSIP Env Enhances Recombinant Ectodomain Durability and Yield

Structure-Based Stabilization of SOSIP Env Enhances Recombinant Ectodomain Durability and Yield

Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge

Glycan-Imprinted Nanoparticle as Artificial Neutralizing Antibody for Efficient HIV-1 Recognition and Inhibition

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