Modulation of TCR avidity of primary HIV-1-specific CD8 T-cell responses by early and potent antiviral therapy responses

Background: CD8 T-cells play a critical role in antiviral immunity. However, mechanisms of virus control and immune correlates of protection are still not fully understood. Among other factors, TCR avidity (antigen sensitivity) is thought to play a critical role. Whereas there is a large consensus that high TCR avidity T-cell responses are correlated to higher efficacy against cancer and acute viral infections, it may be not the case in chronic persistent viral infections. Methods: TCR avidity (measured by the effect concentration 50% [EC50]) of HIV-1-specific CD8 T-cell responses directed against optimal epitopes was investigated in different cohorts of HIV-1- infected subjects (n¼114) including early acute and chronic (progressive and non-progressive) HIV-1-infection. Overall, TCR avidity was investigated in 245 HIV-1-specific CD8 T-cell responses. The relationships between TCR avidity, T-cell differentiation and functional profile including cytokine secretion, proliferation and cytotoxic potential (determined by polychromatic flow cytometry) were analyzed. Results: HIV-1-specific CD8 T-cell responses from patients with acute infection had significantly lower TCR avidity as compared to patients with chronic (progressive or non-progressive) HIVinfection (P¼0.03 and 0.003, respectively). These differences remained significant when the analyses were restricted to common epitopes (same epitopes restricted by the same class I HLA). Interestingly, some patients treated during acute infection underwent spontaneous treatment interruption. Re-exposure to high viral load induced two major effects: a) the increase in TCR avidity of pre-existing high avidity (EC50<0.01) T-cell responses (P<0.02) and b) the generation of new T-cell responses with higher TCR avidity as compared to the average pre-existing T-cell responses. Conclusion: These results suggest that high TCR avidity T-cell responses are selected during the course of HIV-1 infection and that one of the potential driving mechanisms is continuous exposure to HIV-1 antigens. These results advance our understanding of the relationship between TCR avidity and Ag exposure of antiviral memory CD8 T-cells.

The effect of antiretroviral treatment of different durations in primary HIV infection.

OBJECTIVES: To compare immunological, virological and clinical outcomes in persons initiating combination antiretroviral therapy (cART of different durations within 6 months of seroconversion (early treated) with those who deferred therapy (deferred group). DESIGN: CD4 cell and HIV-RNA measurements for 'early treated' individuals following treatment cessation were compared with the corresponding ART-free period for the 'deferred' group using piecewise linear mixed models. Individuals identified during primary HIV infection were included if they seroconverted from 1st January 1996 and were at least 15 years of age at seroconversion. Those with at least 2 CD4 less than 350 cells/microl or AIDS within the first 6 months following seroconversion were excluded. RESULTS: Of 348 'early treated' patients, 147 stopped cART following treatment for at least 6 (n = 38), more than 6-12 (n = 40) or more than 12 months (n = 69). CD4 cell loss was steeper for the first 6 months following cART cessation, but subsequent loss rate was similar to the 'deferred' group (n = 675, P = 0.26). Although those treated for more than 12 months appeared to maintain higher CD4 cell counts following cART cessation, those treated for 12 months or less had CD4 cell counts 6 months after cessation comparable to those in the 'deferred' group. There was no difference in HIV-RNA set points between the 'early' and 'deferred' groups (P = 0.57). AIDS rates were similar but death rates, mainly due to non-AIDS causes, were higher in the 'deferred' group (P = 0.05). CONCLUSION: Transient cART, initiated within 6 months of seroconversion, seems to have no effect on viral load set point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months. Its long-term effects remain inconclusive and need further investigation.

