La filosofia di Hans-Georg Gadamer e il problema del disagio della modernità. Ermeneutica, estetica, etica e politica

L’ermeneutica filosofica di Hans-Georg Gadamer – indubbiamente uno dei capisaldi del pensiero novecentesco – rappresenta una filosofia molto composita, sfaccettata e articolata, per così dire formata da una molteplicità di dimensioni diverse che si intrecciano l’una con l’altra. Ciò risulta evidente già da un semplice sguardo alla composizione interna della sua opera principale, Wahrheit und Methode (1960), nella quale si presenta una teoria del comprendere che prende in esame tre differenti dimensioni dell’esperienza umana – arte, storia e linguaggio – ovviamente concepite come fondamentalmente correlate tra loro. Ma questo quadro d’insieme si complica notevolmente non appena si prendano in esame perlomeno alcuni dei numerosi contributi che Gadamer ha scritto e pubblicato prima e dopo il suo opus magnum: contributi che testimoniano l’importante presenza nel suo pensiero di altre tematiche. Di tale complessità, però, non sempre gli interpreti di Gadamer hanno tenuto pienamente conto, visto che una gran parte dei contributi esegetici sul suo pensiero risultano essenzialmente incentrati sul capolavoro del 1960 (ed in particolare sui problemi della legittimazione delle Geisteswissenschaften), dedicando invece minore attenzione agli altri percorsi che egli ha seguito e, in particolare, alla dimensione propriamente etica e politica della sua filosofia ermeneutica. Inoltre, mi sembra che non sempre si sia prestata la giusta attenzione alla fondamentale unitarietà – da non confondere con una presunta “sistematicità”, da Gadamer esplicitamente respinta – che a dispetto dell’indubbia molteplicità ed eterogeneità del pensiero gadameriano comunque vige al suo interno. La mia tesi, dunque, è che estetica e scienze umane, filosofia del linguaggio e filosofia morale, dialogo con i Greci e confronto critico col pensiero moderno, considerazioni su problematiche antropologiche e riflessioni sulla nostra attualità sociopolitica e tecnoscientifica, rappresentino le diverse dimensioni di un solo pensiero, le quali in qualche modo vengono a convergere verso un unico centro. Un centro “unificante” che, a mio avviso, va individuato in quello che potremmo chiamare il disagio della modernità. In altre parole, mi sembra cioè che tutta la riflessione filosofica di Gadamer, in fondo, scaturisca dalla presa d’atto di una situazione di crisi o disagio nella quale si troverebbero oggi il nostro mondo e la nostra civiltà. Una crisi che, data la sua profondità e complessità, si è per così dire “ramificata” in molteplici direzioni, andando ad investire svariati ambiti dell’esistenza umana. Ambiti che pertanto vengono analizzati e indagati da Gadamer con occhio critico, cercando di far emergere i principali nodi problematici e, alla luce di ciò, di avanzare proposte alternative, rimedi, “correttivi” e possibili soluzioni. A partire da una tale comprensione di fondo, la mia ricerca si articola allora in tre grandi sezioni dedicate rispettivamente alla pars destruens dell’ermeneutica gadameriana (prima e seconda sezione) ed alla sua pars costruens (terza sezione). Nella prima sezione – intitolata Una fenomenologia della modernità: i molteplici sintomi della crisi – dopo aver evidenziato come buona parte della filosofia del Novecento sia stata dominata dall’idea di una crisi in cui verserebbe attualmente la civiltà occidentale, e come anche l’ermeneutica di Gadamer possa essere fatta rientrare in questo discorso filosofico di fondo, cerco di illustrare uno per volta quelli che, agli occhi del filosofo di Verità e metodo, rappresentano i principali sintomi della crisi attuale. Tali sintomi includono: le patologie socioeconomiche del nostro mondo “amministrato” e burocratizzato; l’indiscriminata espansione planetaria dello stile di vita occidentale a danno di altre culture; la crisi dei valori e delle certezze, con la concomitante diffusione di relativismo, scetticismo e nichilismo; la crescente