Preclinical evaluation of HIV-1 therapeutic ex vivo dendritic cell vaccines expressing consensus Gag antigens and conserved Gag epitopes

Niu, Liguo; Termini, James M.; Kanagavelu, Saravana; Gupta, Sachin; Rolland, Morgane; Kulkarni, Viraj; Pavlakis, George N.; Felber, Barbara K.; Mullins, James I.; Fischl, Margaret A.; Stone, Geoffrey W.

doi:10.1016/j.vaccine.2010.12.131

Cited by 25 publications

(24 citation statements)

References 32 publications

(23 reference statements)

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“…We performed fitness competition assays between a chimeric NL4-3 virus encoding a Center-of-Tree (COT) Gag-p24 protein from clade B (Gag-p24-COT-B) and its variants mutated at sites of interest for conserved-element (CE) vaccine designs (3,32,33) that encapsulate segments of HIV-1 that are maximally conserved among HIV-1 group M sequences. The Gag-p24 CE vaccine is composed of seven segments at least 12 aa long, and each element includes one "toggle" amino acid site at which only one of two residues are found in Ͼ99% of the HIV-1 sequences in the HIV database.…”

Section: Mutants Of Gag-p24-cot-bmentioning

confidence: 99%

“…We focused on mutations at 23 residues in Gag-p24 to evaluate aspects of our initial design of a Gag-p24 "conserved-element" (CE) vaccine (3,32,33). This immunogen includes 7 segments that are composed of sites conserved in ϳ98% of circulating sequences, allowing one site per element to be more variable ("toggle" site) if the two residues together represent Ͼ99% of the known viral genetic variation.…”

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confidence: 99%

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HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity

Rolland

Manocheewa

Swain

et al. 2013

J Virol

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bTo overcome the problem of HIV-1 variability, candidate vaccine antigens have been designed to be composed of conserved elements of the HIV-1 proteome. Such candidate vaccines could be improved with a better understanding of both HIV-1 evolutionary constraints and the fitness cost of specific mutations. We evaluated the in vitro fitness cost of 23 mutations engineered in the HIV-1 subtype B Gag-p24 Center-of-Tree (COT) protein through fitness competition assays. While some mutations at conserved sites exacted a high fitness cost, as expected under the assumption that the most conserved residue confers the highest fitness, there was no overall strong relationship between sequence conservation and replicative capacity. By comparing sites that have evolved since the beginning of the epidemic to those that have remain unchanged, we found that sites that have evolved over time were more likely to correspond to HLA-associated sites and that their mutation had limited fitness costs. Our data showed no transcendent link between high conservation and high fitness cost, indicating that merely focusing on conserved segments of HIV-1 would not be sufficient for a successful vaccine strategy. Nonetheless, a subset of sites exacted a high fitness cost upon mutation-these sites have been under selective pressure to change since the beginning of the epidemic but have proved virtually nonmutable and could constitute preferred targets for vaccine design.

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Section: Mutants Of Gag-p24-cot-bmentioning

confidence: 99%

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confidence: 99%

HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity

Rolland

Manocheewa

Swain

et al. 2013

J Virol

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“…One approach currently moving into human phase I clinical trials includes polyvalent mosaic vaccines, which have been shown to improve epitope variant recognition in nonhuman primate (NHP) models compared to consensus or natural immunogens (21)(22)(23). At the same time, the opposite approach focusing variant responses on only highly conserved regions of HIV to provide recognition of more infecting strains is also being considered for HIV vaccine testing (11,(24)(25)(26)(27).…”

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confidence: 99%

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

Sunshine

Kim

Carlson

et al. 2014

J Virol

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A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-␥/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P ‫؍‬ 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P ‫؍‬ 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r ‫؍‬ 0.62, P ‫؍‬ 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r ‫؍‬ ؊0.38, P ‫؍‬ 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r ‫؍‬ 0.50, P ‫؍‬ 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.

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“…35,36 The Gag vaccine has been shown to stimulate persistent and broader HIV-1-specific CTL responses against conserved Gag epitopes in animal models. [37][38][39][40] HLA-B57 HIV-1-infected individuals have been found to have autologous CTL responses against four conserved Gag epitopes, leading to reduced virus replication and viral control. 41 In addition, clinically, effective CTL responses against Gag, but not other viral antigens, have been found to correlate with a significant suppression of HIV-1 replication in patients.…”

Section: -1bbl Signaling Enhances Hiv-1 Vaccine-stimulated Therapeutmentioning

confidence: 99%

Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44+CD62Lhigh IL-7R+ CTLs with up- and downregulation of anti- and pro-apoptosis genes

et al. 2014

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Preclinical evaluation of HIV-1 therapeutic ex vivo dendritic cell vaccines expressing consensus Gag antigens and conserved Gag epitopes

Cited by 25 publications

References 32 publications

HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity

HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44+CD62Lhigh IL-7R+ CTLs with up- and downregulation of anti- and pro-apoptosis genes

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