Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV

Roederer, Mario; Keele, Brandon F.; Schmidt, Stephen D.; Mason, Rosemarie D.; Welles, Hugh C.; Fischer, Will; LaBranche, Celia C.; Foulds, Kathryn E.; Louder, Mark K.; Yang, Zhi Yong; Todd, John Paul; Buzby, Adam P.; Mach, Linh; Shen, Lei; Seaton, Kelly E.; Ward, Brandy M.; Bailer, Robert T.; Gottardo, Raphaël; Gu, Wenjuan; Ferrari, Guido; Alam, S. Munir; Denny, Thomas N.; Montefiori, David C.; Tomaras, Georgia D.; Korber, Bette T.; Nason, Martha; Seder, Robert A.; Koup, Richard A.; Letvin, Norman L.; Rao, Srinivas S.; Nabel, Gary J.; Mascola, John R.

doi:10.1038/nature12893

Cited by 136 publications

(216 citation statements)

References 39 publications

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“…Nonetheless, partial efficacy observed in the RV144 vaccine trial 4 renewed interest in HIV-1 Env as an immunogen candidate. This was corroborated by a recent study describing that vaccine-elicited anti-Env antibodies were sufficient to generate a certain degree of protection against SIV and HIV challenges 5 .…”

Section: Introductionsupporting

confidence: 55%

Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay

Veillette

Coutu

Richard

et al. 2014

JoVE

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HIV-1 envelope glycoproteins (Env) mediate viral entry into target cells and are essential to the infectious cycle. Understanding how those glycoproteins are able to fuel the fusion process through their conformational changes could lead to the design of better, more effective immunogens for vaccine strategies. Here we describe a cell-based ELISA assay that allows studying the recognition of trimeric HIV-1 Env by monoclonal antibodies. Following expression of HIV-1 trimeric Env at the surface of transfected cells, conformation specific anti-Env antibodies are incubated with the cells. A horseradish peroxidase-conjugated secondary antibody and a simple chemiluminescence reaction are then used to detect bound antibodies. This system is highly flexible and can detect Env conformational changes induced by soluble CD4 or cellular proteins. It requires minimal amount of material and no highly-specialized equipment or know-how. Thus, this technique can be established for medium to high throughput screening of antigens and antibodies, such as newly-isolated antibodies. Video LinkThe video component of this article can be found at

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Section: Introductionsupporting

confidence: 55%

Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay

Veillette

Coutu

Richard

et al. 2014

JoVE

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“…It should be noted that in an SIVmac challenge study, where SIV (rather than HIV‐1) mosaic Envs were evaluated, no vaccine‐mediated protection by antibodies was observed in the mosaic Env vaccine group, while animals vaccinated with a natural protein showed reduced rates of acquisition 42. The mosaic‐Env‐vaccinated macaques in this study did, however, have lower peak viremia, and reduced viral loads in early infection.…”

Section: T‐cell Vaccine Design Strategiesmentioning

confidence: 57%

“…Moreover, HIV‐1 mosaic Envs undergo the appropriate conformational shift when bound to CD4,36 and so are assumed to form native‐like proteins. However, the SIV mosaics were not similarly evaluated 42. Also of note, SIV Gag mosaic vaccinated animals in this same study had reduced viral load and improved survival upon SIVmac infection 42…”

Section: T‐cell Vaccine Design Strategiesmentioning

confidence: 87%

“…While the level of vaccine responses to HIV‐1 proteins can be evaluated in NHPs, their protective capacity cannot be assessed, except for responses to the HIV‐1 Env glycoprotein, which can be tested using simian‐human immunodeficiency virus (SHIV) challenge models 40. Using SIVmac proteins instead, the number of vaccine‐elicited SIVmac Gag CTL responses has been correlated with improved viral control in NHPs of SHIVs and SIVmac 41, 42. These observations suggest that the improved T‐cell responses to HIV mosaics in NHPs may translate into better outcomes in human subjects.…”

Section: T‐cell Vaccine Design Strategiesmentioning

confidence: 99%

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Polyvalent vaccine approaches to combat HIV‐1 diversity

Korber

Hraber

Wagh

et al. 2017

Immunological Reviews

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SummaryA key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.

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“…88–91 Martins et al 88 reported that vaccine regimens that did not contain Gag, or Env or a combination of both were largely inefficient in reducing viremia, suggesting that the synergy between Gag-specific T cell responses and antibodies targeting Env were an important requirement in the effective control of the virus, an observation also supported by others. 92 , 93 Roederer et al 89 reported that vaccination with mosaic Gag DNA as prime followed by rAd5 as a booster immunization did not protect from infection but showed reduction of viremia. On the other hand, Hansen et al 90 , 91 reported no protection from virus acquisition but found robust control of viremia in ∼half of the rCMV (SIV Gag) immunized macaques.…”

Section: Discussionmentioning

confidence: 99%

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Valentı́n

et al. 2018

Human Vaccines & Immunotherapeutics

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HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.

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Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV

Cited by 136 publications

References 39 publications

Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay

Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay

Polyvalent vaccine approaches to combat HIV‐1 diversity

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

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