Adenovirus Serotype 26 Utilizes CD46 as a Primary Cellular Receptor and Only Transiently Activates T Lymphocytes following Vaccination of Rhesus Monkeys

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؉ T cell responses were further enhanced when the duration between priming and boosting was extended from 30 to 60 days. Our results demonstrate that heterologous prime-boost vaccine regimens with alternative-serotype Ad vectors elicited more functional memory CD8 ؉ T cells than any of the regimens containing Ad5. In summary, these results suggest that alternative-serotype Ad vectors will prove useful as candidates for vaccine development against human immunodeficiency virus type 1 and other pathogens and also emphasize the importance of a longer rest period between prime and boost for generating optimal CD8 ؉ T cell immunity.

Section: Length Of Antigen Rest Between Priming and Boosting Impacts mentioning

confidence: 99%

“…Recently, it was shown that CD46 is also the primary cellular receptor for Ad26 (9). Although CAR is expressed in humans, nonhuman primates, and mice in similar anatomical locations (5, 7), CD46 is not expressed in mice except in the testes (8).…”

mentioning

confidence: 99%

Comparative Analysis of Simian Immunodeficiency Virus Gag-Specific Effector and Memory CD8 ⁺ T Cells Induced by Different Adenovirus Vectors

Tan

Jin

West

et al. 2013

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“…However, Ad26 and Ad35 vectors are substantially biologically different from Ad5 vectors in terms of tropism, cellular receptor usage, innate immune profile, and adaptive immune phenotypes (16,(27)(28)(29)(30). Moreover, we did not evaluate the effects of Ad5 vectors in the present study.…”

Section: Discussionmentioning

confidence: 85%

“…Ad26 vector-specific CD4 ϩ and CD8 ϩ T cells were quantified in paired blood and foreskin specimens from the vaccinated and sham-immunized animals via ICS as previously described (16). Briefly, isolated PBMC and foreskin lymphocytes were incubated with or without stimulation using a pool of Ad26 hexon peptides (hexon; 6 h stimulation) or empty Ad26 vectors at a multiplicity of infection of 10 4 (Ad26; overnight stimulation).…”

Section: Animals Immunizations and Infectionmentioning

confidence: 99%

Adenovirus Serotype 26 and 35 Vectors Induce Simian Immunodeficiency Virus-Specific T Lymphocyte Responses in Foreskin in Rhesus Monkeys

Balandya

Miller

Beck

et al. 2014

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Foreskin is the principal site of heterosexual HIV-1 infection in men. However, little is known about HIV-1-specific immune responses or inflammation in foreskin. To the best of our knowledge, no previous studies have assessed immune responses to candidate HIV-1 vaccines in foreskin. Using the rhesus monkey model, we show that intramuscular immunization with adenovirus serotype 26 and 35 vectors expressing SIV antigens elicited durable SIV Gag-specific CD4؉ and CD8 ؉ T cell responses in foreskin that were detectable for more than 1 year following vaccination. Gag-specific CD4؉ and CD8 ؉ T cells were also detectable in foreskin of SIV-and SHIV-infected animals and were at least comparable in magnitude to those in peripheral blood. However, unlike peripheral blood T cells, the majority of foreskin T cells exhibited transitional memory or effector memory phenotype and expressed higher levels of the activation markers CD69, HLA-DR, and CCR5, although vaccination did not further enhance foreskin CD4 ؉ T cell activation. These findings suggest that systemic vaccination strategies can elicit potentially important SIV-specific cellular immunity in foreskin. Further characterization of vaccine-elicited immune responses and inflammation in foreskin is warranted. IMPORTANCEWe demonstrate here the induction of SIV-specific cellular immune responses in foreskin by adenovirus serotype 26 and 35 vaccine vectors. Foreskin T cells were more activated than peripheral blood T cells, but foreskin T cells were not further activated by vaccination. These findings suggest that alternative serotype adenovirus vectors induce potentially important immune responses in foreskin.

“…Like other HAdV-C serotypes, Ad6 uses the coxsackievirus and adenovirus receptor (CAR) and ␣v integrins as well as binds vitamin K-dependent clotting factors that modulate its pharmacology (reviewed in reference 10). In contrast, Ad26 is thought to bind CD46 as its primary receptor (11) and to use ␣v integrins (12) but does not appear to bind clotting factors (13). Given their lower seroprevalence and unique biological properties, both Ad6 and Ad26 are being developed as vaccine and oncolytic vectors (12,(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Comparison of the Life Cycles of Genetically Distant Species C and Species D Human Adenoviruses Ad6 and Ad26 in Human Cells

Turner

Middha

Hofherr

et al. 2015

Our understanding of adenovirus (Ad) biology is largely extrapolated from human species C Ad5. Most humans are immune to Ad5, so lower-seroprevalence viruses like human Ad6 and Ad26 are being tested as therapeutic vectors. Ad6 and Ad26 differ at the DNA level by 34%. To better understand how this might impact their biology, we examined the life cycle of the two viruses in human lung cells in vitro. Both viruses infected A549 cells with similar efficiencies, executed DNA replication with identical kinetics within 12 h, and began killing cells within 72 h. While Ad6-infected cells remained adherent until death, Ad26-infected cells detached within 12 h of infection but remained viable. Next-generation sequencing (NGS) of mRNA from infected cells demonstrated that viral transcripts constituted 1% of cellular mRNAs within 6 h and 8 to 16% within 12 h. Quantitative PCR and NGS revealed the activation of key early genes at 6 h and transition to late gene activation by 12 h by both viruses. There were marked differences in the balance of E1A and E1B activation by the two viruses and in the expression of E3 immune evasion mRNAs. Ad6 was markedly more effective at suppressing major histocompatibility complex class I (MHC I) display on the cell surface and in evading TRAIL-mediated apoptosis than was Ad26. These data demonstrate shared as well as divergent life cycles in these genetically distant human adenoviruses. An understanding of these differences expands the knowledge of alternative Ad species and may inform the selection of related Ads for therapeutic development. IMPORTANCEA burgeoning number of adenoviruses (Ads) are being harnessed as therapeutics, yet the biology of these viruses is generally extrapolated from Ad2 and Ad5. Here, we are the first to compare the transcriptional programs of two genetically distant Ads by mRNA next-generation sequencing (NGS). Species C Ad6 and Ad26 are being pursued as lower-seroprevalence Ad vectors but differ at the DNA level by 34%. Head-to-head comparison in human lung cells by NGS revealed that the two viruses generally conform to our general understanding of the Ad transcriptional program. However, fine mapping revealed subtle and strong differences in how these two viruses execute these programs, including differences in the balance of E1A and E1B mRNAs and in E3 immune evasion genes. This suggests that not all adenoviruses behave like Ad2 and Ad5 and that they may have unique strategies to infect cells and evade the immune system. T here are currently nearly 60 genotypes of adenoviruses (Ads) that infect humans, causing an array of ocular, respiratory, digestive, and systemic infections (reviewed in reference 1). Human mastadenoviruses (HAdVs) fall into genetically grouped species A (HAdV-A) through species G (HAdV-G), with the level of sequence diversity across the virome being as high as 40% (2). Despite this drastic genetic diversity, the biology of most Ads is often extrapolated from the study of just two respiratory serotypes of HAdV-C, Ad2 and Ad5.Transcripti...