Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design

Pantophlet, Ralph; Wilson, Ian A.; Burton, Dennis R.

doi:10.1128/jvi.77.10.5889-5901.2003

Cited by 122 publications

(112 citation statements)

References 117 publications

(128 reference statements)

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“…It appears that escape from neutralizing antibodies directed against the SLAM-binding site (by either amino acid changes or sugar shields) compromises the ability of MV-H to bind SLAM. Our results support the idea that sugar shields could be exploited for the development of effective vaccines, such that the immune responses are almost exclusively directed against relevant and unchangeable epitopes (31).…”

Section: Structural and Functional Insights Into Antiviral Drug Desigsupporting

confidence: 75%

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Hanabusa¹,

Kajikawa

Maita

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

225

260

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Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptorbinding head domain exhibits a cubic-shaped ␤-propeller structure and forms a homodimer. N-linked sugars appear to mask the broad regions and cause the two molecules forming the dimer to tilt oppositely toward the horizontal plane. Accordingly, residues of the putative receptor-binding site, highly conserved among MV strains, are strategically positioned in the unshielded area of the protein. These conserved residues also serve as epitopes for neutralizing antibodies, ensuring the serological monotype, a basis for effective MV vaccines. Our findings suggest that sugar moieties in the MV hemagglutinin critically modulate virus-receptor interaction as well as antiviral antibody responses, differently from sugars of the HIV gp120, which allow for immune evasion.x-ray crystallography paramyxovirus ͉ morbillivirus ͉ SLAM ͉ infectious disease ͉ paramyxovirus

show abstract

Section: Structural and Functional Insights Into Antiviral Drug Desigsupporting

confidence: 75%

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Hanabusa¹,

Kajikawa

Maita

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

225

260

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“…In further studies, they focused on the reduction of binding of a wide range of non-neutralizing antibodies by incorporating seven more glycosylation sites in addition to the four alanine mutations. 191 It was interesting to note that these hyperglycosylated Env proteins were not recognized by non-neutralizing antibodies directed towards CD4 BS (such as b3, b6, CD4-IgG2, 15e, F91, F105), however binding of the neutralizing antibody b12 remained, albeit at lower affinity, largely unaffected. Furthermore, hyperglycosylation affected the exposure of conformational epitopes recognized by mAbs 17b, 48d and X5.…”

Section: Structural Optimization To Target Conserved Neutralization Ementioning

confidence: 99%

Role of Neutralizing Antibodies in Protective Immunity Against HIV

Srivastava

Ulmer²,

Barnett³

2005

Human Vaccines

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“…To date, little work has been carried out by way of exploring structural analogs of neutralization epitopes on carbohydrate moieties of the virus, such as the epitope recognized by 2G12. A sixth category of immunogens employs hyperglycosylation and other mutations to mask non-neutralizing 'decoy' epitopes with the hope that this will redirect the B cell response to key conserved elements of Env [189,190]. Early evidence suggests this approach does indeed refocus the antibody response, but it is not clear whether it will yield an improved response against conserved neutralization epitopes on HIV-1 Env [191,192].…”

mentioning

confidence: 99%

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Haynes¹,

Montefiori²

2006

Expert Review of Vaccines

103

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Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

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Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design

Cited by 122 publications

References 117 publications

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Role of Neutralizing Antibodies in Protective Immunity Against HIV

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

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