A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells.

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.

Triggering of TLR-3, -4, NOD2, and DC-SIGN reduces viral replication and increases T-cell activation capacity of HIV-infected human dendritic cells.

A variety of signals influence the capacity of dendritic cells (DCs) to mount potent antiviral cytotoxic T-cell (CTL) responses. In particular, innate immune sensing by pathogen recognition receptors, such as TLR and C-type lectines, influences DC biology and affects their susceptibility to HIV infection. Yet, whether the combined effects of PPRs triggering and HIV infection influence HIV-specific (HS) CTL responses remain enigmatic. Here, we dissect the impact of innate immune sensing by pathogen recognition receptors on DC maturation, HIV infection, and on the quality of HS CTL activation. Remarkably, ligand-driven triggering of TLR-3, -4, NOD2, and DC-SIGN, despite reducing viral replication, markedly increased the capacity of infected DCs to stimulate HS CTLs. This was exemplified by the diversity and the quantity of cytokines produced by HS CTLs primed by these DCs. Infecting DCs with viruses harboring members of the APOBEC family of antiviral factors enhanced the antigen-presenting skills of infected DCs. Our results highlight the tight interplay between innate and adaptive immunity and may help develop innovative immunotherapies against viral infections.

Why individuals fail to collect HIV-test results: an exploratory study at a testing and counseling center in Mexico City.

OBJECTIVE: To identify the characteristics of clients at an HIV clinic in Mexico City who fail to collect their HIV test results and to explore the reasons for non-collection. METHODS: This was an exploratory, cross-sectional study that used 2016 program data from the HIV Testing and Counseling Center in Mexico City. Clients with a negative HIV-test result in 2016 were classified as collectors or non-collectors, and their sociodemographic and behavioral characteristics were compared by multivariate logistic regression. A telephone survey was conducted with individuals who failed to return for their results. RESULTS: In 2016, a total of 729 individuals obtained an HIV negative test result at the Center. Of these, 40% (n = 299) failed to collect results. In multivariate analysis, having a test requested by a physician, instead of by the individual, was the main variable associated with non-collection. The main reasons reported for not collecting were: unawareness of the collection process (23.6%, n = 21), already knowing the result (22.5%, n = 20), and scheduling difficulties (13.5%, n = 12). In all, 35% of clients were reached by telephone and 50% then returned to collect results. CONCLUSION: Modifications to the result-delivery system are needed to increase results collection. Improving communication with clients on the collection process and with physicians that request HIV testing could be viable strategies. Alternative ways of delivering results and using rapid HIV are other possible solutions, as long as risk reduction counseling and intervention are still effectively offered.

CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation.

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection.

Escape from highly effective public CD8+ T-cell clonotypes by HIV.

Mapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed a comprehensive analysis of the effective CD8(+) T-cell clonotypes that constitute responses specific for the HIV p24 Gag-derived KK10 epitope (KRWIILGLNK; residues 263-272) restricted by HLA-B*2705, which are known to confer superior control of viral replication in HIV-infected individuals. Particular KK10-specific CD8(+) T-cell clonotypes, characterized by TRBV4-3/TRBJ1-3 gene rearrangements, were found to be preferentially selected in vivo and shared between individuals. These "public" clonotypes exhibit high levels of TCR avidity and Ag sensitivity, which impart functional advantages and enable effective suppression of HIV replication. The early L(268)M mutation at position 6 of the KK10 epitope enables the virus to avoid recognition by these highly effective CD8(+) T-cell clonotypes. However, alternative clonotypes with variant reactivity provide flexibility within the overall KK10-specific response. These findings provide refined mechanistic insights into the workings of an effective CD8(+) T-cell response against HIV.

