IntroductionPreventative viral vaccines provide protection through induction of immunologic memory, most notably circulating neutralizing antibodies. 1 For some viruses, such as HIV-1, vaccines have failed to induce protective levels of antibodies and the focus of many of the ongoing HIV-1 vaccine efforts has shifted to T-cell responses. 2 Correlates of T-cell-mediated protection to viral infections remain ill-defined because of the not yet fully understood complexity of memory T-cell responses.Replication-defective adenovirus (Ad) vectors are at the forefront of HIV-1 vaccine research and have entered phase 2 clinical trials. [3][4][5] One of the most remarkable features of Ad-based vaccines is their ability to induce exceptionally high and sustained frequencies of transgene product-specific CD8 ϩ T cells that, unlike those induced by other subunit vaccine carriers such as DNA vaccines or poxvirus vectors, do not contract after the initial activation. 6,7 Here we show that replication-defective E1-deleted Ad vector genomes similar to those of Ads acquired by natural infections 8,9 persist. Persistent vector was found in muscle at the site of inoculation, in liver, and in lymphatic tissues of experimental animals. Within lymphatic tissues the vector genomes are enriched in T-cells directed to the antigen encoded by the viral vector. The vector's genome remains transcriptionally active, and the continued presence of transgene products appears to maintain high frequencies of activated antigen-specific CD8 ϩ T cells in addition to a pool of resting memory T cells. Although the concept of persisting vaccines may provide challenges for their eventual use for mass vaccination, concomitantly maintaining high frequencies of effector-like T cells and resting memory T cells may provide a solution to the dilemma of vaccines that rely on T-cell-mediated protection. Materials and methods MiceC57Bl/6 and BALB/c mice were purchased at 6 to 8 weeks of age from Charles River Laboratories (Boston, MA). OT1 and P14 mice were bred at the Animal Facility of the Wistar Institute (Philadelphia, PA) and typed by polymerase chain reaction (PCR) for homozygosity. Animals were treated according to guidelines of the Wistar Institute. Cell linesHEK 293 and HeLa cells were grown in Dulbecco Modified Eagle medium, supplemented with 10% fetal bovine serum. Viruses and viral vectorsAd vectors expressing Gag of HIV-1, the rabies virus glycoprotein or SIINFEKL as a fusion protein with influenza virus nucleoprotein and green fluorescent protein, the glycoprotein of lymphocytic choriomeningitis virus (LCMV), or green fluorescent protein were propagated on HEK 293 cells, purified, and quality-controlled as described previously. 10 Vaccinia virus vectors expressing Gag were grown on HeLa cells and titrated as described. 11 LCMV strain Armstrong was produced as described. 12 Immunization or infection of miceMice were immunized intramuscularly at 6 to 10 weeks of age with vectors diluted in 100 L PBS. Mice were infected with vaccinia virus vectors or L...

In this study we compared a prime-boost regimen with two serologically distinct replication-defective adenovirus (Ad) vectors derived from chimpanzee serotypes C68 and C1 expressing Gag, Pol, gp140, and Nef of human immunodeficiency virus type 1 with a regimen in which replication-defective Ad vectors of the human serotype 5 (AdHu5) were given twice. Experiments were conducted in rhesus macaques that had or had not been preexposed to antigens of AdHu5. There was no significant difference in T-cell responses tested from peripheral blood of the different groups, although responses were overall highest in nonpreexposed animals

Interactions between the herpesvirus entry mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.

Background & Aims Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2%–5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies indicated that patients with pernicious anemia could have an increased risk of cancer. Methods We performed a population-based, case–control study of individuals the SEER-Medicare database, comparing 1,138,390 cancer cases (66–99 y old) to 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection. Results Compared with controls, we found individuals with pernicious anemia to be at increased risk for non-cardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94–2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90–14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40–2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35–2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76–2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32–2.02), liver cancer (OR, 1.49; 95% CI, 1.28– 1.73), myeloma (OR, 1.55; 95% CI, 1.37–1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46–1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53–3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74– 0.92). Conclusion In a population-based, case–control study of individuals the SEER-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.