Outcomes of patients on dual-boosted PI regimens : experience of the Swiss HIV cohort study

Rapport de SynthèseLa thérapie antirétrovirale a progressée de manière significative depuis te début de l'épidémie du syndrome d'immunodéficience acquise (SIDA). Durant les 20 dernières années, plusieurs combinaisons de traitements ont été utilisées avec succès menant à une réduction de la mortalité associée. Par contre, le traitement a aussi engendré des cas de résistances multiples avec comme résultat, le besoin d'utiliser plusieurs molécules en combinaison, et une augmentation des cas de toxicité. Une stratégie souvent employée fût la combinaison de deux molécules inhibitrices de la protéase en même temps en combinaison avec une troisième molécule, le ritonavir. (DBPI).La cohorte Suisse sur le VIH existe depuis 1987 et permet d'étudier de façon longitudinale les patients qui y sont inscrits. Pour ce travail de thèse, nous avons étudié les patients inscrits à la cohorte suisse de 1996 à 2007 qui ont reçu une combinaison DBPI.Pendant la période étudiée, un total de 405 patients ont reçu un traitement DBPI, dont 295 patients ont reçu le DBPI pour plus de 6 mois. La durée médiane du traitement était de 2.2 ans. Sur les 287 patients qui étaient en échec viral au début du traitement (défini comme HIV RNA>400 copies/ml), 64.1% ont réussi à supprimer la virémie et 54.4% ont eu une suppression dans les 24 semaines qui ont suivi le début de la thérapie. Les patients avaient reçu en moyenne 6 combinaisons de traitement différentes avant le début de la thérapie DBPi. Pour les patients qui ont arrêté le traitement DBPI, la cause principale de l'arrêt était due au souhait du patient (48.3%), à l'échec virologique (22.5%) et à la toxicité (15.8%). Les patients ayant reçu le traitement après 1999, ou ayant été traités avec une combinaison de Lopinavir-ritonvir/saquinavir ou lopinavir-ritonavir/atazanavir arrivaient à supprimer leur virémie plus souvent que ceux qui avaient reçu d'autres combinaisons.Cette étude constitue la plus grande étude publiée sur le sujet de l'utilisation des DBPI pour les patients à résistances multiples. Malgré le fait que c'est une étude observationnelle, nous pouvons attester que le taux de succès était de 64.4%, le taux de toxicité était relativement bas (15.8%) et que la plus part des patients ont toléré ces combinaisons, malgré le taux élevé d'effets secondaires souvent rapportés. En somme, cette approche pourrait être envisagée dans des situations ou les nouveaux traitements tels que les inhibiteurs de l'intégrase et du CCR5 ne sont pas encore disponibles.

A enfermagem frente a acidentes de trabalho com material potencialmente contaminado na era do HIV

Realizou-se esta investigação, com os objetivos de identificar a ocorrência de acidentes de trabalho com material pérfuro-cortante potencialmente contaminado, entre enfermeiros e auxiliares de enfermagem de um Hospital de ensino geral do interior do Estado de São Paulo; relacionar a ocorrência destes acidentes com a categoria profissional e anos de trabalho na instituição; identificar o tipo de material pérfuro-cortante causador do acidente e identificar as condutas tomadas após o acidente, pelo acidentado. Para a coleta de dados, através de entrevista individual, utilizou-se um formulário estruturado onde registrava-se, a causa atribuída ao acidente, o período de atuação do profissional acidentado, o objeto causador, a conduta tomada após o acidente. Evidenciou-se que as Precauções Padrão ou as antigas Precauções Universais não são utilizadas como deveriam, conferindo portanto, risco à equipe de enfermagem. Considera-se que esta equipe necessita de orientações específicas através de educação continuada sobre o assunto.

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.

Virological and Immunological Characterization of Novel NYVAC-Based HIV/AIDS Vaccine Candidates Expressing Clade C Trimeric Soluble gp140(ZM96) and Gag(ZM96)-Pol-Nef(CN54) as Virus-Like Particles.