Measuring confidence in physician: Adaptation and validation of TPS in HIV individuals from Mexico / Evaluar confianza en el médico: Adaptación y validación del Trust in Physician Scale (TPS) en personas mexicanas que viven con VIH

Abstract Introduction Patient-physician relationship is associated with ART adherence and medical follow-up in people living with HIV (PLWH). Patient's trust in their doctor is a key component of patient-physician relationship, so adequate and reliable instruments to measure this component are important to evaluate its impact on health outcomes. Objective To evaluate the psychometric properties of a translated and adapted version of Trust in Physician Scale (TPS) in Mexican PLWH. Method A cross-sectional study was carried out in PLWH. Scale was translated to Spanish and culturally adapted. Sociodemographic and TPS data were collected online due to COVID-19 pandemic. Exploratory (EFA) and confirmatory (CFA) factor analysis were carried out in two different samples. Results Data from 215 participants was used to EFA. Five items were eliminated due to low correlation with total scale. Final Cronbach's alpha was .93. A single-factor structure explained 68.8% of the variance. CFA in a sample of 140 participants confirmed adequate fit indices (χ2[7] = 13.015 p = .072, CFI = .997, RMSEA = .057, SMRS = .0015). Discussion and conclusion The final scale was unifactorial and it is made up of six items instead of 11. It seems to be a valid and reliable scale to measure patient's trust in doctors in Mexican PLWH. Further studies are recommended to provide evidence of convergent validity to the instrument.

Resumen Introducción La relación médico-paciente está asociada a la adherencia al tratamiento antirretroviral y al seguimiento médico en las personas que viven con VIH (PVVS). La confianza de los pacientes en sus médicos es un componente clave de la relación médico-paciente, por lo que es importante disponer de instrumentos adecuados y fiables para medir este componente y evaluar su impacto en los resultados de salud. Objetivo Evaluar las propiedades psicométricas de una versión traducida y adaptada de la Trust in Physician Scale (TPS) en PVVS mexicanas. Método Se realizó un estudio transversal en adultos con VIH. La escala fue traducida al español y adaptada culturalmente. Los datos sociodemográficos y de la TPS se recogieron en línea debido a la pandemia de COVID-19. Se realizaron análisis factoriales exploratorios (AFE) y confirmatorios (AFC) en dos muestras diferentes. Resultados Se utilizaron los datos de 215 participantes para el AFE. Se eliminaron cinco ítems debido a la baja correlación con la escala total. El alfa de Cronbach final fue de .93. Una estructura unifactorial explicó el 68.8% de la varianza. El AFC en una muestra de 140 participantes confirmó la adecuación del modelo mostrando índices de ajuste adecuados (χ2[7] = 13.015 p = .072, CFI = .997, RMSEA =.057, SMRS = .0015). Discusión y conclusión La escala final fue unifactorial y se compuso de seis ítems en lugar de 11. Parece ser una escala válida y fiable para medir la confianza del paciente en los médicos en PVVS mexicanas. Se recomiendan más estudios para buscar evidencia de validez convergente del instrumento.

Why individuals fail to collect HIV-test results: an exploratory study at a testing and counseling center in Mexico City / Por qué las personas no retiran los resultados de las pruebas del VIH: estudio exploratorio en un centro de pruebas y asesoramiento en Ciudad de México / Por que os pacientes não voltam para buscar os resultados do teste do HIV: estudo exploratório em um centro de testagem e aconselhamento na cidade do México

ABSTRACT Objective To identify the characteristics of clients at an HIV clinic in Mexico City who fail to collect their HIV test results and to explore the reasons for non-collection. Methods This was an exploratory, cross-sectional study that used 2016 program data from the HIV Testing and Counseling Center in Mexico City. Clients with a negative HIV-test result in 2016 were classified as collectors or non-collectors, and their sociodemographic and behavioral characteristics were compared by multivariate logistic regression. A telephone survey was conducted with individuals who failed to return for their results. Results In 2016, a total of 729 individuals obtained an HIV negative test result at the Center. Of these, 40% (n = 299) failed to collect results. In multivariate analysis, having a test requested by a physician, instead of by the individual, was the main variable associated with non-collection. The main reasons reported for not collecting were: unawareness of the collection process (23.6%, n = 21), already knowing the result (22.5%, n = 20), and scheduling difficulties (13.5%, n = 12). In all, 35% of clients were reached by telephone and 50% then returned to collect results. Conclusion Modifications to the result-delivery system are needed to increase results collection. Improving communication with clients on the collection process and with physicians that request HIV testing could be viable strategies. Alternative ways of delivering results and using rapid HIV are other possible solutions, as long as risk reduction counseling and intervention are still effectively offered.

