RESUMO
BACKGROUND: We aimed to describe the mechanisms of immunological recovery and the effects of blocking CCR5 in patients starting ART with advanced HIV-infection. METHODS: This was a sub-study of a 48 week double-blind, clinical trial where patients starting ART with CD4+ cell counts <100 cells/uL were randomized to receive maraviroc or a placebo. CD4+ and CD8+ cell maturation phenotypes, expression of PD-1 and CCR5, and activation indices were measured at weeks 0, 4, 12, 24, and 48. The reactivity of CD4+ and CD8+cells with peptides of CMV and MTb, and with Staphylococcal enterotoxin B (SEB) was assessed by intracellular expression of IFNγ, TNFα, and CD40 ligand at weeks 0, 4, and 12 of ART. RESULTS: Forty patients were included in the study (Maraviroc = 22; placebo = 18). Sustained increases in CD8+ cells and in proportions of CCR5+ CD4+ and CD8+ cells were observed in the maraviroc arm. Early increases in the proportions of activated (CD38+, HLA-DR+), PD-1+ CD4+, and CD8+ cells and more matured CD8+ cells, were observed in the maraviroc arm. T cell responses to CMV, MTb, and SEB did not differ by treatment arms. CONCLUSIONS: During antiretroviral therapy in advanced HIV infection, maraviroc retains mature, activated CCR5+ cells in circulation without impact on CD4+ T cell recovery or T cell reactivity to antigen or superantigen.
RESUMO
Protection against HIV-1 infection in exposed seronegative (ESN) individuals likely involves natural resistance mechanisms that have not been fully elucidated. Human beta defensins (HBD) are antimicrobial peptides found primarily in mucosae, the main ports of HIV entry. HBD-2 and 3 mRNA are induced by HIV-1 in human oral epithelial cells and exhibit strong anti-HIV-1 activity; in addition, polymorphisms in the DEFB1 gene, which encodes HBD-1, have been associated with resistance/susceptibility to different infections, including HIV-1. Here, we have assessed the association of HBD expression with the ESN phenotype. Peripheral blood and vaginal/endocervical and oral mucosal samples were taken from 47 ESN, 44 seropositive (SP) and 39 healthy controls (HC). HBD-1, 2 and 3 mRNA copy numbers were quantified by real time RT-PCR and A692G/G1654A/A1836G polymorphisms in the DEFB1 gene were detected by restriction fragment length polymorphisms and confirmed by nucleotide sequencing. ESN expressed significantly greater mRNA copy numbers of HBD-2 and 3 in oral mucosa than HC; p=0.0002 and p=0.007, respectively. mRNA copy numbers of HBD-1, 2 and 3 in vaginal/endocervical mucosa from ESN and HC were similar. Homozygosity for the A692G polymorphism was significantly more frequent in ESN (0.39) than in SP (0.05) (p=0.0002). In summary, ESN exhibited enhanced mucosal expression of the innate defense genes HBD-2 and 3; however, additional studies are required to verify these results and the potential association of the A692G polymorphism to the relative resistance of ESN to HIV-1 infection.
Assuntos
Perfilação da Expressão Gênica , HIV-1/imunologia , RNA Mensageiro/biossíntese , beta-Defensinas/genética , Adolescente , Adulto , Endométrio/imunologia , Feminino , Frequência do Gene , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Vagina/imunologia , beta-Defensinas/biossínteseRESUMO
A University-based hospital in Bogotá, Colombia, developed and implemented an educational intervention to complement a new structured antibiotic order form. This intervention was performed after assessing the appropriateness of the observed antibiotic prescribing practices using a quasi-experimental study. An application of interrupted time series intervention analysis was conducted in three antibiotic groups (aminoglycosides, cephradine/cephalothin, and ceftazidime/cefotaxime) and their hospital weekly rate of incorrect prescriptions before and after the intervention. A fourth time series was defined on prophylactic antibiotic use in elective surgery. Preintervention models were used in the postintervention series to test for pre-post series level differences. An abrupt constant change was significant in the first, third, and fourth time series indicating a 47, 7.3, and 20% reduction of incorrect prescriptions after the intervention. We conclude that a structured antibiotic order form, coupled with graphic and educational interventions can improve antibiotic use in a university hospital.