RESUMO
The majority of HIV-1 infections occur via sexual intercourse. Women are the most affected by the epidemic, particularly in developing countries, due to their socio-economic dependence on men and the fact that they are often victims of gender based sexual violence. Despite significant efforts that resulted in the reduction of infection rates in some countries, there is still need for effective prevention methods against the virus. One of these methods for preventing sexual transmission in women is the use of microbicides. In this review we provide a summary of the progress made toward the discovery of affordable and effective HIV-1 microbicides and suggest future directions. We show that there is a wide range of compounds that have been proposed as potential microbicides. Although most of them have so far failed to show protection in humans, there are many promising ones currently in pre-clinical studies and in clinical trials.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Descoberta de Drogas , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Animais , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Feminino , Genitália Feminina/virologia , Infecções por HIV/transmissão , Humanos , Masculino , Mucosa/virologia , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Doenças Virais Sexualmente Transmissíveis/transmissão , Doenças Virais Sexualmente Transmissíveis/virologiaRESUMO
Mycobacterium tuberculosis, the causative agent of tuberculosis, is characterized by the abundance of species specific, antigenic cell wall lipids called mycolic acids. These wax-like molecules all share an identical, amphiphilic mycolic motif, but have different functional groups in a long hydrophobic hydrocarbon mero-chain that divide them into three main classes: alpha-, keto- and methoxy-mycolic acids. Whereas alpha-mycolic acids constitutively maintain an abundance of around 50%, the ratio of methoxy- to keto-mycolic acid types may vary depending on, among other things, the growth stage of M. tuberculosis. In human patients, antibodies to mycolic acids have shown potential as diagnostic serum biomarkers for active TB. Variations in mycolic acid composition affect the antigenic properties and can potentially compromise the precision of detection of anti-mycolic acids antibodies in patient sera to natural mixtures. We demonstrate this here with combinations of synthetic mycolic acid antigens, tested against TB patient and control sera. Combinations of methoxy- and α-mycolic acids are more antigenic than combinations of keto- and α-mycolic acids, showing the former to give a more sensitive test for TB biomarker antibodies. Natural mixtures of mycolic acids isolated from mature cultures of M. tuberculosis H37Rv give the same sensitivity as that with synthetic methoxy- and α-mycolic acids in combination, in a surface plasmon resonance inhibition biosensor test. To ensure that the antigenic activity of isolates of natural mycolic acids is reproducible, we cultured M. tuberculosis H37Rv on Middlebrook 7H10 solid agar plates to stationary growth phase in a standardized, optimal way. The proportions of mycolic acid classes in various batches of the isolates prepared from these cultures were compared to a commercially available natural mycolic acid isolate. LC-MS/MS and NMR data for quantitation of mycolic acids class compositions show that the variation in batches is small, suggesting that the quality of the results for anti-mycolic acid antibody detection in the TB patients should not be affected by different batches of natural mycolic acid antigens if prepared in a standard way.
Assuntos
Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/química , Ácidos Micólicos/imunologia , Tuberculose/diagnóstico , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/isolamento & purificação , Biomarcadores/sangue , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Humanos , Mycobacterium tuberculosis/química , Testes Sorológicos , Espectrometria de Massas em Tandem , Tuberculose/imunologiaAssuntos
Bactérias/genética , Bacteriófago T7/genética , Epitopos/genética , Biblioteca de Peptídeos , Fosfotirosina/genética , Proteínas Tirosina Quinases/genética , Animais , Anticorpos , Fusão Gênica Artificial , Epitopos/imunologia , Expressão Gênica/genética , Vetores Genéticos , Humanos , Camundongos , Fosforilação , Fosfotirosina/imunologia , Reação em Cadeia da Polimerase , Proteínas Recombinantes/genética , Análise de Sequência de DNARESUMO
Macrophages, centrally involved in both the innate and adaptive arms of the immune system are not only the chief target of the human immunodeficiency virus (HIV), but also its main reservoir and vehicle of transmission. Macrophage-tropic (M-tropic) viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of preferential T cell- and/or dual-tropic HIV-1 variants. Functional impairment of HIV-infected macrophages plays a role in the immune dysregulation characteristic of acquired immunodeficiency syndrome (AIDS). Efforts directed at understanding the cellular and molecular mechanisms underlying HIV-macrophage interactions remain the basis for devising novel and efficacious therapeutic strategies against HIV ant the AIDS epidemic.
