Adoption of an “Open” Envelope Conformation Facilitating CD4 Binding and Structural Remodeling Precedes Coreceptor Switch in R5 SHIV-Infected Macaques

A change in coreceptor preference from CCR5 to CXCR4 towards the end stage disease in some HIV-1 infected individuals has been well documented, but the reasons and mechanisms for this tropism switch remain elusive. It has been suggested that envelope structural constraints in accommodating amino acid changes required for CXCR4 usage is an obstacle to tropism switch, limiting the rate and pathways available for HIV-1 coreceptor switching. The present study was initiated in two R5 SHIVSF162P3N-infected rapid progressor macaques with coreceptor switch to test the hypothesis that an early step in the evolution of tropism switch is the adoption of a less constrained and more “open” envelope conformation for better CD4 usage, allowing greater structural flexibility to accommodate further mutational changes that confer CXCR4 utilization. We show that, prior to the time of coreceptor switch, R5 viruses in both macaques evolved to become increasingly sCD4-sensitive, suggestive of enhanced exposure of the CD4 binding site and an “open” envelope conformation, and this correlated with better gp120 binding to CD4 and with more efficient infection of CD4low cells such as primary macrophages. Moreover, significant changes in neutralization sensitivity to agents and antibodies directed against functional domains of gp120 and gp41 were seen for R5 viruses close to the time of X4 emergence, consistent with global changes in envelope configuration and structural plasticity. These observations in a simian model of R5-to-X4 evolution provide a mechanistic basis for the HIV-1 coreceptor switch

Assistência Farmacêutica no Sistema Único de Saúde: da Política Nacional de Medicamentos à Atenção Básica à Saúde Pharmaceutical Assistance in the Basic Units of Health: from the National Drug Policy to the Basic Attention to Health

Este artigo é um estudo de revisão teórica que discute a Assistência Farmacêutica no Sistema Único de Saúde, resgatando-se brevemente a história da Política Nacional de Medicamentos, os mecanismos de financiamento no processo de descentralização da saúde e a Assistência Farmacêutica na Atenção Básica à Saúde. A ampliação do acesso da população ao sistema de saúde exigiu mudanças na distribuição de medicamentos, de maneira a aumentar a cobertura e ao mesmo tempo minimizar custos. Identificam-se avanços no arcabouço jurídico e institucional: descentralização da gestão das ações da assistência farmacêutica; ampliação do acesso da população aos medicamentos essenciais; e estruturação da assistência farmacêutica nos municípios. No entanto, persistem ações prioritárias em relação ao financiamento e cobertura populacional, em detrimento da qualidade dos processos. Conclui-se que em muitos municípios brasileiros ocorrem baixa disponibilidade e descontinuidade da oferta de medicamentos essenciais; dispensação por trabalhadores sem qualificação; condições inadequadas de armazenamento que comprometem a qualidade dos medicamentos; prescrição de medicamentos que não pertencem à Relação Nacional de Medicamentos Essenciais; e problemas relacionados ao acesso dos usuários à farmacoterapia.<br>This study of theoretical revision discuss the Pharmaceutical Assistance in the Basic Units of Health, rescuing briefly the history of the National Drug Policy, the mechanisms of financing in the process of health decentralization and Pharmaceutical Assistance on the Basic Attention to Health. The expansion of the population access to the health system has demanded changes on drug distribution in order to increase the coverage and at the same time to reduce costs. It was identified advances in legal and institutional structures: the management decentralization of actions on pharmaceutical assistance; the expansion of the population access to essential medicines; and the establishment of the pharmaceutical assistance in some cities. However, it still persists priority actions in relation to the financing and population coverage, in detriment of quality processes. The conclusion is that, many Brazilian cities has low availability and discontinuity of essential medicine offer; dispensation by workers without qualification; inadequate conditions of storage that compromise the quality of medicines; medicine prescription that does not belong to the National Reference of Essential Medicines; and problems related to the access of users to the pharmacotherapy