Molecular and biological analysis on the horizontal transfer of insect transposons in Baculoviruses

Summary During the infection of Lepidoptera larvae with baculoviruses the horizontal escape of Tc1-like transposons, termed TCl4.7 and TCp3.2, from the genome of the host Cryptophlebia leucotreta and Cydia pomonella into the genome of Cydia pomonella granulovirus was observed. In this study we addressed the question whether the transposon harboring viruses had a replication advantage over the wild-type and became dominant in the virus population or whether the activity of the host transposable elements is stimulated by virus infection. Biological characterization studies demonstrated that the transposon containing viruses killed C. pomonella larvae slower than CpGV-M. In co-infection experiments of C. pomonella larvae using a mixture of CpGV-M and mutant viruses as inoculum, it was shown that the transposon carrying mutants had a significant selection disadvantage compared to CpGV-M. Transcription levels of the transposase gene of TCp3.2 were investigated in virus infected and uninfected larvae. These experiments demonstrated that a higher level of transposase transcription was detectable in CpGV-M infected than in mock infected control larvae. This observation gave strong evidence that CpGV-M infection might trigger the activity of transposon TCp3.2 within the genome of Cydia pomonella. Our results suggest that the horizontal transfer of insect host transposons into baculovirus genomes might be induced by virus infection.

Immune escape durch Überexpression von HER-2/neu

In Tumoren und Onkogen-transformierten Zellen finden sich häufig Defizienzen in der Expression von Komponenten der MHC Klasse I-Antigenprozessierung, die mit einer verminderten MHC Klasse I-Oberflächenexpression und einer reduzierten Sensitivität der Zellen gegenüber einer ZTL-vermittelten Lyse gekoppelt sein können. Da in den meisten Fällen die reduzierten Expressionsmuster über Zytokine revertiert werden können, werden verschiedene Regulationsmechanismen als Ursache für die Defizienzen postuliert. Auch in Zellen, die den „human epidermal growth factor receptor 2“ (HER-2/neu) überexprimieren, wurden derartige „Immune escape“-Mechanismen identifiziert. Aufgrund der Amplifikation und/oder Überexpression dieses Onkogens in Tumoren, die mit einer schnellen Progression der Erkrankung und einer schlechten Heilungsprognose assoziiert ist, wurden zahlreiche Therapien entwickelt, die auf einer Mobilisierung des Immunsystems gegenüber HER-2/neu oder dessen Blockade durch spezifische Antikörper abzielen. Die bisher jedoch nur unzureichenden Erfolge dieser Therapien könnten ihre Ursache in einer verminderten Immunogenität der HER-2/neu+-Zellen aufgrund von Defizienzen in der MHC Klasse I-Antigenprozessierung haben, weshalb die Untersuchung der molekularen Ursachen dieser Suppression für die Therapie von HER-2/neu+-Tumoren von besonderer Bedeutung ist. In dieser Arbeit wurde anhand eines in vitro-Systems ein HER-2/neu-vermittelter „Immune escape“-Phänotyp charakterisiert und die zugrunde liegenden molekularen Mechanismen untersucht. Hierzu wurden murine, HER-2/neu--NIH3T3-Zellen mit HER-2/neu-transfizierten NIH3T3-Zellen verglichen. Die Untersuchung zeigte, dass die Oberflächenexpression von MHC Klasse I-Antigenen bei einer HER-2/neu-Überexpression vermindert ist. Dies ist assoziiert mit reduzierten Expressionen von LMP2, LMP10, PA28a, PA28b, ERAAP, TAP1, TAP2, und Tapasin, einem blockiertem TAP-Transport und einer fehlenden Sensitivität gegenüber einer ZTL-vermittelten Lyse. Da die analysierten Defekte durch eine Stimulation mit IFN‑g wieder revertiert werden können, wird eine transkriptionelle oder translationelle Regulation der betroffenen Gene durch HER-2/neu postuliert. Aufgrund dieser Ergebnisse ist eine T-Zell-vermittelte Therapie von HER-2/neu+-Tumoren als kritisch anzusehen. Die Untersuchung der Promotoren von TAP1/LMP2, TAP2 und Tapasin ergab geringere und durch IFN‑g-induzierbare Promotoraktivitäten in den HER-2/neu+-Zellen im Vergleich zu den HER-2/neu—-Zellen. Mittels Mutagenese-PCR und Gelretardationsanalysen konnte die Bindung eines Komplexes an zwei E2F- und einer P300-Bindungsstelle im Tapasin-Promotor identifiziert werden, die für die HER-2/neu-vermittelte Hemmung der Tapasin-Promotor­aktivität essentiell ist. Eine Inaktivierung der E2F- und P300-Motve in den TAP1/LMP2- und TAP2-Promotoren hatte dagegen keinen Einfluss auf die HER-2/neu-vermittelte Blockade der Promotoraktivität. Ein Vergleich der Promotoraktivitäten der HER-2/neu+- mit Ras-transformierten Zellen ergab, dass die TAP1/LMP2- und TAP2-Promotoren in beiden Zellen supprimiert werden, während der Tapasin-Promotor bei Ras-Transformation nicht beein­trächtigt ist. Der Einsatz von Inhibitoren zeigte, dass die Suppression des Tapasin-Promotors vermutlich über die PLC-g-PKC-Kaskade erfolgt. Dagegen konnte mit Inhibitoren gegen MAPK und PI3Kinase kein vergleichbarer Effekt erzielt werden. Aufgrund dieser Daten wird postuliert, dass HER-2/neu über die Signalkaskade PLC-g–PKC–E2F/P300 die Tapasin-Promotoraktivität supprimiert, wohingegen noch bisher unbekannte Signalkaskaden von HER-2/neu und Ras zu einer Hemmung der TAP1/LMP2- und TAP2-Promotoraktivität führen. Da die Komplexbildung von E2F und P300 auch im Zellzyklus eine Rolle spielt, wird eine negative Korrelation zwischen Zell-Proliferation und MHC Klasse I-Antigenpräsentation postuliert, die Gegenstand künftiger Studien sein wird.