incapacità a relazionarsi in maniera adeguata e significativa all’arte, alla poesia e alla cultura, sempre più degradate a mero entertainment; infine, le problematiche legate alla diffusione di armi di distruzione di massa, alla concreta possibilità di una catastrofe ecologica ed alle inquietanti prospettive dischiuse da alcune recenti scoperte scientifiche (soprattutto nell’ambito della genetica). Una volta delineato il profilo generale che Gadamer fornisce della nostra epoca, nella seconda sezione – intitolata Una diagnosi del disagio della modernità: il dilagare della razionalità strumentale tecnico-scientifica – cerco di mostrare come alla base di tutti questi fenomeni egli scorga fondamentalmente un’unica radice, coincidente peraltro a suo giudizio con l’origine stessa della modernità. Ossia, la nascita della scienza moderna ed il suo intrinseco legame con la tecnica e con una specifica forma di razionalità che Gadamer – facendo evidentemente riferimento a categorie interpretative elaborate da Max Weber, Martin Heidegger e dalla Scuola di Francoforte – definisce anche «razionalità strumentale» o «pensiero calcolante». A partire da una tale visione di fondo, cerco quindi di fornire un’analisi della concezione gadameriana della tecnoscienza, evidenziando al contempo alcuni aspetti, e cioè: primo, come l’ermeneutica filosofica di Gadamer non vada interpretata come una filosofia unilateralmente antiscientifica, bensì piuttosto come una filosofia antiscientista (il che naturalmente è qualcosa di ben diverso); secondo, come la sua ricostruzione della crisi della modernità non sfoci mai in una critica “totalizzante” della ragione, né in una filosofia della storia pessimistico-negativa incentrata sull’idea di un corso ineluttabile degli eventi guidato da una razionalità “irrazionale” e contaminata dalla brama di potere e di dominio; terzo, infine, come la filosofia di Gadamer – a dispetto delle inveterate interpretazioni che sono solite scorgervi un pensiero tradizionalista, autoritario e radicalmente anti-illuminista – non intenda affatto respingere l’illuminismo scientifico moderno tout court, né rinnegarne le più importanti conquiste, ma più semplicemente “correggerne” alcune tendenze e recuperare una nozione più ampia e comprensiva di ragione, in grado di render conto anche di quegli aspetti dell’esperienza umana che, agli occhi di una razionalità “limitata” come quella scientista, non possono che apparire come meri residui di irrazionalità. Dopo aver così esaminato nelle prime due sezioni quella che possiamo definire la pars destruens della filosofia di Gadamer, nella terza ed ultima sezione – intitolata Una terapia per la crisi della modernità: la riscoperta dell’esperienza e del sapere pratico – passo quindi ad esaminare la sua pars costruens, consistente a mio giudizio in un recupero critico di quello che egli chiama «un altro tipo di sapere». Ossia, in un tentativo di riabilitazione di tutte quelle forme pre- ed extra-scientifiche di sapere e di esperienza che Gadamer considera costitutive della «dimensione ermeneutica» dell’esistenza umana. La mia analisi della concezione gadameriana del Verstehen e dell’Erfahrung – in quanto forme di un «sapere pratico (praktisches Wissen)» differente in linea di principio da quello teorico e tecnico – conduce quindi ad un’interpretazione complessiva dell’ermeneutica filosofica come vera e propria filosofia pratica. Cioè, come uno sforzo di chiarificazione filosofica di quel sapere prescientifico, intersoggettivo e “di senso comune” effettivamente vigente nella sfera della nostra Lebenswelt e della nostra esistenza pratica. Ciò, infine, conduce anche inevitabilmente ad un’accentuazione dei risvolti etico-politici dell’ermeneutica di Gadamer. In particolare, cerco di esaminare la concezione gadameriana dell’etica – tenendo conto dei suoi rapporti con le dottrine morali di Platone, Aristotele, Kant e Hegel – e di delineare alla fine un profilo della sua ermeneutica filosofica come filosofia del dialogo, della solidarietà e della libertà.