The generation of vaccines against HIV/AIDS able to induce long-lasting protective immunity remains a major goal in the HIV field. The modest efficacy (31.2%) against HIV infection observed in the RV144 phase III clinical trial highlighted the need for further improvement of HIV vaccine candidates, formulation, and vaccine regimen. In this study, we have generated two novel NYVAC vectors, expressing HIV-1 clade C gp140(ZM96) (NYVAC-gp140) or Gag(ZM96)-Pol-Nef(CN54) (NYVAC-Gag-Pol-Nef), and defined their virological and immunological characteristics in cultured cells and in mice. The insertion of HIV genes does not affect the replication capacity of NYVAC recombinants in primary chicken embryo fibroblast cells, HIV sequences remain stable after multiple passages, and HIV antigens are correctly expressed and released from cells, with Env as a trimer (NYVAC-gp140), while in NYVAC-Gag-Pol-Nef-infected cells Gag-induced virus-like particles (VLPs) are abundant. Electron microscopy revealed that VLPs accumulated with time at the cell surface, with no interference with NYVAC morphogenesis. Both vectors trigger specific innate responses in human cells and show an attenuation profile in immunocompromised adult BALB/c and newborn CD1 mice after intracranial inoculation. Analysis of the immune responses elicited in mice after homologous NYVAC prime/NYVAC boost immunization shows that recombinant viruses induced polyfunctional Env-specific CD4 or Gag-specific CD8 T cell responses. Antibody responses against gp140 and p17/p24 were elicited. Our findings showed important insights into virus-host cell interactions of NYVAC vectors expressing HIV antigens, with the activation of specific immune parameters which will help to unravel potential correlates of protection against HIV in human clinical trials with these vectors. IMPORTANCE: We have generated two novel NYVAC-based HIV vaccine candidates expressing HIV-1 clade C trimeric soluble gp140 (ZM96) and Gag(ZM96)-Pol-Nef(CN54) as VLPs. These vectors are stable and express high levels of both HIV-1 antigens. Gag-induced VLPs do not interfere with NYVAC morphogenesis, are highly attenuated in immunocompromised and newborn mice after intracranial inoculation, trigger specific innate immune responses in human cells, and activate T (Env-specific CD4 and Gag-specific CD8) and B cell immune responses to the HIV antigens, leading to high antibody titers against gp140. For these reasons, these vectors can be considered vaccine candidates against HIV/AIDS and currently are being tested in macaques and humans.

Avaliação dos riscos da infecção pelo HIV segundo diferentes práticas sexuais na perspectiva de estudantes universitários e especialistas em HIV/AIDS

Avaliar as crenças acerca dos graus e riscos atribuídos pelos universitários a diferentes práticas sexuais e comparálas com a atribuição feita por especialistas em AIDS, constituíram o objetivo deste estudo. Um questionário composto por 25 itens (Escala de Probabilidade do tipo Likert), referentes à práticas/hábitos sexuais foi aplicado a alunos dos cursos de graduação em Enfermagem e Obstetrícia, Medicina, Psicologia, Farmácia-Bioquímica, que aquiesceram em respondê-lo. Através deanálise fatorial, usando-se o Sistema Varimax de Rotação, 25 itens foram distribuídos em sete fatores, sendo cinco itens excluídos. Dos 20 itens, 5 foram analisados neste trabalho, compondo dois fatores. O Fator X foi constituído pelos itens 1(sexo vaginal com preservativo) e 2(sexo anal com preservativo). No Fator Y foram alocados os itens: 3(relação com pessoa do sexo oposto), 4(relação vaginal sem preservativo) e 5(sexo anal sem preservativo). Em 80% dos 5 itens, observou-se que os estudantes apresentam conhecimento compatível ao preconizado pelos especialistas. Entretanto faz-se necessária a educação continuada a estes alunos, considerando-os enquanto pessoa e futuro profissional prestador de assistência aos indivíduos infectados pelo HIV ou com AIDS.

Perfil de mulheres portadoras do HIV de uma maternidade no Rio de Janeiro

A AIDS/SIDA tem atemorizado a população mundial nas últimas décadas. Preocupadas com a alta incidência de portadoras do HIV admitidas numa maternidade pública do Município do Rio de Janeiro, as autoras interessaramse em investigar o fenômeno traçando o perfil das gestantes no período de 1987-1996. Através de um estudo retrospectivo, em abordagem quantitativa, foram analisados os registros de 102 prontuários. Os resultados evidenciaram que a população estudada era composta, em sua maioria, por solteiras com idades entre 19 e 33 anos, com baixa escolaridade e ocupação principal de "prendas do lar"; tendo sido contaminadas através de contato sexual. Verificou-se a falta de conhecimento do grupo afetado quanto às formas de exposição ao vírus e a importância da adoção de medidas voltadas para prevenção da contaminação e educação para a saúde.

Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery.