Analysing the possible influence of transposon TCl4.7 insertion on the function of the genome of Cydia pomonella granulovirus

CpGV-MCp5 is a natural mutant of the Cydia pomonella Granulovirus (Mexican isolate) (CpGV-M) that harbors an insect host transposon termed TCl4.7 in its genome. TCl4.7 is located between the open reading frames Cp15 and Cp16 and separates two homologous regions hr3 and hr4, which have been recently shown to be origins of replication of CpGV-M. The MCp5 has a significant replication disadvantage in the presence of the wild-type CpGV-M. In this study, the possible effects of TCl4.7 transposon insertion on the genome function of its insertion site has been analysed. The role of Cp15 and Cp16 in the context of the virus infection cycle was examined by generating a CpGV-Bacmid (CpBAC) and Cp15 knock-out (CpBACCp15KO) and Cp16 knock-out (CpBACCp16KO) mutants. The mutant CpBACCp15KO was not able to replicate in CM larvae suggesting that Cp15 was essential for virus replication. In contrast, the mutant CpBACCp16KO infected CM larvae and produced viable occlusion bodies (OBs) demonstrating that Cp16 is a non-essential gene for virus in vivo infection of C. pomonella. The temporal transcription of Cp15 and Cp16, as well as of Cp31 (F protein) as a control, was analysed using RT-PCR and quantitative real-time PCR. It suggested a general delay or reduction of gene transcription of MCp5 compared to the parental CpGV-M. Western blot analyses using anti-Cp15 and anti-Cp16 polyclonal antibodies, however, did not show any immuno-reactive response. Thus, a direct influence of TCl4.7 on the expression of Cp15 and Cp16 could not be substantiated. To investigate whether the interruption of hr3 and hr4 palindromes affects the virus replication, two mutant bacmids with a deletion of hr3 and hr4 (CpBAChr3/hr4-KO) and another with an insertion of a Kanamycin resistance cassette between hr3 and hr4 (CpBAChr3-kan-hr4) were generated. Both mutant bacmids replicated and produced infectious virus OBs, which did not significantly differ in their median lethal concentration (LC50) and median survival time (ST50) compared to the parental CpBAC. Interestingly, the mutant CpBAChr3-kan-hr4 was very effectively out-competed by parental CpBAC, when CM larvae were co-infected with known ratios of OBs of CpBAC and the mutant CpBAChr3-kan-hr4. These observations suggested a functional co-operation between hr3 and hr4 which was interrupted by the KanR insertion in CpBAChr3-kan-hr4 and possibly by TCl4.7 transposon insertion in the mutant MCp5. This hypothesis may explain the observed replication disadvantage of the mutants MCp5 and CpBAChr3-kan-hr4 in the presence of the parental viruses CpGV-M and CpBAC, respectively.

Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells

Immune responses have the important function of host defense and protection against pathogens. However, the immune response also causes inflammation and host tissue injury, termed immunopathology. For example, hepatitis B and C virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. Similarly, after infection with lymphocytic choriomeningitis virus (LCMV) in mice, the adaptive immune response causes liver cell damage, choriomeningitis and destruction of lymphoid organ architecture. The immunopathological sequel during LCMV infection has been attributed to cytotoxic CD8(+) T cells. However, we now show that during LCMV infection CD4(+) T cells selectively induced the destruction of splenic marginal zone and caused liver cell damage with elevated serum alanin-transferase (ALT) levels. The destruction of the splenic marginal zone by CD4(+) T cells included the reduction of marginal zone B cells, marginal zone macrophages and marginal zone metallophilic macrophages. Functionally, this resulted in an impaired production of neutralizing antibodies against LCMV. Furthermore, CD4(+) T cells reduced B cells with an IgM(high)IgD(low) phenotype (transitional stage 1 and 2, marginal zone B cells), whereas other B cell subtypes such as follicular type 1 and 2 and germinal center/memory B cells were not affected. Adoptive transfer of CD4(+) T cells lacking different important effector cytokines and cytolytic pathways such as IFNγ, TNFα, perforin and Fas-FasL interaction did reveal that these cytolytic pathways are redundant in the induction of immunopathological sequel in spleen. In conclusion, our results define an important role of CD4(+) T cells in the induction of immunopathology in liver and spleen. This includes the CD4(+) T cell mediated destruction of the splenic marginal zone with consecutively impaired protective neutralizing antibody responses.

Phosphatidylethanol (PEth) as a Biomarker of Alcohol Consumption in HIV-Positive Patients in Sub-Saharan Africa

Background:  Alcohol is heavily consumed in sub-Saharan Africa and affects HIV transmission and treatment and is difficult to measure. Our goal was to examine the test characteristics of a direct metabolite of alcohol consumption, phosphatidylethanol (PEth). Methods:  Persons infected with HIV were recruited from a large HIV clinic in southwestern Uganda. We conducted surveys and breath alcohol concentration (BRAC) testing at 21 daily home or drinking establishment visits, and blood was collected on day 21 (n = 77). PEth in whole blood was compared with prior 7-, 14-, and 21-day alcohol consumption. Results:  (i) The receiver operator characteristic area under the curve (ROC-AUC) was highest for PEth versus any consumption over the prior 21 days (0.92; 95% confidence interval [CI]: 0.86 to 0.97). The sensitivity for any detectable PEth was 88.0% (95% CI: 76.0 to 95.6) and the specificity was 88.5% (95% CI: 69.8 to 97.6). (ii) The ROC-AUC of PEth versus any 21-day alcohol consumption did not vary with age, body mass index, CD4 cell count, hepatitis B virus infection, and antiretroviral therapy status, but was higher for men compared with women (p = 0.03). (iii) PEth measurements were correlated with several measures of alcohol consumption, including number of drinking days in the prior 21 days (Spearman r = 0.74, p < 0.001) and BRAC (r = 0.75, p < 0.001). Conclusions:  The data add support to the body of evidence for PEth as a useful marker of alcohol consumption with high ROC-AUC, sensitivity, and specificity. Future studies should further address the period and level of alcohol consumption for which PEth is detectable.

