Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations

Expression profile of human Fc receptors in mucosal tissue: implications for antibody-dependent cellular effector functions targeting HIV-1 transmission

The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the initial events in mucosal transmission and dissemination warrants further mechanistic studies

Assessment of the impact of physical activity on the cycloergometer and walking along the corridor on the volume of air leak from the lung of the patients after lung cancer surgery.

Wstęp. Rak płuca stanowi duży problem zdrowotny na świecie, ze względu na jego częstość występowania. Jednym z powikłań po operacyjnym leczeniu raka płuca jest występujący przeciek powietrza z miąższu płuca. Rehabilitacja pacjentów po chirurgicznym leczeniu raka płuca zmniejsza częstość występowania powikłań płucnych, natomiast nie znany jest bezpośredni wpływ fizjoterapii na przebieg pooperacyjnego przecieku powietrza. Przez poznanie czynników ryzyka można zapobiegać temu powikłaniu pooperacyjnemu. Cel pracy. Ocena wpływu wysiłku fizycznego wykonywanego na cykloergometrze i podczas spaceru po korytarzu na wielkość przecieku powietrza u pacjentów po operacji z powodu raka płuca. Sprawdzenie czy czynniki takie jak: DLCO, FEV1, BMI, ilość paczkolat, stopień wydolności fizycznej przed i po operacji, rodzaj dostępu operacyjnego czy wykonanej operacji mają wpływ na wystąpienie pooperacyjnego przecieku powietrza.Materiał i metoda. Przeprowadzono badanie prospektywne w grupie 40 pacjentów po operacji raka płuca. Grupę badaną stanowiło 22 chorych z przeciekiem powietrza, a grupę kontrolną 18 chorych bez przecieku powietrza. Pacjenci z obu grup wykonywali wysiłek fizyczny na cykloergometrze lub spacer po korytarzu. Wykonano trzy próby badania, pierwszą w zerowej dobie, bezpośrednio po uruchomieniu pacjenta, drugą w pierwszej dobie po operacji, a trzecią w dniu poprzedzającym usunięcie drenu. Analizę statystyczną wykonano za pomocą testów: t-studenta, testu niezależności chi² (p<0,05).Wyniki. U pacjentów wykonujących wysiłek fizyczny na cykloergometrze ograniczenie przecieku powietrza było większe niż w grupie chorych spacerujących po korytarzu. Największa różnica w zmniejszeniu się przecieku powietrza była widoczna w próbie I i II. Tylko wartość DLCO wykazywała istotną statystycznie korelację z wystąpieniem przecieku powietrza. Wnioski. 1. Aktywność fizyczna na cykloergometrze w porównaniu do spaceru po korytarzu w większym stopniu wpływa na ograniczenie przecieku powietrza u pacjentów po operacji raka płuca, przez co może być skuteczną formą rehabilitacji chorych z tym powikłaniem. 2. DLCO może być prognostycznym czynnikiem w przewidywaniu wystąpienia przecieku powietrza. Pacjenci u których wystąpił przeciek powietrza mają niską wartość DLCO przed operacją (poniżej 80%).Introduction. Lung cancer is common health problem around the world, because of frequency of occurrence. One of the complications of lung cancer surgery is air leak from the lung parenchyma. Postoperative rehabilitation reduces the incidence of pulmonary complications, but the effect of physiotherapy on air leak is unknown. This postoperative complication can be prevented by knowledge the risk factors. Objectives. Assessment of the influence of physical activity on the cycloergometer and walking along the corridor on the volume of air leak from the lung of the patients after lung cancer surgery. Checking whether factor such as: DLCO, FEV1, BMI, pack years, physical performance before and after surgery, operative techniques or types of surgical resections have a influence on the occurrence of postoperative air leak.Materials and methods. A prospective study was performed on a group of 40 patients after lung cancer surgery. The study group consisted of 22 patients with air leak, and the control group consisted of 18 patients without air leak. Patients from both groups were exercising on a cycloergometer or were walking through the corridor. During the study three attempts were made with each patients, the first - in the zero day after mobilization of the patients, the second - in the first day after the surgery, and the third - in the day predicting the chest tube removal. Statistical analysis was made using the test: Student's t-test and chi-square test of independence (p<0,05). Results. The reduction of air leak from the lung of the patients exercised on a cycloergometer was greater than in the group of patients walked through the corridor. The biggest difference in the reduction of air leak was seen in study attempts I and II. Only the value of DLCO showed a statistically significant correlation with the occurrence of air leak.Conclusion. 1. Physical activity on a cycloergometer, compared to walking along the corridor, has a greater impact on reducing air leak from the lung of the patients after lung cancer surgery, which may be an effective form of rehabilitation for the patients with this complication.2. DLCO can be a prognostic factor in predicting the occurrence of an air leak. Patients who experience air leakage have a low DLCO value before surgery (less than 80%)

