CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication $in$ $vivo$. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct $ex-vivo$ samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.Version of Recor

Sobre la confl uencia Cuerpos, Política, Trabajo, Emoción y Arte en las Intervenciones en el Campo de lo Social. Cartografías del enseñaraprender e investigar desde la experiencia de nuestro espacio curricular.

Nuestra comunicación recupera refl exivamente una experiencia piloto que venimos ensayando en el ámbito de formación universitaria en la que propiciamos un espacio pedagógico curricular inscripto en una Asignatura Electiva correspondiente al quinto año de la Licenciatura de Trabajo Social. La misma se confi gura en torno a la formación de trabajadoras/es que intervienen en el campo de lo social. Apuntamos al registro del conocimiento vivencial, mediante el entrenamiento de los cuerpos y el senti-pensamiento. En esta línea, nuestra apuesta se halla ligada a promover procesos de movilización de actitudes, de auto-cuidado y de cuidado colectivo de trabajadoras/es sociales, a través de expresiones artísticas para las intervenciones en el campo de lo social, desde una perspectiva de género y de derechos humanos. En este artículo recuperamos una cartografía conceptual, categorial y metodológica con aquellas fuentes inspiradoras de nuestra propuesta, asociadas en mayor magnitud, con las técnicas del psicodrama derivada de la Escuela de Pavlovsky. A partir del análisis de un material como son las resonancias, entendidas como un documento elaborado desde la escritura situada; desde el registro corporal y emocional y que fueron escritas tanto por estudiantes como por el equipo docente facilitador, recuperamos algunos registros subjetivos de un proceso que es singular y colectivo en pos de elaborar caminos de continuidad de procesos pedagógicos en consonancia con estas coordenadas.</jats:p

Sobre la confluencia Cuerpos, política, trabajo, emoción y arte en las intervenciones en el campo de lo social : cartografías del enseñar aprender e investigar desde la experiencia de nuestro espacio curricular

Nuestra comunicación recupera refl exivamente una experiencia piloto que venimos ensayando en el ámbito de formación universitaria en la que propiciamos un espacio pedagógico curricular inscripto en una Asignatura Electiva correspondiente al quinto año de la Licenciatura de Trabajo Social. La misma se confi gura en torno a la formación de trabajadoras/es que intervienen en el campo de lo social. Apuntamos al registro del conocimiento vivencial, mediante el entrenamiento de los cuerpos y el senti-pensamiento. En esta línea, nuestra apuesta se halla ligada a promover procesos de movilización de actitudes, de auto-cuidado y de cuidado colectivo de trabajadoras/es sociales, a través de expresiones artísticas para las intervenciones en el campo de lo social, desde una perspectiva de género y de derechos humanos. En este artículo recuperamos una cartografía conceptual, categorial y metodológica con aquellas fuentes inspiradoras de nuestra propuesta, asociadas en mayor magnitud, con las técnicas del psicodrama derivada de la Escuela de Pavlovsky. A partir del análisis de un material como son las resonancias, entendidas como un documento elaborado desde la escritura situada; desde el registro corporal y emocional y que fueron escritas tanto por estudiantes como por el equipo docente facilitador, recuperamos algunos registros subjetivos de un proceso que es singular y colectivo en pos de elaborar caminos de continuidad de procesos pedagógicos en consonancia con estas coordenadas.Our communication refl exively recovers a pilot experience that we have been rehearsing in the fi eld of university education in which we promote a curricular pedagogical space inscribed in an Elective Subject corresponding to the fi fth year of the Social Work Degree. It is confi gured around the training of workers who intervene in the social fi eld. Our aim is to register experiential knowledge, through the training of bodies and feel-thought. In this line, our commitment is linked to promoting processes of mobilization of attitudes, selfcare and collective care of social workers, through artistic expressions for interventions in the fi eld of social issues, from a perspective of gender and human rights. In this article we recover a conceptual, categorical and methodological cartography with those inspirational sources of our proposal, associated in greater magnitude, with the techniques of psychodrama derived from the Pavlovsky School. From the analysis of a material such as resonances, understood as a document produced from the written script; from the corporal and emotional record, which were written by students as well as by the facilitating teaching team, we recovered some subjective records of a process that is singular and collective in order to elaborate paths of continuity within the pedagogical processes in consonance with these coordinates.Fil: Abraham, Martin. Universidad Nacional de Rosario; Argentina

Alternative Effector-Function Profiling Identifies Broad HIV-Specific T-Cell Responses in Highly HIV-Exposed Individuals Who Remain Uninfected

The characterization of host immune responses to human immunodeficiency virus (HIV) in HIV controllers and individuals with high exposure but seronegativity to HIV (HESN) is needed to guide the development of effective preventive and therapeutic vaccine candidates. However, several technical hurdles severely limit the definition of an effective virus-specific T-cell response. By using a toggle-peptide approach, which takes HIV sequence diversity into account, and a novel, boosted cytokine staining/flow cytometry strategy, we here describe new patterns of T-cell responses to HIV that would be missed by standard assays. Importantly, this approach also allows detection of broad and strong virus-specific T-cell responses in HESN individuals that are characterized by a T-helper type 1 cytokine–like effector profile and produce cytokines that have been associated with potential control of HIV infection, including interleukin 10, interleukin 13, and interleukin 22. These results establish a novel approach to improve the current understanding of HIV-specific T-cell immunity and identify cellular immune responses and individual cytokines as potential markers of relative HIV resistance. As such, the findings also help develop similar strategies for more-comprehensive assessments of host immune responses to other human infections and immune-mediated disorders

Demographic and main clinical characteristics of the 25 controllers and 25 non-controllers tested^a.

<p><i>^a</i>Data are expressed as median (min-max range),</p><p><i>^b</i>n, (%),</p><p><i>^c</i>UD: undetectable viremia (<49 copies/ml).</p

Definition of the viral targets of protective HIV-1-specific T cell responses

Abstract Background The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity. Methods Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders. Results For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes. Conclusions The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.</p

Definition of the viral targets of protective HIV-1-specific T cell responses

Background: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity. Methods: Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a “protective ratio” (PR) was calculated as the ratio of median viral loads (VL) between OLP nonresponders and responders. Results: For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals’ viral loads than their HLA class I genotypes. Conclusions: The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.Peer Reviewe

High avidity responses are enriched in HIV-1 controllers and mediate superior variant recognition.

<p>(<b>A</b>) Comparison of functional avidity of all COT-M Gag p24 responses titrated in controllers (n = 219 responses) vs. non-controllers (n = 255 responses) (<b>B</b>) Comparison of functional avidities limited to responses targeting the same 10 mer OLP in the two groups (n = 52 responses, Wilcoxon). In (<b>C</b>) the total breadth (number) of the response to the tested COT-M Gag p24 variant peptides (n = 88) is indicated for controllers and non-controllers. (<b>D</b>) Shows the percentage of variant peptides that were reactive when the COT-M sequence elicited a response (“cross-reactive responses”) and (<b>E</b>) indicates responses to variant peptides for which the COT-M sequence did not elicit a response (“gained responses”). The association between functional avidity and cross-reactivity is shown in (<b>F</b>) where responses with functional avidities in either the first quartile of all titrated responses (SD50%<1,401 ng/ml) or the second or third quartile (SD50% 1,401–71,594 ng/ml) or the fourth quartile (SD50%>71,594 ng/ml) were defined as “high”, “intermediate” and low” avidity responses. The percentage of variants that elicited a response was compared between the three groups (Fishers Exact Test).</p