Evolution of the Human Immunodeficiency Virus Type 2 Envelope in the First Years of Infection is Associated with the Dynamics of the Neutralizing Antibody Response

Background: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth. Results: CD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies. Conclusion: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

Environment and Health in Children Day Care Centres (ENVIRH) - Study Rationale and Protocol

Background: Indoor air quality (IAQ) is considered an important determinant of human health. The association between exposure to volatile organic compounds, particulate matter, house dust mite, molds and bacteria in day care centers (DCC) is not completely clear. The aim of this project was to study these effects. Methods --- study design: This study comprised two phases. Phase I included an evaluation of 45 DCCs (25 from Lisbon and 20 from Oporto, targeting 5161 children). In this phase, building characteristics, indoor CO2 and air temperature/relative humidity, were assessed. A children’s respiratory health questionnaire derived from the ISAAC (International Study on Asthma and Allergies in Children) was also distributed. Phase II encompassed two evaluations and included 20 DCCs selected from phase I after a cluster analysis (11 from Lisbon and 9 from Oporto, targeting 2287 children). In this phase, data on ventilation, IAQ, thermal comfort parameters, respiratory and allergic health, airway inflammation biomarkers, respiratory virus infection patterns and parental and child stress were collected. Results: In Phase I, building characteristics, occupant behavior and ventilation surrogates were collected from all DCCs. The response rate of the questionnaire was 61.7% (3186 children). Phase II included 1221 children. Association results between DCC characteristics, IAQ and health outcomes will be provided in order to support recommendations on IAQ and children’s health. A building ventilation model will also be developed. Discussion: This paper outlines methods that might be implemented by other investigators conducting studies on the association between respiratory health and indoor air quality at DCC.

Invasive Assessment of the Coronary Microcirculation Using the Index of Microcirculatory Resistance: Description and Validation of an Animal Model

INTRODUCTION: The index of microcirculatory resistance (IMR) enables/provides quantitative, invasive, and real-time assessment of coronary microcirculation status. AIMS: The primary aim of this study was to validate the assessment of IMR in a large animal model, and the secondary aim was to compare two doses of intracoronary papaverine, 5 and 10 mg, for induction of maximal hyperemia and its evolution over time. METHODS: Measurements of IMR were performed in eight pigs. Mean distal pressure (Pd) and mean transit time (Tmn) were measured at rest and at maximal hyperemia induced with intracoronary papaverine, 5 and 10 mg, and after 2, 5, 8 and 10 minutes. Disruption of the microcirculation was achieved by selective injection of 40-μm microspheres via a microcatheter in the left anterior descending artery. RESULTS: In each animal 14 IMR measurements were made. There were no differences between the two doses of papaverine regarding Pd response and IMR values - 11 ± 4.5 U with 5 mg and 10.6 ± 3 U with 10 mg (p=0.612). The evolution of IMR over time was also similar with the two doses, with significant differences from resting values disappearing after five minutes of intracoronary papaverine administration. IMR increased with disrupted microcirculation in all animals (41 ± 16 U, p=0.001). CONCLUSIONS: IMR provides invasive and real-time assessment of coronary microcirculation. Disruption of the microvascular bed is associated with a significant increase in IMR. A 5-mg dose of intracoronary papaverine is as effective as a 10-mg dose in inducing maximal hyperemia. After five minutes of papaverine administration there is no significant difference from resting hemodynamic status.