High-order parametric generation of coherent XUV radiation.

Extreme ultraviolet (XUV) radiation finds numerous applications in spectroscopy. When the XUV light is generated via high-order harmonic generation (HHG), it may be produced in the form of attosecond pulses, allowing access to unprecedented ultrafast phenomena. However, the HHG efficiency remains limited. Here we present an observation of a new regime of coherent XUV emission which has a potential to provide higher XUV intensity, vital for applications. We explain the process by high-order parametric generation, involving the combined emission of THz and XUV photons, where the phase matching is very robust against ionization. This introduces a way to use higher-energy driving pulses, thus generating more XUV photons.

Absolute gas density profiling in high-order harmonic generation: erratum.

In this erratum, we correct two numerical errors due to conversion mistakes from our previous published manuscript [Opt. Express 26, 6001 (2018)]. In the original manuscript, the two errors compensated each other such that the conclusions remain perfectly unchanged.

Prevalence of human papillomavirus, human immunodeficiency virus and other sexually transmitted infections among female sex workers in Togo: a national cross-sectional survey.

OBJECTIVES: Sub-Saharan Africa is a region with high incidence of both human immunodeficiency virus (HIV) and cervical cancer. We conducted the first national study in Togo to assess prevalence of human papillomavirus (HPV), HIV and other sexually transmitted infections (STIs) among female sex workers (FSW). METHODS: A multicentric cross-sectional study was conducted among FSW recruited in hot spots (clubs, streets) in four Togolese cities. HPV and STIs were tested from cervical and anal swabs. HIV and syphilis were screened with rapid tests. RESULTS: In all, 310 FSW were recruited; HIV and cervical high-risk HPV (hrHPV) prevalence were 10.6% (33/310) and 32.9% (102/310), respectively. The most frequent hrHPV types were HPV58 (13.6%, 19/140), HPV35 (12.9%, 18/140), HPV31 (12.1%, 17/140) and HPV16 (10.7%, 15/140). Prevalence of hrHPV and multiple hrHPV infections showed higher rates in HIV-positive than in HIV-negative FSW (48.5% versus 31.0%, p 0.04 and 21.2% versus 9.0%, p 0.03; respectively). Prevalence of hrHPV was higher in cervical than anal swabs (34.1% versus 20.7%, p 0.0004). High-risk HPV anal infections were more frequent among HIV-positive than HIV-negative FSW (51.9% versus 17.3%, p 2 × 10-5). Concomitant anal and cervical hrHPV infections were present in 43.2% (41/95) of hrHPV-positive FSW. Overall prevalence in the cervix of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium and Trichomonas vaginalis were 4.2%, 6.1%, 5.5% and 6.5%, respectively. CONCLUSIONS: This first African study on paired cervical and anal samples showed a high prevalence of genital HPV infections with a rather high rate of concomitant HPV infections but low type concordance. We report an unusual distribution of hrHPV types. These findings highlight the critical need for implementation of a national HPV vaccination strategy.

Absolute gas density profiling in high-order harmonic generation.

We propose and implement a method to determine the absolute density profile of a gas jet producing high-order harmonics. By measuring the transverse profile of the fluorescence emitted by the plasma, we retrieve the local density in the gas jet. We use this technique during the optimization of the high-harmonics of 515 nm, 10 µJ, 130 fs pulses at 500 kHz and find that we can generate in absorption-limited conditions.

In vitro susceptibility to mecillinam of Escherichia coli strains isolated from the urine of pregnant women.

OBJECTIVES: Pivmecillinam is a safe beta-lactam for use in pregnancy. It has been widely used for the treatment of lower urinary tract infections (UTIs) in the Nordic countries where its efficacy, minor impact on the microbiota, and low level of resistance among the Escherichia coli strains have been proven. However, susceptibility data related to E. coli involved in asymptomatic bacteriuria and lower UTIs in pregnant women is lacking. We aimed to support the 2015 recommendations issued by the French Infectious Diseases Society (SPILF) on gestational UTI, with a particular focus on pivmecillinam. MATERIAL AND METHODS: Antimicrobial susceptibility testing was performed by 12 hospitals with a maternity department on 235 E. coli strains isolated from the urine of pregnant women. Susceptibility to mecillinam was tested by disk diffusion method using the 2015 recommendations of the antibiogram committee of the French microbiology society (CA-SFM). RESULTS: Global susceptibility to mecillinam was 86.4%. Susceptibility to mecillinam was 96.5% for strains susceptible to amoxicillin-clavulanic acid and 38.7% for resistant strains. All six extended-spectrum beta-lactamase-producing E. coli strains were susceptible to mecillinam. CONCLUSION: Given the efficacy and safety of pivmecillinam during pregnancy, it may be used for the documented treatment of asymptomatic bacteriuria and acute cystitis in pregnant women. It also represents an alternative for the treatment of multidrug-resistant bacterial infections.

Evaluating the management of 493 patients presenting with bacteremia in 23 northern French hospitals.