Tight junctions in brain barriers during central nervous system inflammation

Homeostasis within the central nervous system (CNS) is a prerequisite to elicit proper neuronal function. The CNS is tightly sealed from the changeable milieu of the blood stream by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the BBB is established by specialized endothelial cells of CNS microvessels, the BCSFB is formed by the epithelial cells of the choroid plexus. Both constitute physical barriers by a complex network of tight junctions (TJs) between adjacent cells. During many CNS inflammatory disorders, such as multiple sclerosis, human immunodeficiency virus infection, or Alzheimer's disease, production of pro-inflammatory cytokines, matrix metalloproteases, and reactive oxygen species are responsible for alterations of CNS barriers. Barrier dysfunction can contribute to neurological disorders in a passive way by vascular leakage of blood-borne molecules into the CNS and in an active way by guiding the migration of inflammatory cells into the CNS. Both ways may directly be linked to alterations in molecular composition, function, and dynamics of the TJ proteins. This review summarizes current knowledge on the cellular and molecular aspects of the functional and dysfunctional TJ complexes at the BBB and the BCSFB, with a particular emphasis on CNS inflammation and the role of reactive oxygen species.

Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections

Colonisation of the gastrointestinal tract by anaerobic bacteria, protozoa, trematodes, cestodes and/or nematodes and other infectious pathogens, including viruses, represents a major cause of morbidity and mortality in Africa, South America and southeast Asia, as well as other parts of the world. Nitazoxanide is a member of the thiazolide class of drugs with a documented broad spectrum of activity against parasites and anaerobic bacteria. Moreover, the drug has recently been reported to have a profound activity against hepatitis C virus infection. In addition, nitazoxanide exhibits anti-inflammatory properties, which have prompted clinical investigations for its use in Crohn's disease. Studies with nitazoxanide derivatives have determined that there must be significantly different mechanisms of action acting on intracellular versus extracellular pathogens. An impressive number of clinical studies have shown that the drug has an excellent bioavailability in the gastrointestinal tract, is fast acting and highly effective against gastrointestinal bacteria, protozoa and helminthes. A recent Phase II study has demonstrated viral response (hepatitis C) to monotherapy, with a low toxicity and an excellent safety profile over 24 weeks of treatment. Pre-clinical studies have indicated that there is a potential for application of this drug against other diseases, not primarily affecting the liver or the gastrointestinal tract.

Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. METHODS: We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. RESULTS: A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). CONCLUSIONS: In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabetes.

Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets

Platelets are known to contain platelet factor 4 and beta-thromboglobulin, alpha-chemokines containing the CXC motif, but recent studies extended the range to the beta-family characterized by the CC motif, including RANTES and Gro-alpha. There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets. This study shows that platelets have functional CCR1, CCR3, CCR4, and CXCR4 chemokine receptors. Polymerase chain reaction detected chemokine receptor messenger RNA in platelet RNA. CCR1, CCR3, and especially CCR4 gave strong signals; CXCR1 and CXCR4 were weakly positive. Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weak signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative. Immunoprecipitation and Western blotting with polyclonal antibodies to cytoplasmic peptides clearly showed the presence of CCR1 and CCR4 in platelets in amounts comparable to monocytes and CCR4 transfected cells, respectively. Chemokines specific for these receptors, including monocyte chemotactic protein 1, macrophage inflammatory peptide 1alpha, eotaxin, RANTES, TARC, macrophage-derived chemokine, and stromal cell-derived factor 1, activate platelets to give Ca(++) signals, aggregation, and release of granule contents. Platelet aggregation was dependent on release of adenosine diphosphate (ADP) and its interaction with platelet ADP receptors. Part, but not all, of the Ca(++) signal was due to ADP release feeding back to its receptors. Platelet activation also involved heparan or chondroitin sulfate associated with the platelet surface and was inhibited by cleavage of these glycosaminoglycans or by heparin or low molecular weight heparin. These platelet receptors may be involved in inflammatory or allergic responses or in platelet activation in human immunodeficiency virus infection.