Nowe kino rosyjskie wobec tradycji literackiej i filmowej

The monograph entitled New Russian Cinema in View of Literary and Film Tradition consists of 6 basic parts: introduction and 5 chapters, which are devoted to the interpretation of five different films made by acclaimed contemporary directors. Chapter 1 is the attempt of reading the original film Doctor Ragin (2004), made by Kirill Serebrennikov on the basis of Anton Chekhov’s story Chamber no. 6. The aforementioned artist is considered one of the most famous and talented Russian directors, who work both in the domain of theatre and cinematography. In Doctor Ragin he managed to show the illusory side of the difference between a hospital room and the world outside. The main problem of the analyzed work is the history of madness of the whole country, in which there are no clear borders between madhouses and the everyday life of the society which claims to be sane. Chamber no. 6 is shown in the film as the safety option, a kind of “island”, asylum, where a man can protect himself against total madness. The film can be read as the diagnosis of the world which is insane, showing the roots of mental problems, which can be found both in the past and in the present. Chapter 2 tries to answer the question to what extent the problems in Fyodor Dostoyevsky’s novel are still understandable and up-to-date for the contemporary reader. To do so we focus on Menahem Golan’s Crime and Punishment adaptation. Translating the dramatic structure of the novel to the language of film, the director is fixing his attention on the central thought in the novel – hope – which can be associated with the spiritual and moral rebirth of man in the context of cultural and social reevaluation. This realignment ousts the bond with the source of the life-giving power (God) and supersedes the love for the Other from the universal awareness. Through distinctly extended sign-symbolic layer of the film, which sends the spectator beyond visual contexts, the director is trying to fulfil basic aims of the film: giving information, teaching and edifying.Chapter 3 focuses on the artistic function of the ordinary in the film The River by Aleksei Balabanov, an unfinished work based on W. Sieroszewski's story The bottom of misery. The exact reconstruction of everyday Yakut's life, their customs, language and folklore, allows us to put The River in the context of the tradition of ethnographic films. The large amount of everyday life details in the visual layer creates symbolic meaning of adapted ethnographic elements (such as grass cutting, repairing fishing nets, preparing meals, clothes, items etc.). Intended mythologization of the depicted world leads to the process of renewal and reinterpretation of archetypes. The film orientation towards archetypal symbols can be noticed in the tendency of the artist's creative adaptation of the cultural heritage of the Nation of the North and in the attempt of universalization of aesthetic values. Balabanov seems to place the new tragic model, constructed by the storyline, in the space of everydayness. The artistic device, aimed at the transformation of the classic perception of the tragic, is primarily based on excluding the tragic from the sphere of sublimity, destructing pathos as well as showing semantic depth of everyday life elements. Chapter 4 concentrates on the film The Return by Andrey Zvyagintsev in the light of the director’s artistic method. The aim of this part of the book is the attempt to find elements of Zvyagintsev’s artistic world, which can be defined as original and integral components of his artistic method. Therefore, as a result of the analysis of some selected scenes we come to the conclusion that Zvyagintsev's works can be marked by such characteristic features as symmetrically constructed frames, appearance of different variants of geometric figures in the space of the frame, dominance of long, static frames, presence of blurred and dark colors, meaningful silence, semispherical (in Yuri Lotman’s understanding) density of individual frames. In Zvyagintsev’s film we can also observe frequent repetition of the motifs of water, photograph, sacrifice, as well as biblical and cultural-mythological symbols. The repetition of various motifs is used by Zvyagintsev as the artistic device of the loop, the sign of cyclicality and compositional framework. We can also notice that the titles of the films are very important, they can be treated as a kind of hint, an interpretation key, using which the viewer is able to perceive the picture on a deeper level. Chapter 5 aims to interpret metaphors of death in Renata Litvinova’s film The Last Tale of Rita (Последняя сказка Риты, 2012) in the context of Susan Sontag’s concepts, which were expressed first of all in her work Illness as Metaphor. The analysis proves not only the relevance of the American writer’s thoughts in the domain of myths and images associated with death, which are present in collective memory, it also shows a number of similarities between the style of retro glamour adapted by the director and Sontag’s philosophy of new sensitivity called camp. As a result of the process of contextualization the attention is turned to the aesthetization procedures used by Litvinova in order to romanticize and neutralize the phenomenon of death. They are introduced due to the adaptation of carnival stylization as well as intertextual references to the poetics of surrealism and fairy tales. The analysis focuses on the process of understanding death metaphors in the text of the film, which at the same time constitutes the attempt of decoding symbolic leitmotivs, methods of theatralization and ritualization of behavior, including selected montage solutions used in the movie

