A Vaccine Encoding Conserved Promiscuous HIV CD4 Epitopes Induces Broad T Cell Responses in Mice Transgenic to Multiple Common HLA Class II Molecules

Current HIV vaccine approaches are focused on immunogens encoding whole HIV antigenic proteins that mainly elicit cytotoxic CD8+ responses. Mounting evidence points toward a critical role for CD4+ T cells in the control of immunodeficiency virus replication, probably due to cognate help. Vaccine-induced CD4+ T cell responses might, therefore, have a protective effect in HIV replication. In addition, successful vaccines may have to elicit responses to multiple epitopes in a high proportion of vaccinees, to match the highly variable circulating strains of HIV. Using rational vaccine design, we developed a DNA vaccine encoding 18 algorithm-selected conserved, “promiscuous” (multiple HLA-DR-binding) B-subtype HIV CD4 epitopes - previously found to be frequently recognized by HIV-infected patients. We assessed the ability of the vaccine to induce broad T cell responses in the context of multiple HLA class II molecules using different strains of HLA class II- transgenic mice (-DR2, -DR4, -DQ6 and -DQ8). Mice displayed CD4+ and CD8+ T cell responses of significant breadth and magnitude, and 16 out of the 18 encoded epitopes were recognized. By virtue of inducing broad responses against conserved CD4+ T cell epitopes that can be recognized in the context of widely diverse, common HLA class II alleles, this vaccine concept may cope both with HIV genetic variability and increased population coverage. The vaccine may thus be a source of cognate help for HIV-specific CD8+ T cells elicited by conventional immunogens, in a wide proportion of vaccinees

Follicular CD4 T Helper Cells As a Major HIV Reservoir Compartment: A Molecular Perspective

Effective antiretroviral therapy (ART) has prevented the progression to AIDS and reduced HIV-related morbidities and mortality for the majority of infected individuals. However, a lifelong administration of ART is necessary, placing an inordinate burden on individuals and public health systems. Therefore, discovering therapeutic regimens able to eradicate or functionally cure HIV infection is of great importance. ART interruption leads to viral rebound highlighting the establishment and maintenance of a latent viral reservoir compartment even under long-term treatment. Follicular helper CD4 T cells (TFH) have been reported as a major cell compartment contributing to viral persistence, consequent to their susceptibility to infection and ability to release replication-competent new virions. Here, we discuss the molecular profiles and potential mechanisms that support the role of TFH cells as one of the major HIV reservoirs

Broad and Cross-Clade CD4(+) T-Cell Responses Elicited by a DNA Vaccine Encoding Highly Conserved and Promiscuous HIV-1 M-Group Consensus Peptides

T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4(+) T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4(+) T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4(+) T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IA(b) and IA(d). Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-gamma secretion against 11 out of the 27 peptides in BALB/c mice; CD4(+) and CD8(+) T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4(+) and CD8(+) T cells, able to simultaneously proliferate and produce IFN-gamma and TNF-alpha, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS.Brazilian National Research Council (CNPq) [420166/2005-0]Brazilian National Research Council (CNPq)Sao Paulo State Research Funding Agency (FAPESP) [2004/15856-9, 2006/50096-0, 2008/57881-0]Sao Paulo State Research Funding Agency (FAPESP)Brazilian Program for STD and AIDS, Ministry of HealthBrazilian Program for STD and AIDS, Ministry of Health [914/BRA/3014-UNESCO/Kallas]Sao Paulo City Health Department [2004-0.168.922-7/Kallas]Sao Paulo City Health DepartmentBrazilian Council for Scientific and Technological Development - CNPq productivity awardsBrazilian Council for Scientific and Technological Development CNPq productivity award

Capacidade funcional de indivíduos com insuficiência cardíaca avaliada pelo teste de esforço cardiopulmonar e classificação da New York Heart Association

