Diversity of oligosaccharide structures on the envelope glycoprotein gp 120 of human immunodeficiency virus 1 from the lymphoblastoid cell line H9. Presence of complex-type oligosaccharides with bisecting N-acetylglucosamine residues.

Mizuochi, Tsuguo; Matthews, Thomas J.; Kato, Masaaki; Hamako, Jiharu; Titani, Koiti; Solomon, J; Feizi, Ten

doi:10.1016/s0021-9258(19)38919-7

Cited by 155 publications

(20 citation statements)

References 32 publications

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“…3 Gp120 has 24 asparagine (N) linked carbohydrate chains (referred to as N-glycans) which "camouflage" (mask) a large proportion of the antigenic peptides and are referred to as the "glycan-shield". [3][4][5][6] Synthesis of glycans due to mutations that form more glycosylation sites (i.e., the sequon N-X-S/T) contributes to additional masking of gp120 antigens and thus, to evasion from the anti-HIV neutralizing antibodies. 3 The S-protein of SARS-CoV-2 has 22 N-glycans.…”

Section: The Variants Conundrum In Gene-based Vs Whole-virus Vaccinesmentioning

confidence: 99%

“…O-glycans (linked to serine or threonine) on the viral glycoproteins also carry SA. [4][5][6][7][8][9] An example of SA on N-glycans of a glycoprotein is illustrated as the left glycan in Figure 1. The same glycans are present on APC and on other cells in the body.…”

Section: Immunogenicity Of Enveloped Whole-virus Vaccinesmentioning

confidence: 99%

“…10 Antigen-masking by the glycan-shield-It is estimated that the glycan-shields on viruses such as HIV and SARS-CoV-2 cover ~65% of the surface of the gp120 and S-protein, respectively. [3][4][5][6][7][8] In addition, there are Oglycosylated glycan on viral glycoproteins which together with the N-glycans mask many of the antigenic peptides from recognition by B cell receptors and by the corresponding antibodies. The combination of negative charge repulsion by sialic acids and masking of antigenic peptides by the glycan-shield results in suboptimal efficacy of some inactivated virus vaccines for stimulation of the immune system in vaccinated individuals.…”

Section: Immunogenicity Of Enveloped Whole-virus Vaccinesmentioning

confidence: 99%

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Increasing Efficacy of Enveloped Whole-Virus Vaccines by In situ Immune-Complexing with the Natural Anti-Gal Antibody

Galili

2021

MRAJ

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The appearance of variants of mutated virus in course of the Covid-19 pandemic raises concerns regarding the risk of possible formation of variants that can evade the protective immune response elicited by the single antigen S-protein gene-based vaccines. This risk may be avoided by inclusion of several antigens in vaccines, so that a variant that evades the immune response to the S-protein of SARS-CoV-2 virus will be destroyed by the protective immune response against other viral antigens. A simple way for preparing multi-antigenic enveloped-virus vaccines is using the inactivated whole-virus as vaccine. However, immunogenicity of such vaccines may be suboptimal because of poor uptake of the vaccine by antigen-presenting-cells (APC) due to electrostatic repulsion by the negative charges of sialic-acid on both the glycan-shield of the vaccinating virus and on the carbohydrate-chains (glycans) of APC. In addition, glycan-shield can mask many antigenic peptides. These effects of the glycan-shield can be reduced and immunogenicity of the vaccinating virus markedly increased by glycoengineering viral glycans for replacing sialic-acid units on glycans with a-gal epitopes (Gala1-3Galb1-4GlcNAc-R). Vaccination of humans with inactivated whole-virus presenting a-gal epitopes (virusa-gal) results in formation of immune-complexes with the abundant natural anti-Gal antibody that binds to viral a-gal epitopes at the vaccination site. These immune-complexes are targeted to APC for rigorous uptake due to binding of the Fc portion of immunocomplexed anti-Gal to Fcg receptors on APC. The APC further transport the large amounts of internalized vaccinating virus to regional lymph nodes, process and present the virus antigenic peptides for the activation of many clones of virus specific helper and cytotoxic T-cells. This elicits a protective cellular and humoral immune response against multiple viral antigens and an effective immunological memory. The immune response to virusa-gal vaccine was studied in mice producing anti-Gal and immunized with inactivated influenza-virusa-gal. These mice demonstrated 100-fold increase in titer of the antibodies produced, a marked increase in T-cell response, and a near complete protection against challenge with a lethal dose of live influenza-virus, in comparison to a similar vaccine lacking a-gal epitopes. This glycoengineering can be achieved in vitro by enzymatic reaction with neuraminidase removing sialic-acid and with recombinant a1,3galactosyltransferase (a1,3GT) synthesizing a-gal epitopes, by engineering host-cells to contain several copies of the a1,3GT gene (GGTA1), or by transduction of this gene in a replication-defective adenovirus vector into host-cells. Theoretically, these methods for increased immunogenicity may be applicable to all enveloped viruses with N-glycans on their envelope.