Image1_Pre-clinical evaluation of antiproteases as potential candidates for HIV-1 pre-exposure prophylaxis.pdf

Previous studies on highly HIV-1-exposed, yet persistently seronegative women from the Punwami Sex Worker cohort in Kenya, have shed light on putative protective mechanisms, suggesting that mucosal immunological factors, such as antiproteases, could be mediating resistance to HIV-1 transmission in the female reproductive tract. Nine protease inhibitors were selected for this study: serpin B4, serpin A1, serpin A3, serpin C1, cystatin A, cystatin B, serpin B13, serpin B1 and α-2-macroglobulin-like-protein 1. We assessed in a pilot study, the activity of these antiproteases with cellular assays and an ex vivo HIV-1 challenge model of human ecto-cervical tissue explants. Preliminary findings with both models, cellular and tissue explants, established an order of inhibitory potency for the mucosal proteins as candidates for pre-exposure prophylaxis when mimicking pre-coital use. Combination of all antiproteases considered in this study was more active than any of the individual mucosal proteins. Furthermore, the migration of cells out of ecto-cervical explants was blocked indicating potential prevention of viral dissemination following amplification of the founder population. These findings constitute the base for further development of these mucosal protease inhibitors for prevention strategies.</p

Combinations of Entry and Reverse Transcriptase Inhibitors as Candidate Microbicides

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The execution of the profession of a psychologist in selected European Union Member States and Norway

The paper presents information on the legal regulation of the profession of a psychologist in Austria, Belgium, the Czech Republic, Denmark, Finland, France, Germany, Portugal, and Norway. In the European Union law that profession is covered by the so-called general system of recognition of professional qualifications. The article examines legal provisions regulating the profession, the qualification and educational requirements, and the conditions for practising psychology in the above-mentioned countries

Mixed valence trimers in cation radical salts of TMTTF with the planar bis(6-sulfo-8-quinolato) platinum complex [Pt(qS)(2)](2-)

International audienceElectrocrystallization of TMTTF (tetramethyltetrathiafulvalene) in the presence of the dianionic [Pt(qS)(2)](2-)platinum complex (qS: 5-sulfo-8-quinolinol) afforded simultaneously two phases. Phase A with isolated dicationic (TMTTF)(2)(2+)species is fully insulating and characterized by C-H hydrogen bonds with the anionic sulfonate moieties. Phase B is a mixed valence salt formulated as (TMTTF)(3)[Pt(qS)(2)]. It is organized into strongly trimerized chains, with a notably higher conductivity (sigma(RT)= 4 x 10(-5)S cm(-1)). The charge distribution within the TMTTF trimers has been evaluated from the intramolecular bond distances, and IR and Raman spectra, converging all to a +0.5/+1/+0.5 motif, which is not modified at lower temperatures. Spectroscopic studies of such trimeric structures are scarce and the doublet (or triplet) structure expected in the IR of trimers is clearly identified here in the EMV-activated nu(8)(a(g)) mode associated with the totally symmetric vibration of methyl groups, in relation to the weak C-HMIDLINE HORIZONTAL ELLIPSISO hydrogen bonds between the radical cation and the dianionic [Pt(qS)(2)](2-)platinum complex