Sirtuin-2, NAD-Dependent Deacetylase, is a new potential therapeutic target for HIV-1 infection and HIV-related neurological dysfunction

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction

Novel, in-natural-infection subdominant HIV-1 CD8⁺ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines

<div><p>Background</p><p>Fine definition of targeted CD8⁺ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Here, lymphocytes from volunteers, who had received candidate HIVconsv vaccines expressing conserved sub-protein regions of HIV-1, were used to define the optimum-length target epitopes and their HLA restriction. In HIV-1-positive patients, CD8⁺ T-cell responses predominantly recognize immunodominant, but hypervariable and therefore less protective epitopes. The less variable, more protective epitopes in conserved regions are typically subdominant. Therefore, induction of strong responses to conserved regions by vaccination provides an opportunity to discover novel important epitopes.</p><p>Methods</p><p>Cryopreserved lymphocytes from vaccine recipients were expanded by stimulation with 15-mer responder peptides for 10 days to establish short term-cell-line (STCL) effector cells. These were subjected to intracellular cytokine staining using serially truncated peptides and peptide-pulsed 721.221 cells expressing individual HLA class I alleles to define minimal epitope length and HLA restriction by stimulation of IFN-γ and TNF-α production and surface expression of CD107a.</p><p>Results</p><p>Using lymphocyte samples of 12 vaccine recipients, we defined 14 previously unreported optimal CD8⁺ T-cell HIV-1 epitopes and their four-digit HLA allele restriction (6 HLA-A, 7 HLA-B and 1 HLA-C alleles). Further 13 novel targets with incomplete information were revealed.</p><p>Conclusions</p><p>The high rate of discovery of novel CD8⁺ T-cell effector epitopes warrants further epitope mining in recipients of the conserved-region vaccines in other populations and informs development of HIV-1/AIDS vaccines.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01151319" target="_blank">NCT01151319</a></p></div

Specificity of CD8+ T-Cell Responses Following Vaccination with Conserved Regions of HIV-1 in Nairobi, Kenya

Sub-Saharan Africa carries the biggest burden of the human immunodeficiency virus type 1 (HIV-1)/AIDS epidemic and is in an urgent need of an effective vaccine. CD8+ T cells are an important component of the host immune response to HIV-1 and may need to be harnessed if a vaccine is to be effective. CD8+ T cells recognize human leukocyte antigen (HLA)-associated viral epitopes and the HLA alleles vary significantly among different ethnic groups. It follows that definition of HIV-1-derived peptides recognized by CD8+ T cells in the geographically relevant regions will critically guide vaccine development. Here, we study fine details of CD8+ T-cell responses elicited in HIV-1/2-uninfected individuals in Nairobi, Kenya, who received a candidate vaccine delivering conserved regions of HIV-1 proteins called HIVconsv. Using 10-day cell lines established by in vitro peptide restimulation of cryopreserved PBMC and stably HLA-transfected 721.221/C1R cell lines, we confirm experimentally many already defined epitopes, for a number of epitopes we define the restricting HLA molecule(s) and describe four novel HLA-epitope pairs. We also identify specific dominance patterns, a promiscuous T-cell epitope and a rescue of suboptimal T-cell epitope induction in vivo by its functional variant, which all together inform vaccine design

Conserved-region vaccine immunogen and the HIV-CORE 002 trial regimens.

<p>(A) The box.A schematic representation of the chimaeric design of the first generation conserved immunogen HIVconsv. Capital letters above HIVconsv regions indicate the clade of origin, from which the consensus amino sequence for that region was derived. Individual HIV-1 proteins of region origin are colour coded. (B) The two vaccine regimens of the HIV-CORE 002 trial [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176418#pone.0176418.ref018" target="_blank">18</a>] that the volunteers analyzed in this study received. ChAdV–recombinant non-replicating simian (chimpanzee) adenovirus 63 ChAdV63.HIVconsv; MVA—recombinant non-replicating poxvirus modified vaccinia virus Ankara MVA.HIVconsv; and DNA–‘naked’ plasmid pSG2.HIVconsv DNA. (C and D) Optimal epitope mapping was performed using thawed vaccine-recipients’ PBMCs, which were <i>in vitro</i> expanded with the parental 15-mer peptides for 10 days to establish STCL. (C) Frequencies of vaccine-elicited, HIV-1-specific, <i>in vitro</i> 15-mer peptide (x-axis)-expanded sequential PBMC samples of several volunteers from 5 (black) and 12 (grey) months after the last vaccine administration. Specific cells were enumerated in an IFN-γ ELISPOT assay. Panel (D) overviews the frequencies of peptide-specific CD8⁺ STCLs over the volunteers and peptides used. Frequencies of specific cells from all tested volunteers expanded by the same 15-mer peptide are shown next to each other above each peptide given on the x-axis. Top and bottom graphs show frequencies of CD8⁺ T cells producing IFN-γ and TNF-α, respectively. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176418#pone.0176418.s021" target="_blank">S2 Table</a> for the list of peptides and responding volunteers.</p

Mapped human CD8⁺ T-cell epitopes in the conserved regions of HIVconsv.

<p>Mapped human CD8⁺ T-cell epitopes in the conserved regions of HIVconsv.</p

Guía de práctica clínica para el manejo del cáncer de pulmón de células pequeñas: enfermedad extensa

Antecedentes: El cáncer de células pequeñas (CPCP) representa el 13-15% del total de neoplasias primarias de pulmón. Se caracteriza por su rapidez en la tasa de crecimiento y en el desarrollo de metástasis a distancia. Objetivos: Orientar y estandarizar el tratamiento del CPCP enfermedad extensa en México basado en evidencia clínica nacional e internacional. Material y métodos: Este documento se desarrolló como una colaboración del Instituto Nacional de Cancerología y la Sociedad Mexicana de Oncología en cumplimiento con estándares internacionales. Se integró un grupo conformado por oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. Resultados: Se consensaron, por el método Delphi y en reuniones a distancia, las recomendaciones en CPCP enfermedad extensa, producto de preguntas de trabajo. Se identificó y evaluó la evidencia científica que responde a cada una de dichas preguntas clínicas antes de incorporarla al cuerpo de la guía. Conclusión: Esta guía proporciona recomendaciones clínicas para el manejo de la enfermedad extensa del CPCP y durante el proceso de toma de decisiones de los clínicos involucrados con su manejo en nuestro país para mejorar la calidad de la atención clínica para estos pacientes

The immunogenetic diversity of the HLA system in Mexico correlates with underlying population genetic structure

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