RESUMEN Objetivo Determinar las características de las personan que acuden a un consultorio de atención de la infección por el VIH en Ciudad de México y no regresan a retirar los resultados de las pruebas de detección del VIH, y explorar las razones de este comportamiento. Métodos Este fue un estudio exploratorio y transversal que usó datos del programa correspondientes al 2016 de un centro de pruebas de detección del VIH y asesoramiento conexo en Ciudad de México. Se clasificó a las personas con resultado negativo en la prueba de detección del VIH en dos grupos, las que "retiraron los resultados" y las que "no retiraron los resultados"; sus características sociodemográficas y conductuales fueron comparadas mediante regresión logística multifactorial. Se realizó una encuesta telefónica a las personas que no regresaron a buscar sus resultados. Resultados En el 2016, 729 personas tuvieron un resultado negativo en la prueba de detección del VIH en el centro. De ellas, 40% (n = 299) no acudieron a retirar los resultados. En el análisis multifactorial, la variable principal asociada con el hecho de no acudir a buscar los resultados fue que la prueba hubiera sido solicitada por un médico, en vez de que la persona hubiera acudido por sí misma a realizársela. Las principales razones informadas para no presentarse a buscar los resultados fueron: desconocimiento de que debían ir a buscarlos (23,6%, n = 21), conocimiento previo del resultado (22,5%, n = 20) y problemas de horarios (13,5%, n = 12). En total, se logró contactar por teléfono a 35% de las personas y 50% luego acudieron a retirar los resultados. Conclusiones Es necesario modificar el sistema de entrega de resultados para aumentar el número de personas que acuden a retirarlos. Algunas estrategias viables podrían ser mejorar la comunicación sobre el mecanismo de entrega de resultados con los pacientes y los médicos que solicitan las pruebas de detección del VIH. Otras soluciones posibles podrían ser mecanismos alternativos para informar los resultados o realización de pruebas rápidas de detección del VIH, siempre que se siga ofreciendo asesoramiento sobre la reducción de riesgos e intervenciones eficaces.

RESUMO Objetivo Identificar as características dos pacientes de um serviço ambulatorial especializado em HIV na cidade do México que não voltam para buscar os resultados do teste do HIV e examinar os motivos para não voltarem para buscar os resultados. Métodos Estudo exploratório transversal realizado com dados de 2016 obtidos em um centro de testagem e aconselhamento de HIV na cidade do México. Os pacientes com resultados negativos no teste de HIV em 2016 foram divididos entre dois grupos: os que voltaram para buscar os resultados e os que não voltaram para buscar os resultados. As características sociodemográficas e de comportamento destes pacientes foram comparadas em um modelo de regressão logística multivariada. Uma pesquisa por telefone foi realizada com os que não voltaram para buscar os resultados do teste. Resultados Ao todo, em 2016, 729 pacientes tiveram resultados negativos no teste de HIV no serviço ambulatorial. Destes, 40% (n = 299) não voltaram para buscar os resultados. Na análise multivariada, ter o teste solicitado por um médico, em vez de pelo próprio indivíduo, foi a principal variável associada a não voltar para buscar os resultados. Os principais motivos informados para não voltar para buscar os resultados foram: desconhecimento do procedimento para buscar os resultados (23,6%, n = 21), saber previamente o resultado (22,5%, n = 20) e dificuldade para marcar um horário (13,5%, n = 12). Ao todo, 35% dos pacientes foram localizados por telefone e 50% voltaram para buscar os resultados. Conclusões É preciso modificar o sistema de informe dos resultados para aumentar o número de pacientes que voltam para buscá-los. Melhorar a comunicação com os pacientes sobre o processo de informe dos resultados e com os médicos que solicitam o teste de HIV poderia ser uma estratégia viável. Maneiras alternativas de informar os resultados e o uso do teste rápido de HIV são outras soluções possíveis, contanto que se continue a oferecer aconselhamento para redução dos riscos e intervenção.