O objetivo deste estudo foi avaliar a capacidade discriminativa da classificação da New York Heart Association (NYHA) em indivíduos com insuficiência cardíaca (IC) classes II e III por meio de variáveis do teste de esforço cardiopulmonar (TECP). Participaram do estudo 17 pessoas com IC classe II (44,47±10,11 anos; fração de ejeção ventricular 32,11±10,37%) e 15 classe III (46,73±8,74 anos; fração de ejeção ventricular 30,46±10,23%) da NYHA que realizaram TECP máximo em esteira ergométrica. De acordo com a distribuição dos dados, houve correlação de Pearson ou Spearman e, para comparação entre classes, utilizou-se o teste t de Student. Foram encontradas correlações significativas (pThe purpose of this study was to evaluate the capacity of the New York Heart Association (NYHA) classification to discriminate heart failure (HF) individuals classes II and III using cardiopulmonary exercise test (CPET) variables. Seventeen patients class II (age 44.47±10.11 years; ejection fraction 32.11±10.37%) and 15 class III (age 46.73±8.74 years; ejection fraction 30.46±10.23%) of NYHA participated in this study. They did a maximal CPET in a treadmill ergometer. According to the distribution of data, correlation of Pearson or Spearman was performed and, to compare the functional classes of NYHA, the Student's t-test was used. Significant correlations (

A DNA Vaccine Encoding Multiple HIV CD4 Epitopes Elicits Vigorous Polyfunctional, Long-Lived CD4+ and CD8+ T Cell Responses

T-cell based vaccines against HIV have the goal of limiting both transmission and disease progression by inducing broad and functionally relevant T cell responses. Moreover, polyfunctional and long-lived specific memory T cells have been associated to vaccine-induced protection. CD4+ T cells are important for the generation and maintenance of functional CD8+ cytotoxic T cells. We have recently developed a DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18), capable of eliciting broad CD4+ T cell responses in multiple HLA class II transgenic mice. Here, we evaluated the breadth and functional profile of HIVBr18-induced immune responses in BALB/c mice. Immunized mice displayed high-magnitude, broad CD4+/CD8+ T cell responses, and 8/18 vaccine-encoded peptides were recognized. In addition, HIVBr18 immunization was able to induce polyfunctional CD4+ and CD8+ T cells that proliferate and produce any two cytokines (IFNγ/TNFα, IFNγ/IL-2 or TNFα/IL-2) simultaneously in response to HIV-1 peptides. For CD4+ T cells exclusively, we also detected cells that proliferate and produce all three tested cytokines simultaneously (IFNγ/TNFα/IL-2). The vaccine also generated long-lived central and effector memory CD4+ T cells, a desirable feature for T-cell based vaccines. By virtue of inducing broad, polyfunctional and long-lived T cell responses against conserved CD4+ T cell epitopes, combined administration of this vaccine concept may provide sustained help for CD8+ T cells and antibody responses- elicited by other HIV immunogens

Production and hydration of calcium sulfoaluminate-belite cements derived from aluminium anodising sludge

Calcium sulfoaluminate-belite cement (CSAB) offers lower CO2 emissions in its production, compared with Portland cement. However, for the production of CSAB a high amount of alumina is required, and the scarcity and high cost of high-purity bauxite make these cements costly at present. In this study, the use of uncalcined aluminium anodising sludge (AAS) as the main source of alumina to produce CSAB clinkers, replacing bauxite, was assessed. The CSAB clinkers produced were mainly composed of ye’elimite and belite, along with minor traces of alite, and/or brownmillerite, depending on the alumina source. Clinkers derived from AAS as a source of aluminium showed a lower content of ye’elimite (35.5%), as well as the formation of alite (8.2%) when compared to a reference clinker produced with reagent-grade materials. Comparable hydration products were identified in the hydrated cements independent of the alumina source used. The use of AAS to produce CSAB cement was proven to be technically feasible, and the cement thus produced has desirable technical characteristics, presenting high mechanical strength (>40 MPa in paste samples)