Current drug targets. Infectious disorders最新文献_第2页

Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. hiv感染人群中的胰岛素抵抗:线粒体功能障碍的潜在作用

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880163

C M Shikuma, L J Day, M Gerschenson

{"title":"Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction.","authors":"C M Shikuma, L J Day, M Gerschenson","doi":"10.2174/1568005054880163","DOIUrl":"https://doi.org/10.2174/1568005054880163","url":null,"abstract":"Insulin resistance is accepted as the underlying fundamental defect that predates and ultimately leads to the development of type 2 (adult onset) diabetes mellitus in the general non-human immunodeficiency virus (HIV)-infected population. Insulin resistance is also a major component of the metabolic syndrome that, in association with other factors such as hypertension, hypercholesterolemia, and central obesity, defines a pre-diabetic atherogenic state that leads to adverse cardiovascular events. Growing evidence now suggests that mitochondrial dysfunction in skeletal muscle may be the mechanism whereby insulin resistance is induced. The prevalence of insulin resistance, glucose intolerance, and diabetes in the HIV-infected population has dramatically increased following the common use of highly active antiretroviral therapy (HAART). The development of insulin resistance in the HIV-infected population is likely to be multifactorial reflecting genetic predisposition, direct and indirect effects of both the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) class of antiretroviral therapy, and a possible contribution from chronic inflammatory changes induced by HIV. Indirect effects of antiretroviral therapy on insulin resistance may be mediated through both the visceral adiposity and peripheral fat depletion components of lipodystrophy as well as through fatty infiltration in liver and muscle. Based on current knowledge, mitochondrial dysfunction can be hypothesized to play a key role in each of these components.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"255-62"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25599965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 53

Paracoccidioides brasiliensis, paracoccidioidomycosis, and antifungal antibiotics. 巴西副球孢子虫，副球孢子菌病和抗真菌抗生素。

Current drug targets. Infectious disorders Pub Date : 2005-09-01 DOI: 10.2174/1568005054880118

G Visbal, G San-Blas, J Murgich, H Franco

{"title":"Paracoccidioides brasiliensis, paracoccidioidomycosis, and antifungal antibiotics.","authors":"G Visbal, G San-Blas, J Murgich, H Franco","doi":"10.2174/1568005054880118","DOIUrl":"https://doi.org/10.2174/1568005054880118","url":null,"abstract":"Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), a human systemic, chronic and progressive mycosis. Preferred antifungals are sulfamethoxazol-trimethoprim, itraconazole, amphotericin B. Treatment is lengthy, the drugs may have undesirable side effects, and some are costly. Occasional resistant strains have been reported. Therefore, the search for more selective and efficient antifungals to treat this and other mycoses continues. Ajoene, chemically derived from garlic, behaves as an antifungal agent against P. brasiliensis and other fungi. Its antiproliferative effects in P. brasiliensis are associated with a reduction of phosphatidyl choline, a concomitant increase in its precursor phosphatidyl ethanolamine, and a large increase in unsaturated fatty acids in the pathogenic yeast phase. The sterol biosynthetic pathway has been largely studied for the search of antifungals. Azoles and allilamines act on differents steps of this pathway. However, they may interfere with similar steps in the host. Hence, the search for drugs that may act on more specific steps is ongoing. One such step focuses on the sterol C-methylations catalyzed by the enzyme (S)-adenosyl-L-methionine: Delta(24) - sterol methyl transferase (SMT). SMT inhibitors such as azasterols and derivatives (AZA1, AZA2, AZA3) have proven highly effective as antiproliferative agents against protozoa and some fungi, among them, P. brasiliensis. Their chemical synthesis and structure, and their molecular electrostatic potential are discussed in order to understand their mechanism of action, and derive rationally designed improvements on these molecules, that would favour a higher efficacy and selectivity.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 3","pages":"211-26"},"PeriodicalIF":0.0,"publicationDate":"2005-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054880118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25601680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 36

Fundamental immunology and what it can teach us about HIV vaccine development. 基础免疫学及其对HIV疫苗开发的启示。

