How Can HIV-Type-1-Env Immunogenicity Be Improved to Facilitate Antibody-Based Vaccine Development?

Klasse, Per Johan; Sanders, Rogier W.; Cerutti, Andrea; Moore, John P.

doi:10.1089/aid.2011.0053

Cited by 70 publications

(78 citation statements)

References 162 publications

(202 reference statements)

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“…It has been reported that increased CD40 stimulation, either by an anti-CD40 Ab or by transgenic CD40L overexpression, augments early Ab responses but significantly reduces their t 1/2 due to premature germinal center regression (54,55). In line with these observations is the remarkably short lifespan of Env-specific Abs induced by vaccination (56)(57)(58).…”

Section: Discussionmentioning

confidence: 75%

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann

Niezold

Temchura

et al. 2015

The Journal of Immunology

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The importance of Fc-dependent effector functions of Abs induced by vaccination is increasingly recognized. However, vaccination of mice against HIV envelope (Env) induced a skewed Th cell response leading to Env-specific Abs with reduced effector function. To overcome this bias, GagPol-specific Th cells were harnessed to provide intrastructural help for Env-specific B cells after immunization with virus-like particles containing GagPol and Env. This led to a balanced Env-specific humoral immune response with a more inflammatory Fc glycan profile. The increased quality in the Ab response against Env was confirmed by FcγR activation assays. Because the Env-specific Th cell response was also biased in human vaccinees, intrastructural help is an attractive novel approach to increase the efficacy of prophylactic HIV Env-based vaccines and may also be applicable to other particulate vaccines.

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Section: Discussionmentioning

confidence: 75%

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann

Niezold

Temchura

et al. 2015

The Journal of Immunology

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“…However, the improvement in immunogenicity is not yet good enough to conclude that any forms of gp140 trimers, in their current iteration, are good enough to use in practical HIV-1 vaccines. The challenge is to determine what structural and other factors limit the immunogenicity of gp140 trimers and design ways to overcome any problems that are identified (22). Structural studies are of critical importance in this regard.…”

Section: Discussionmentioning

confidence: 99%

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Harris

Borgnia

Shi

et al. 2011

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

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146

180

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The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env. viral entry | cryoelectron microscopy | HIV spike | HIV vaccine | AIDS vaccine

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“…Paradoxically, this realization introduces another major challenge: Antibody responses to gp120-based vaccines persist poorly in humans or other mammalian species (reviewed in ref. 22). The point is moot whether this problem is unique to HIV gp120 or extends to responses against other viral vaccines, as suggested for the influenza virus hemagglutinin (23); it must be solved for an effective HIV vaccine.…”

mentioning

confidence: 99%

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

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

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The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

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How Can HIV-Type-1-Env Immunogenicity Be Improved to Facilitate Antibody-Based Vaccine Development?

Cited by 70 publications

References 162 publications

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

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