Immunodominance of HLA-B27-restricted HIV KK10-specific CD8(+) T-cells is not related to naïve precursor frequency.

The factors that determine the immunodominance, efficacy and almost ubiquitous presence of CD8(+) T-cell responses to the HLA-B27-restricted HIV-1 p24 Gag-derived KK10 epitope remain to be fully elucidated. Here, we show that neither the precursor frequency nor the priming capacity of KK10-reactive CD8(+) T-cells within the naïve pool differ substantially in comparison to other specificities. These data implicate alternative mechanisms in the relative protection conferred by CD8(+) T-cell responses to this epitope.

Lentiviral vectors encoding HIV-1 polyepitopes induce broad CTL responses in vivo.

Lentiviral vectors have been tested as vaccination vectors in anti-tumoral and anti-viral models. They efficiently transduce dendritic cells and stimulate strong T-cell responses against the encoded antigen. However, their capacity to stimulate a cytotoxic T-lymphocyte (CTL) response against several antigens has not been evaluated. Broad anti-human immunodeficiency virus 1 (HIV-1) T-cell immune responses are important for the control of HIV replication. We evaluated the potential of polyepitope-encoding lentiviral vectors to induce broad anti-HIV CTL responses. We constructed two lentiviral vectors coding for an HLA-A2- or HLA-B7-restricted polyepitope and evaluated their immunogenicity by direct injection of vector particles in HLA-A2 or HLA-B7 transgenic mice. In vitro cytotoxicity assays showed that a single immunization induces a strong, diversified, and long-lasting CTL response in both mouse models. CTL responses were directed against all 13 epitopes in the HLA-A2 system and 8 out of 12 in the HLA-B7 system. A second immunization augmented the number of responding mice in the HLA-A2 system but not in the HLA-B7 system. HLA-B7-immunized mice mounted strong interferon-gamma (IFN-gamma)-secreting T-cell responses against a majority of the epitopes and lysed peptide-loaded target cells in vivo. CTL responses in HLA-B7 mice were only partially dependent on CD4 T-cell help. This work underlines the potential of lentiviral vectors as candidates for therapeutic vaccination against acquired immunodeficiency syndrome.

A single immunization with a minute dose of a lentiviral vector-based vaccine is highly effective at eliciting protective humoral immunity against West Nile virus.

BACKGROUND: Lentiviral vectors, due to their capacity to transduce non-dividing cells, have become precious and worldwide used gene transfer systems. Their ability to efficiently and stably transduce dendritic cells (DCs) has led to their successful use as vaccination vectors for eliciting strong, specific and protective cellular immune responses mostly in anti-tumoral but also in anti-viral applications. However, the ability of lentiviral vectors to elicit an antibody-based protective immunity has, to date, not been evaluated. In the present study, we evaluated the potential of a lentiviral vector-based vaccine to elicit humoral immunity against West Nile virus (WNV). WNV is a mosquito-borne flavivirus that emerged in North America and causes encephalitis in humans, birds and horses. Neutralizing anti-WNV antibodies have been shown to be crucial for protection against WNV encephalitis. METHODS: The ability of lentiviral vector TRIP/sE(WNV), expressing the secreted soluble form of the envelope E-glycoprotein (sE(WNV)) from the highly virulent IS-98-ST1 strain of WNV, to induce a specific humoral response and protection against WNV infection was assessed in a mouse model of WNV encephalitis. RESULTS: Remarkably, a single immunization with a minute dose of TRIP/sE(WNV) was efficient at eliciting a long-lasting, protective and sterilizing humoral immunity, only 1 week after priming. CONCLUSIONS: This study broadens the applicability of lentiviral vectors as efficient non-replicating vaccines against pathogens for which a neutralizing humoral response is one active arm of the protective immunity. The TRIP/sE(WNV) lentiviral vector appears to be a promising tool for veterinary vaccination against zoonotic WNV.