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201562

N Avrion Mitchison, Quentin Sattentau

{"title":"Fundamental immunology and what it can teach us about HIV vaccine development.","authors":"N Avrion Mitchison, Quentin Sattentau","doi":"10.2174/1568005054201562","DOIUrl":"https://doi.org/10.2174/1568005054201562","url":null,"abstract":"This survey covers the immunological background to development of an HIV vaccine, starting from an overview of present understanding of the mechanisms of immunoregulation. It follows the uptake, processing and presentation of an antigen, from its initial uptake by a dendritic cell and its deposit on the dendrites of follicular dendritic cells. It pursues the antigen through uptake by B cells, presentation of epitopes to helper T cells and the eventual production of antibody. In the second arm of the immune response it follows synapse formation between dendritic cell and CD4/CD8 cells leading to production of CTL. It identifies epitope linkage as a key element in directing these pathways. It identifies the principal functions of the various types of cell cooperation. Continuing, it focuses on topics relevant to vaccine development: Th1/Th2 balance: new adjuvants based on ligands of TLRs and other activators of innate immunity, as well as new forms of intervention in antigen processing. We urge that the new vaccine fusion constructs be evaluated against a fusion gold standard rather than against antigen alone. These considerations open new strategies of HIV vaccine development. . Finally we urge that vaccine trials should include storage of individual DNA samples, in order to gain better understanding of the genetic parameters of vaccine efficacy.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"87-93"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25152033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

HIV-1: the confounding variables of virus neutralization. HIV-1:病毒中和的混杂变量。

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201535

Peter L Nara, George Lin

{"title":"HIV-1: the confounding variables of virus neutralization.","authors":"Peter L Nara, George Lin","doi":"10.2174/1568005054201535","DOIUrl":"https://doi.org/10.2174/1568005054201535","url":null,"abstract":"The development of an effective vaccine against HIV-1 would be greatly facilitated by the ability to elicit potent, high affinity antibodies that are capable of broad neutralization, viral inactivation and protection against infection and/or disease. New insights into the structure and function of the HIV-1 envelope glycoprotein (Env) that mediates viral fusion and entry may ultimately lead to strategies successful in eliciting these protective antibody responses. Insights have been gained regarding HIV-1 Env attachment and receptor engagement, the fusion process and kinetics, and the structural/functional attributes of Env that allow humoral immune evasion. In addition, studies of a limited number of broadly neutralizing human monoclonal antibodies have shed some light as to how antibodies may penetrate the immune evading armor that HIV-1 has evolved. As the elusive goal of generating these types of antibodies emerge and are developed in the context of generating new candidate HIV-1 vaccines, a relevant in vitro measurement of neutralization by these types of antibodies becomes a complex task. This is in part due to a list of confounding variables which include: the physical and genomic nature (amino acid variation) of the infecting virion, the type of target cells, the concentration and clonality of the reactants, assay format and design, the affinity and kinetics of the reaction, receptors/coreceptors and attachment factors, and soluble host factors. This review will focus on the past, current, and future knowledge required to advance the field of HIV-1 humoral immunity as it impacts future HIV-1 vaccine development.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"157-70"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Non-human primate models for AIDS vaccine research. 用于艾滋病疫苗研究的非人类灵长类动物模型。

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201508

Shiu-Lok Hu

{"title":"Non-human primate models for AIDS vaccine research.","authors":"Shiu-Lok Hu","doi":"10.2174/1568005054201508","DOIUrl":"https://doi.org/10.2174/1568005054201508","url":null,"abstract":"Since the discovery of simian immunodeficiency viruses (SIV) causing AIDS-like diseases in Asian macaques, non-human primates (NHP) have played an important role in AIDS vaccine research. A multitude of vaccines and immunization approaches have been evaluated, including live attenuated viruses, DNA vaccines, viral and bacterial vectors, subunit proteins, and combinations thereof. Depending on the particular vaccine and model used, varying degrees of protection have been achieved, including prevention of infection, reduction of viral load, and amelioration of disease. In a few instances, potential safety concerns and vaccine-enhanced pathogenicity have also been noted. In the past decade, sophisticated methodologies have been developed to define the mechanisms of protective immunity. However, a clear road map for HIV vaccine development has yet to emerge. This is in part because of the intrinsic nature of the surrogate model and in part because of the improbability of any single model to fully capture the complex interactions of natural HIV infection in humans. The lack of standardization, the limited models available, and the incomplete understanding of the immunobiology of NHP contribute to the difficulty to extrapolate findings from such models to HIV vaccine development. Until efficacy data become available from studies of parallel vaccine concepts in humans and macaques, the predictive value of any NHP model remains unknown. Towards this end, greater appreciation of the utility and limitations of the NHP model and further developments to better mimic HIV infection in humans will likely help inform future AIDS vaccine efforts.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"193-201"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 87