p300/CBP tyrosine phosphorylation in response to dna damage activated by c-Abl tyrosine kinase

The nuclear signaling that is triggered in response to DNA damage entails the recruitment and assembly of repair proteins and the induction of genes involved in the activation of cell cycle checkpoint, apoptosis or senescence. The extensive changes in chromatin structure underlying these processes suggest that chromatin-modifying enzymes could be relevant targets of DNA damage-activated signaling. The acetyltransferases p300 and CBP participate in DNA damage-activated responses, including local histone hyperacetylation, cell cycle regulation, and co-activation of DNA damage activated proteins, such as p53, p73 and BRCA1. However, the link between DNA damage and p300/CBP activation has not been identified.We have detected p300 tyrosine phosphorylation in response to DNA damage. We show that the DNA damage-activated cAbl tyrosine kinase enters the nuclei of cells exposed to genotoxic agents and phosphorylates p300 on a tyrosine residue within the bromodomain that is conserved in p300, CBP and many other bromodomain-containing proteins. Antibodies against tyrosine phosphorylated p300/CBP show a DNA damage-inducible nuclear staining, suggesting that p300 tyrosine phosphorylation is an event linking DNA damage and chromatin modifications.

Il paesaggio urbano tra ferrovia e città. Progetto di spazi aperti a Viserba

La presente tesi prende avvio all’interno del Laboratorio di Sostituzione di tessuto urbano del professor Antonio Esposito. Il tema è quello, diventato sempre più attuale negli ultimi decenni, della relazione tra gli spazi delle infrastrutture ed il paesaggio urbano. Gli spazi della mobilità finiscono per diventare degli spazi di risulta che anzichè creare dei collegamenti, vocazione principale delle infrastrutture per la mobilità nello specifico, diventano delle fratture all’interno della città, che dividono anzichè unire. L’area di intervento è a Viserba, località balneare nelle vicinanze di Rimini, caratterizzata da una crescita del tessuto urbano esponenziale sviluppatasi interamente nell’ultimo secolo, ma il problema interessa tutte le località sulla costa romagnola, tagliate in due dal passaggio della ferrovia. Il nuovo piano strategico del Comune di Rimini si pone il problema di offrire, finalmente, alla città un sistema della mobilità che consenta di fare a meno dell’automobile non a causa di meri divieti, ma per l’esistenza di valide alternative di trasporto che, consentendo eguale efficacia nella mobilità, riportano ad una più giusta dimensione relazionale le funzioni dell’abitare e del vivere città e territorio. Nella prospettiva di liberare dal mezzo privato la fascia turistica del litorale e di allentare la pressione automobilistica sulle periferie, il tracciato della ferrovia assume ancor più il valore di asse centrale distributivo per il sistema di trasporto pubblico di massa. Condizione fondamentale è che la permeabilità fra le zone a mare e a monte della ferrovia sia incrementata, attraverso la creazione di adeguati ed ampi attraversamenti urbani (non semplicisottopassaggi) che si appoggino ad “una trama verde” di percorsi e spazi di ricucitura della città con il suo mare. Questo è il contesto in cui si inserisce il progetto, che quindi risulta essere di grande attinenza alla contemporaneità.

Immunofluorescence versus xTAG multiplex PCR for the detection of respiratory picornavirus infections in children

BACKGROUND: Polymerase chain reaction (PCR) is a sensitive tool for detection of respiratory picornaviruses. However, the clinical relevance of picornavirus detection by PCR is unclear. Immunofluorescence (IF), widely used to detect other respiratory viruses, has recently been introduced as a promising detection method for respiratory picornaviruses. OBJECTIVES: To compare the clinical manifestations of respiratory picornavirus infections detected by IF with those of respiratory picornavirus infections detected by xTAG multiplex PCR in hospitalized children. STUDY DESIGN: During a 1-year period, nasopharyngeal aspirates (NPA) from all children hospitalized due to an acute respiratory infection were prospectively analyzed by IF. All respiratory picornavirus positive IF samples and 100 IF negative samples were further tested with xTAG multiplex PCR. After exclusion of children with co-morbidities and viral co-infections, monoinfections with respiratory picornaviruses were detected in 108 NPA of 108 otherwise healthy children by IF and/or PCR. We compared group 1 children (IF and PCR positive, n=84) with group 2 children (IF negative and PCR positive, n=24) with regard to clinical manifestations of the infection. RESULTS: Wheezy bronchitis was diagnosed more often in group 1 than in group 2 (71% vs. 46%, p=0.028). In contrast, group 2 patients were diagnosed more frequently with pneumonia (17% vs. 6%, p=0.014) accompanied by higher levels of C-reactive protein (46mg/l vs. 11mg/l, p=0.009). CONCLUSIONS: Picornavirus detection by IF in children with acute respiratory infection is associated with the clinical presentation of wheezy bronchitis. The finding of a more frequent diagnosis of pneumonia in picornavirus PCR positive but IF negative children warrants further investigation.

Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy

Background Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. Aims To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. Methods T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-γ-ELISpot responses to HCV core peptides, that predominantly stimulate CD4+ T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals. Results The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log10 IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (−0.3 log10 IU/ml, p=0.02). Conclusions Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

High specificity of line-immunoassay based algorithms for recent HIV-1 infection independent of viral subtype and stage of disease

Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIATM HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. Methods Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. Results HIV-1 RNA <50 copies/mL was associated with significantly lower reactivity to all five HIV-1 antigens of the Inno-Lia and impaired specificity of most algorithms. Among 412 patients either untreated or with HIV-1 RNA ≥50 copies/mL despite HAART, the median specificity of the algorithms was 96.5% (range 92.0-100%). The only factor that significantly promoted false-incident results in this group was age, with false-incident results increasing by a few percent per additional year. HIV-1 clade, HIV-1 RNA, CD4 percentage, sex, disease stage, and testing modalities exhibited no significance. Results were similar among 190 untreated patients. Conclusions The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients.

IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.

Sensitive and rapid detection of ganciclovir resistance by PCR based MALDI-TOF analysis

Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in transplant recipients. Resistance against ganciclovir is increasingly observed. According to current guidelines, direct drug resistance testing is not always performed due to high costs and work effort, even when resistance is suspected.

Twelve years' detection of respiratory viruses by immunofluorescence in hospitalised children: impact of the introduction of a new respiratory picornavirus assay

Background Direct immunofluorescence assays (DFA) are a rapid and inexpensive method for the detection of respiratory viruses and may therefore be used for surveillance. Few epidemiological studies have been published based solely on DFA and none included respiratory picornaviruses and human metapneumovirus (hMPV). We wished to evaluate the use of DFA for epidemiological studies with a long-term observation of respiratory viruses that includes both respiratory picornaviruses and hMPV. Methods Since 1998 all children hospitalized with respiratory illness at the University Hospital Bern have been screened with DFA for common respiratory viruses including adenovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza virus 1-3. In 2006 assays for respiratory picornaviruses and hMPV were added. Here we describe the epidemiological pattern for these respiratory viruses detected by DFA in 10'629 nasopharyngeal aspirates collected from 8'285 patients during a 12-year period (1998-2010). Results Addition of assays for respiratory picornaviruses and hMPV raised the proportion of positive DFA results from 35% to 58% (p < 0.0001). Respiratory picornaviruses were the most common viruses detected among patients ≥1 year old. The seasonal patterns and age distribution for the studied viruses agreed well with those reported in the literature. In 2010, an hMPV epidemic of unexpected size was observed. Conclusions DFA is a valid, rapid, flexible and inexpensive method. The addition of assays for respiratory picornaviruses and hMPV broadens its range of viral detection. DFA is, even in the "PCR era", a particularly adapted method for the long term surveillance of respiratory viruses in a pediatric population.

Genetic variations in IL28B and allergic disease in children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences.

Diagnostic performance of line-immunoassay based algorithms for incident HIV-1 infection

Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have previously demonstrated that a patient's antibody reaction pattern in a confirmatory line immunoassay (INNO-LIA™ HIV I/II Score) provides information on the duration of infection, which is unaffected by clinical, immunological and viral variables. In this report we have set out to determine the diagnostic performance of Inno-Lia algorithms for identifying incident infections in patients with known duration of infection and evaluated the algorithms in annual cohorts of HIV notifications. Methods Diagnostic sensitivity was determined in 527 treatment-naive patients infected for up to 12 months. Specificity was determined in 740 patients infected for longer than 12 months. Plasma was tested by Inno-Lia and classified as either incident (< = 12 m) or older infection by 26 different algorithms. Incident infection rates (IIR) were calculated based on diagnostic sensitivity and specificity of each algorithm and the rule that the total of incident results is the sum of true-incident and false-incident results, which can be calculated by means of the pre-determined sensitivity and specificity. Results The 10 best algorithms had a mean raw sensitivity of 59.4% and a mean specificity of 95.1%. Adjustment for overrepresentation of patients in the first quarter year of infection further reduced the sensitivity. In the preferred model, the mean adjusted sensitivity was 37.4%. Application of the 10 best algorithms to four annual cohorts of HIV-1 notifications totalling 2'595 patients yielded a mean IIR of 0.35 in 2005/6 (baseline) and of 0.45, 0.42 and 0.35 in 2008, 2009 and 2010, respectively. The increase between baseline and 2008 and the ensuing decreases were highly significant. Other adjustment models yielded different absolute IIR, although the relative changes between the cohorts were identical for all models. Conclusions The method can be used for comparing IIR in annual cohorts of HIV notifications. The use of several different algorithms in combination, each with its own sensitivity and specificity to detect incident infection, is advisable as this reduces the impact of individual imperfections stemming primarily from relatively low sensitivities and sampling bias.

Caveolin-1 is required for signaling and membrane targeting of EphB1 receptor tyrosine kinase

Eph receptor tyrosine kinases are key players during the development of the embryonic vasculature; however, their role and regulation in adult angiogenesis remain to be defined. Caveolae are flask-shaped invaginations of the cell membrane; their major structural protein, caveolin-1, has been shown to regulate signaling molecules localized in these micro-domains. The interaction of caveolin-1 with several of these proteins is mediated by the binding of its scaffolding domain to a region containing hydrophobic amino acids within these proteins. The presence of such a motif within the EphB1 kinase domain prompted us to investigate the caveolar localization and regulation of EphB1 by caveolin-1. We report that EphB1 receptors are localized in caveolae, and directly interact with caveolin-1 upon ligand stimulation. This interaction, as well as EphB1-mediated activation of extracellular-signal-regulated kinase (ERK), was abrogated by overexpression of a caveolin-1 mutant lacking a functional scaffolding domain. Interaction between Ephs and caveolin-1 is not restricted to the B-subclass of receptors, since we show that EphA2 also interacts with caveolin-1. Furthermore, we demonstrate that the caveolin-binding motif within the kinase domain of EphB1 is primordial for its correct membrane targeting. Taken together, our findings establish caveolin-1 as an important regulator of downstream signaling and membrane targeting of EphB1.

Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients

PURPOSE: To assess the outcomes and patterns of failure in solitary plasmacytoma (SP). METHODS AND MATERIALS: The data from 258 patients with bone (n = 206) or extramedullary (n = 52) SP without evidence of multiple myeloma (MM) were collected. A histopathologic diagnosis was obtained for all patients. Most (n = 214) of the patients received radiotherapy (RT) alone; 34 received chemotherapy and RT, and 8 surgery alone. The median radiation dose was 40 Gy. The median follow-up was 56 months (range 7-245). RESULTS: The median time to MM development was 21 months (range 2-135), with a 5-year probability of 45%. The 5-year overall survival, disease-free survival, and local control rate was 74%, 50%, and 86%, respectively. On multivariate analyses, the favorable factors were younger age and tumor size <4 cm for survival; younger age, extramedullary localization, and RT for disease-free survival; and small tumor and RT for local control. Bone localization was the only predictor of MM development. No dose-response relationship was found for doses >30 Gy, even for larger tumors. CONCLUSION: Progression to MM remains the main problem. Patients with extramedullary SP had the best outcomes, especially when treated with moderate-dose RT. Chemotherapy and/or novel therapies should be investigated for bone or bulky extramedullary SP.

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Assessment of recent HIV-1 infection by a line immunoassay for HIV-1/2 confirmation

BACKGROUND: Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this "recency" information can also be gained from an HIV confirmatory assay. METHODS AND FINDINGS: The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (< or = 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%-46%). CONCLUSIONS: Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.