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Section: The Variants Conundrum In Gene-based Vs Whole-virus Vaccinesmentioning

confidence: 99%

Section: Immunogenicity Of Enveloped Whole-virus Vaccinesmentioning

confidence: 99%

Section: Immunogenicity Of Enveloped Whole-virus Vaccinesmentioning

confidence: 99%

See 1 more Smart Citation

Increasing Efficacy of Enveloped Whole-Virus Vaccines by In situ Immune-Complexing with the Natural Anti-Gal Antibody

Galili

2021

MRAJ

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“…The conclusion from these studies is that the number of possible oligosaccharide structures present on gp120 outnumbers the 24 potential glycosylation sites present on the glycoprotein. Therefore, alternative structures occur on some of the glycosylation sites and numerous glycosylation variants of the gp120 are produced even in one cell line (13). The varied glycosylation is beneficial for the virus because it allows the virus to escape the immune system's response to the original invading virus by always appearing to the immune system as a new pathogen.…”

Section: Hiv Glycoprotein Structurementioning

confidence: 99%

An Evaluation of Human Immunodeficiency Virus Pathogenicity and Treatment Using Glycobiology

Leligdowicz

2020

MJM

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“…It has been suggested that the conservation of the high-mannose epitope for the 2G12 antibody might be related to the preservation of mannose structure that facilitates DC-SIGN interaction. N-linked glycosylation patterns in HIV Env are further complicated by the fact that different cell types, H9 and Chinese hamster ovary(Mizuochi et al, 1988(Mizuochi et al, , 1990, and primary T cells and macrophages have different patterns of glycan modification(Liedtke et al, 1997;Lin et al, 2003;Willey et al, 1996). DC-SIGN preferentially binds to HIV Env gp120 enriched for highmannose oligosaccharides, which are typically produced…”

mentioning

confidence: 99%

Tracking HIV-1 genetic variation: recombination and N-linked glycosylation sites

Zhang¹

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The last 26 years saw a rampant global epidemic of HIV-1. HIV-1!s extraordinary diversity is seeded by a high mutation rate, rapid replication, frequent recombination, and strategic placement and loss and gain of N-linked glycosylation sites. In this thesis, the genetic variation of HIV-1 was investigated with special focus on recombination and N-linked glycosylation sites.Using phylogenetic analyses, distance methods, and HIV-1 subtying tools including one called jumping profile hidden Markov model, HIV-1 recombinants dominating HIV epidemic in three different geographical regions were examined. We found that CRF13_cpx includes sections of the rare subtype J, and that breakpoint inference can be greatly improved using all available sequences within a CRF family. We confirmed that CRF02_AG, a recombinant between subtype A and G that is prevalent in West and West Central Africa, is an old recombinant. The main recombination events that generated CRF02 took place before the 1970!s, before HIV-1 had started to spread worldwide and the currently recognized subtypes had formed.Recombinants consisting of subtypes B and C are frequently found in the HIV-1 epidemic of Asia, especially in southwest China where they are associated with different drug trafficking routes. Our study suggested that CRF07 was derived from a recombination between CRF08 and subtype B. However, it is possible that the currently defined CRF07 is not the direct product of this recombination event. Lastly, we found that recent recombination between subtypes B and F in Argentina and Brazil, two epicenters in South America, has created many different, but related, recombinant forms. Taken together, it appears as if the HIV-1 epidemic is becoming more complex as it moves ahead into the future. Recombination among co-circulating forms creates new forms of HIV-1 that are now starting to dominate the epidemic in certain parts of the world.We developed methods to track N-linked glycosylation sites (sequons) in HIV-1 as they shift positions and vary in local densities. Comparing primate lentiviruses, hepatitis C virus, and influenza A viruses showed that generating and tolerating shifting sequons is a unique evolutionary avenue for HIV-1 immune evasion. In addition, we found the primate lentiviral lineages have host species -dependent levels of sequon shifting, with HIV-1 in humans the most extreme. Further, unlike influenza A hemagglutinin H3 HA1 that accumulates sequons over time, HIV does not have a net increase in the number of sites over time at the population level, indicating that variation in number and placement, not accumulation of N-linked glycosylation sites, is more critical for HIV-1 immune evasion.The studies detailed in this thesis, together with our great effort in resubtyping > 150,000 sequences in the Los Alamos HIV sequence database, enables us to draw a more comprehensive and dynamic picture of the global HIV-1 epidemic. LIST OF ORIGINAL PAPERSThe thesis is based on the following original papers. They are referred to in the text by the R...

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Diversity of oligosaccharide structures on the envelope glycoprotein gp 120 of human immunodeficiency virus 1 from the lymphoblastoid cell line H9. Presence of complex-type oligosaccharides with bisecting N-acetylglucosamine residues.

Cited by 155 publications

References 32 publications

Increasing Efficacy of Enveloped Whole-Virus Vaccines by In situ Immune-Complexing with the Natural Anti-Gal Antibody

Increasing Efficacy of Enveloped Whole-Virus Vaccines by In situ Immune-Complexing with the Natural Anti-Gal Antibody

An Evaluation of Human Immunodeficiency Virus Pathogenicity and Treatment Using Glycobiology

Tracking HIV-1 genetic variation: recombination and N-linked glycosylation sites

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