Differentiation of CD8 T cells in response to acute and chronic viral infections: implications for HIV vaccine development. CD8 T细胞在急性和慢性病毒感染反应中的分化:对HIV疫苗开发的影响

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201544

J D Miller, D Masopust, E J Wherry, S Kaech, G Silvestri, R Ahmed

引用次数: 19

Inactivated- or killed-virus HIV/AIDS vaccines. 灭活或灭活艾滋病毒/艾滋病疫苗。

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201599

Haynes W Sheppard

{"title":"Inactivated- or killed-virus HIV/AIDS vaccines.","authors":"Haynes W Sheppard","doi":"10.2174/1568005054201599","DOIUrl":"https://doi.org/10.2174/1568005054201599","url":null,"abstract":"Inactivated or \"killed\" virus (KV) is a \"classical\" approach that has produced safe and effective human and veterinary vaccines but has received relatively little attention in the effort to develop an HIV/AIDS vaccine. Initially, KV and rgp120 subunit vaccines were the two most obvious approaches but, unfortunately, rgp120 has not been efficacious and the KV approach has been limited by a variety of scientific, technical, and sociological factors. For example, when responses to cellular antigens, present on SIV grown in human cells, proved to be largely responsible for efficacy, the KV approach was widely discounted. Similarly, when lab-adapted HIV-1 appeared to lose envelope glycoprotein during preparation (not the case for primary isolates), this was viewed as a fundamental barrier to the KV concept. Also, a preference for \"safer\", genetically-engineered vaccines, and emphasis on cellular immunity, have left KV low on the priority list for funding agencies and investigators. The recent suggestion that \"native\" trimeric gp120 displays conserved conformational neutralization epitopes, along with the failure of rgp120, and difficulties in raising strong cellular responses with DNA or vectored vaccines, has restored some interest in the KV concept. In the past 15 years, several groups have initiated pre-clinical development of KV candidates for SIV or HIV and promising, albeit limited, information has been produced. In this chapter we discuss the rationale (including pros and cons) for producing and testing killed-HIV vaccines, the prospects for success, the nature and scope of research needed to test the KV concept, what has been learned to date, and what remains undone.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"131-41"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Antibodies: can they protect against HIV infection? 抗体:它们能预防HIV感染吗?

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201580

C M Mc Cann, R J Song, R M Ruprecht

{"title":"Antibodies: can they protect against HIV infection?","authors":"C M Mc Cann, R J Song, R M Ruprecht","doi":"10.2174/1568005054201580","DOIUrl":"https://doi.org/10.2174/1568005054201580","url":null,"abstract":"More than 20 million people have died since the discovery of human immunodeficiency virus (HIV), yet a broadly reactive AIDS vaccine remains elusive. Neutralizing antibody (nAb) response-based vaccine strategies were the first to be tested; however, when the difficulty in neutralizing primary HIV isolates was recognized, vaccine development focused instead on generating cytotoxic T-lymphocyte (CTL) responses. Recently, interest in anti-HIV nAbs has been revived by the impressive protection achieved in primates given passive immunization with neutralizing monoclonal antibodies (nmAbs) isolated from HIV clade B-infected individuals. The nmAbs used in these studies target conserved, functionally important epitopes in HIV gp120 and gp41. Regimens involving combinations of such human nmAbs or high-dose single-agent nmAb protected monkeys against intravenous (iv) and mucosal challenges with simian-human immunodeficiency virus (SHIV) strains encoding X4, X4R5 or R5 HIV env genes. In several such studies, sterilizing immunity was achieved, thus providing proof-of-concept that nAbs targeting conserved epitopes can be fully protective. The existence of these broadly reactive nmAbs suggests that it may be possible to design immunogens capable of inducing similar nAb responses by active vaccination. Unraveling the three-dimensional structures involved in the nmAb-HIV Env epitope interactions may facilitate the future development of a potent AIDS vaccine. This review is focused on the importance of nAbs in protecting against HIV infection or in containing viral spread, with particular emphasis on the successful use of nmAbs in passive immunization studies. The implications of the data from these studies on AIDS vaccine design in general are also discussed.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"95-111"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 41