INTRODUCTION: Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe. METHODS: In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre- or postpublication of national guidelines recommending vaginal delivery. RESULTS: Overall, 2663 women with 3013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2354) before to 7% (42/599) after the change in guidelines (P < 0.001). CONCLUSION: There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.

The polymorphic nature of HIV type 1 env V4 affects the patterns of potential N-glycosylation sites in proviral DNA at the intrahost level.

We have previously shown that env V4 from HIV-1 plasma RNA is highly heterogeneous within a single patient, due to indel-associated polymorphism. In this study, we have analyzed the variability of V4 in proviral DNA from unfractionated PBMC and sorted T and non-T cell populations within individual patients. Our data show that the degree of sequence variability and length polymorphism in V4 from HIV provirus is even higher than we previously reported in plasma. The data also show that the sequence of V4 depends largely on the experimental approach chosen. We could observe no clear trend for compartmentalization of V4 variants in specific cell types. Of interest is the fact that some variants that had been found to be predominant in plasma were not detected in any of the cell subsets analyzed. Consistently with our observations in plasma, V3 was found to be relatively conserved at both interpatient and intrapatient level. Our data show that V4 polymorphism involving insertions and deletions in addition to point mutations results in changes in the patterns of sequons in HIV-1 proviral DNA as well as in plasma RNA. These rearrangements may result in the coexistence, within the same individual, of a swarm of different V4 regions, each characterized by a different carbohydrate surface shield. Further studies are needed to investigate the mechanism responsible for the variability observed in V4 and its role in HIV pathogenesis.

A assistência de enfermagem aos portadores de HIV/Aids no vislumbrar da sua epidemia em Ribeirão Preto: relato de experiÊncia de uma equipe de enfermagem

Trata-se de um relato de experiência vivenciada por uma equipe de enfermagem de uma Unidade de Internação, de um hospi tal geral do interior paulista, ao planejar e prestar assistência de enfermagem ao portador do HIV/Aids, no início da epidemia, em 1985.

Compreendendo a sexualidade de indivíduos portadores de HIV-1

Esta investigação teve como objetivo identificar dificuldades sexuais vivenciadas por pessoas em crise de HIV-1. Trata-se de uma pesquisa de caráter descritivo, norteada pela Teoria da Crise. Intrevistou-se de cinco portadores de HIV-1, com seguimento médico numa cidade do interior paulista. As entrevistas foram semi-estruturadas, gravadas e transcritas. A análise dos dados foi baseada em MEIHY (1996) e BARDIN (1994). Concluímos que os sujeitos do estudo apresentaram adaptação negativa frente às dificuldades sexuais, sociais e emocionais. Os resultados apontam para a necessidade de intervenções efetivas de enfermagem junto a pessoa, portadora de HIV-1, em crise.

Necessidades de qualificação da equipe de enfermagem para a assistência aos clientes portadores do HIV e da Aids

Discorre-se sobre as necessidades de qualificação específica das equipes de enfermagem dos Centros de Referência de Doenças Sexualmente Transmissíveis e Aids da Secretaria Municipal da Saúde de São Paulo, para a assistência aos clientes portadores do HIV e da Aids. Foram enviados questionários abertos, para todos os profissionais da equipe de enfermagem de todas as unidades do Programa Municipal de DST/Aids. Do total de 671 profissionais de enfermagem, 453 responderam ao questionário. Como necessidades de qualificação foram apontadas: biossegurança, preparo e administração de medicamentos específicos e assistência de enfermagem aos clientes com HIV e Aids.

Percepção de risco para HIV/AIDS de mulheres faveladas segundo o modelo de crenças em saúde

Este estudo, com abordagem qualitativa, teve como referenciais a Antropologia Cultural e o método etnográfico. Objetivou identificar a percepção de risco de infecção pelo HIV de mulheres moradoras em uma favela. Constou de entrevistas e observação participante do contexto. Os constructos do Modelo de Crenças em Saúde foram utilizados para análise dos dados. Nesta ótica, verificou-se que as mulheres não se vêem com suscetibilidade para infectar-se pelo HIV pelos seus parceiros, situação que se modifica diante da informação da infidelidade destes, Diante desta descoberta, motivam-se a exigir medidas de proteção para evitar infecção pelo HIV no relacionamento com o companheiro.