[HIV-associated thrombocytopenia]

Thrombocytopenia is a relatively frequent hematological complication of HIV (human immunodeficiency virus) infection. The incidence of thrombocytopenia in a cohort of 359 homo- or bisexual men with HIV infection was 3%, while it was 9% in a cohort of 321 HIV positive persons with a history of intravenous drug abuse. We followed 42 thrombocytopenic patients prospectively to study the clinical significance of thrombocytopenia in these patients. Thrombocytopenia was significantly more severe in intravenous drug abusers than in homo- or bisexual men: 52% of the drug abusers had thrombocyte counts below 10,000/mm3, compared with only 9% of the homo- or bisexual men. Symptoms of bleeding, almost always harmless skin or mucosal bleeding, were found in 45% of patients with a history of intravenous drug abuse and in 18% of the homo- or bisexual men. Life-threatening bleeding episodes did not occur during a median observation period of approximately one year. Prednisone was the most commonly used drug in symptomatic thrombocytopenia and had demonstrable effect only while being administered. After medication was stopped the thrombocyte counts usually fell to pretreatment values. Our findings suggest that therapy of HIV-associated thrombocytopenia should be reserved for severely symptomatic patients, particularly since this symptom of HIV infection rarely causes serious complications and we do not know the influence of drugs such as corticosteroids on the progression rate of HIV-infection.

Evaluation of the transforming growth factor beta1 codon 25 (Arg-->Pro) polymorphism in alcoholic liver disease

INTRODUCTION: Liver cirrhosis develops only in a minority of heavy drinkers. Genetic factors may account for some variation in the progression of fibrosis in alcoholic liver disease (ALD). Transforming growth factor beta 1 (TGFbeta1) is a key profibrogenic cytokine in fibrosis and its gene contains several polymorphic sites. A single nucleotide polymorphism at codon 25 has been suggested to affect fibrosis progression in patients with chronic hepatitis C virus infection, fatty liver disease, and hereditary hemochromatosis. Its contribution to the progression of ALD has not been investigated sufficiently so far. PATIENTS AND METHODS: One-hundred-and-fifty-one heavy drinkers without apparent ALD, 149 individuals with alcoholic cirrhosis, and 220 alcoholic cirrhotics who underwent liver transplantation (LTX) were genotyped for TGFbeta1 codon 25 variants. RESULTS: Univariate analysis suggested that genotypes Arg/Pro or Pro/Pro are associated with decompensated liver cirrhosis requiring LTX. However, after adjusting for patients' age these genotypes did not confer a significant risk for cirrhosis requiring LTX. CONCLUSION: TGFbeta1 codon 25 genotypes Arg/Pro or Pro/Pro are not associated with alcoholic liver cirrhosis. Our study emphasizes the need for adequate statistical methods and accurate study design when evaluating the contribution of genetic variants to the course of chronic liver diseases.