Application of the polyvalent approach to HIV-1 vaccine development. 多价方法在HIV-1疫苗研制中的应用

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201517

Julia L Hurwitz, Karen S Slobod, Tim D Lockey, Shixia Wang, Te-Hui W Chou, Shan Lu

{"title":"Application of the polyvalent approach to HIV-1 vaccine development.","authors":"Julia L Hurwitz, Karen S Slobod, Tim D Lockey, Shixia Wang, Te-Hui W Chou, Shan Lu","doi":"10.2174/1568005054201517","DOIUrl":"https://doi.org/10.2174/1568005054201517","url":null,"abstract":"One major obstacle to the design of a global HIV-1 vaccine is viral diversity. Presently, data suggest that a single antigen will not suffice to generate broadly reactive neutralizing antibodies to protect all individuals against all subtypes of HIV-1 infection. While some of the neutralizing epitopes are identified in the constant regions of the HIV-1 envelope (Env) glycoprotein, many are localized to variable regions and differ conformationally from one virus to the next. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage adoption of the same approach for HIV-1 vaccine design. The critical question is which envelope antigens should be combined in a vaccine cocktail to provide maximum protection against HIV-1. A review of the existing human vaccines based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Data generated from several groups actively working on candidate polyvalent HIV-1 vaccines are summarized. Information presented in this review highlights the potential and importance of the polyvalent vaccine approach for the future development of an effective HIV-1 vaccine.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"143-56"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 35

Predicting the potential public health impact of disease-modifying HIV vaccines in South Africa: the problem of subtypes. 预测南非改善疾病的艾滋病毒疫苗的潜在公共卫生影响:亚型问题。

Current drug targets. Infectious disorders Pub Date : 2005-06-01 DOI: 10.2174/1568005054201616

Sally M Blower, Erin N Bodine, Kathie Grovit-Ferbas

{"title":"Predicting the potential public health impact of disease-modifying HIV vaccines in South Africa: the problem of subtypes.","authors":"Sally M Blower, Erin N Bodine, Kathie Grovit-Ferbas","doi":"10.2174/1568005054201616","DOIUrl":"https://doi.org/10.2174/1568005054201616","url":null,"abstract":"Current HIV vaccines in development appear unlikely to prevent infection, but could provide benefits by increasing survival; such vaccines are described as disease-modifying vaccines. We review the current status of vaccines and modeling vaccines. We also predict the impact that disease-modifying vaccines could have in South Africa, where multiple subtypes are co-circulating. We model transmissibility/fitness differences among subtypes. We used uncertainty analyses to model vaccines with four characteristics: (i) take, (ii) duration of immunity, (iii) reduction in transmissibility/fitness, and (iv) increase in survival. We reconstructed, and forecasted, the South African epidemic from 1940 to 2140 (assuming no vaccination). We predict that: (i) incidence will peak in 2014, decline, and stabilize, (ii) prevalence will continue to rise, and (iii) the AIDS death rate curve will peak in 2022. Our predictions show that (over the next 135 years) the epidemic in South Africa will switch from a predominantly Subtype C epidemic to an epidemic driven by other subtypes. We predict that the epidemic could remain unchanged, even with mass vaccination with a vaccine that is equally effective against all co-circulating subtypes. However, if the non-C subtypes are less (or equally) transmissible as Subtype C then disease-modifying vaccines could result in eradication. Thus, in countries where multiple-subtypes are co-circulating it is critical to realize that small biological differences among subtypes will have dramatic consequences for the effectiveness of HIV vaccination campaigns. A slight difference in fitness will determine whether a disease-modifying vaccine has almost no impact on the epidemic or can achieve eradication.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"5 2","pages":"179-92"},"PeriodicalIF":0.0,"publicationDate":"2005-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005054201616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25153130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20