An outbreak of mumps in a population partially vaccinated with the Rubini strain

Since 1991, 6 years after the recommendation of universal childhood triple vaccination against measles, mumps and rubella (M + M + R), Switzerland has been confronted with an increasing number of mumps cases affecting both vaccinated and unvaccinated children. The M + M + R vaccine mainly used in the Swiss population after 1986 contains the highly attenuated Rubini strain of mumps virus. We analysed an outbreak of 102 suspected mumps cases by virus isolation, determination of IgM antibodies to mumps virus in 27 acute phase sera, and verification of vaccination histories. Mumps was confirmed by virus isolation in 88 patients, of whom 72 had previously received the Rubini vaccine strain. IgM antibodies to mumps virus were detected in 24/27 acute phase serum samples. A group of 92 subjects from the same geographic area without signs of mumps virus infection served as controls. IgG antibodies to mumps virus and vaccination status were assessed in these children. The vaccination rate in these controls was 61%, with equal seropositivity for unvaccinated and Rubini-vaccinated subjects. These data support other recent reports which indicate an insufficient protective efficacy of current mumps vaccines.

Influenza-associated myositis in children

BACKGROUND: Influenza-associated myositis (IAM) is an infrequent and poorly known complication of influenza virus infection in children. The aim of this study was to describe five cases of IAM and to review the literature on IAM in children. PATIENTS AND METHODS: We conducted a retrospective analysis of cases of IAM diagnosed at two university children's hospitals in Switzerland during two consecutive influenza seasons. Findings were compared with 39 individual case reports and five publications summarizing an additional 272 cases identified by a medical online library (MEDLINE) search. RESULTS: Overall, 316 cases were analyzed. IAM typically occurred in school-aged children with a 2:1 male predominance. Influenza B and A viruses were identified in 76% and 24% of cases, respectively. The median interval between onset of influenza and onset of IAM was 3 days (range 0-18). The calf muscles were involved alone or together with other muscle groups in 69% and 31% of cases, respectively. Blood creatine phosphokinase (CPK) concentration was invariably elevated. Median duration to clinical recovery was 3 days (range 1-30). Rhabdomyolysis occurred in ten of 316 patients (3%), was more common in girls (80%), more often associated with influenza A (86%), and led to renal failure in eight patients (80%). CONCLUSION: Clinical and laboratory findings of IAM are highly characteristic and allow a rapid diagnosis during the influenza season.

[Odynophagia of a young mother]

We report the case of a 34-year old mother presenting in the emergency unit because of fever and odynophagia. Herpetic esophagitis with Herpes simplex virus primoinfection in a immunocompetent patient was diagnosed. The virus was transmitted by her own child which came to be hospitalised because of herpetic stomatitis. In the blood chemistry pancreas enzymes were elevated which we interpreted as herpetic pancreatitis because of coincidence with herpetic esophagitis.

Toward global prevention of sexually transmitted infections (STIs): The need for STI vaccines.

An estimated 499 million curable sexually transmitted infections (STIs; gonorrhea, chlamydia, syphilis, and trichomoniasis) occurred globally in 2008. In addition, well over 500 million people are estimated to have a viral STI such as herpes simplex virus type 2 (HSV-2) or human papillomavirus (HPV) at any point in time. STIs result in a large global burden of sexual, reproductive, and maternal-child health consequences, including genital symptoms, pregnancy complications, cancer, infertility, and enhanced HIV transmission, as well as important psychosocial consequences and financial costs. STI control strategies based primarily on behavioral primary prevention and STI case management have had clear successes, but gains have not been universal. Current STI control is hampered or threatened by several behavioral, biological, and implementation challenges, including a large proportion of asymptomatic infections, lack of feasible diagnostic tests globally, antimicrobial resistance, repeat infections, and barriers to intervention access, availability, and scale-up. Vaccines against HPV and hepatitis B virus offer a new paradigm for STI control. Challenges to existing STI prevention efforts provide important reasons for working toward additional STI vaccines. We summarize the global epidemiology of STIs and STI-associated complications, examine challenges to existing STI prevention efforts, and discuss the need for new STI vaccines for future prevention efforts.