OBJECTIVES: We aimed to update the epidemiology of bacteremia and evaluate their management and short-term outcome. METHODS: We conducted a prospective multicenter survey from October to November 2011. Consecutive patients with at least one positive blood culture (BC) were included in the study. We evaluated the type and adequacy of empirical and documented antibiotic therapy, time to active antibiotic therapy, compliance with guidelines, and 10-day outcome. RESULTS: A total of 23 public and private hospitals and 633 patients (493 true pathogens and 140 contaminants) were included in the study. Patients' wards were medicine (57%), surgery (19%), intensive care (14%), onco/hematology (3.7%), pediatrics (3.4%), infectious diseases (1.8%), and obstetrics (1.2%). Main pathogens were Escherichia coli (36%), Staphylococcus aureus (16%), coagulase-negative staphylococci, and Klebsiella sp. (8% each). A total of 43 (8.7%) multidrug-resistant strains were observed, including 26 extended-spectrum beta-lactamase strains and 15 methicillin-resistant S. aureus strains. An antibiotic active against the isolated pathogen was used in 74% of empirical and 96% of documented therapies. Median time between BC and administration of an active drug was 0.61 day. Empirical antibiotic therapies were protocol-compliant in 77% of cases. Few (4%) patients with contaminated BC received an antibiotic therapy (all inappropriate). Day-10 mortality was 12.1%, higher in patients presenting with severe sepsis or septic shock (22.5%) than in patients presenting with non-severe bacteremia (7.1%; P<0.0001). CONCLUSION: The management of bacteremia seems satisfactory in these volunteer hospitals but bacteremia remains a severe infection.

Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study.

OBJECTIVE: Evaluation of the long-term HPV-16/18 AS04-adjuvanted vaccine immunogenicity persistence in women. DESIGN: Multicentre, open-label, long-term follow-up (NCT00947115) of a primary phase-III study (NCT00196937). SETTING: Six centres in Germany and Poland. POPULATION: 488 healthy women (aged 15-55 years, age-stratified into groups: 15-25, 26-45, and 46-55 years) who received three vaccine doses in the primary study. METHODS: Immune responses were evaluated in serum and cervicovaginal secretion (CVS) samples 6 years after dose 1. Anti-HPV-16/18 geometric mean titres (GMTs) were measured by enzyme-linked immunosorbent assay (ELISA), and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) were recorded. MAIN OUTCOME MEASURES: Anti-HPV-16/18 seropositivity rates and GMTs 6 years after dose 1. RESULTS: At 6 years after dose 1, all women were seropositive for anti-HPV-16 and ≥97% were seropositive for anti-HPV-18 antibodies. GMTs ranged from 277.7 to 1344.6 EU/ml, and from 97.6 to 438.2 EU/ml, for anti-HPV-16 and anti-HPV-18, respectively. In all age groups, GMTs were higher (anti-HPV-16, 9.3-45.1-fold; anti-HPV-18, 4.3-19.4-fold) than levels associated with natural infection (29.8 EU/ml). A strong correlation between serum and CVS anti-HPV-16/18 levels was observed, with correlation coefficients of 0.81-0.96 (anti-HPV-16) and 0.69-0.84 (anti-HPV-18). Exploratory modelling based on the 6-year data predicted vaccine-induced anti-HPV-16/18 levels above natural infection levels for at least 20 years, except for anti-HPV-18 in the older age group (piecewise model). One vaccine-related and two fatal SAEs were reported. CONCLUSIONS: At 6 years after vaccination, immune responses induced by the HPV-16/18 AS04-adjuvanted vaccine were sustained in all age groups.

Ultrafast short-range disordering of femtosecond-laser-heated warm dense aluminum.

We have probed, with time-resolved x-ray absorption near-edge spectroscopy (XANES), a femtosecond-laser-heated aluminum foil with fluences up to 1 J/cm2. The spectra reveal a loss of the short-range order in a few picoseconds. This time scale is compared with the electron-ion equilibration time, calculated with a two-temperature model. Hydrodynamic simulations shed light on complex features that affect the foil dynamics, including progressive density change from solid to liquid (∼10 ps). In this density range, quantum molecular dynamics simulations indicate that XANES is a relevant probe of the ionic temperature.

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women.

BACKGROUND: Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741). METHODS: Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N=65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N=50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration. RESULTS: Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated. CONCLUSION: A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.

Resistance profiles of emtricitabine and lamivudine in tenofovir-containing regimens.

OBJECTIVES: To compare the frequency of the selection of the M184V/I resistance mutation in HIV-infected patients who experienced virological failure while receiving emtricitabine (FTC) or lamivudine (3TC), administered with tenofovir disoproxil fumarate (TDF) and either efavirenz (EFV) or a ritonavir-boosted protease inhibitor (PI; lopinavir or atazanavir). METHODS: Patient data held at two clinical centres in France were analysed retrospectively. Eligible patients had experienced virological suppression (plasma HIV RNA <200 copies/mL) for ≥ 6 months before experiencing their first virological failure (at least two measurements of plasma HIV RNA ≥ 200 copies/mL). RESULTS: Of the 880 patients eligible for the study, 278 patients had experienced virological failure while receiving FTC + TDF + ritonavir-boosted PI, 257 while receiving FTC + TDF + EFV, 178 while receiving 3TC + TDF + EFV and 167 while receiving 3TC + TDF + ritonavir-boosted PI. Proportions of patients harbouring the M184V/I mutation were 24% (n = 62) for those who received FTC + TDF + EFV versus 51% (n = 91) for 3TC + TDF + EFV (P < 0.0001; Fisher's exact test); proportions were 11% (n = 30) for FTC + TDF + ritonavir-boosted PI versus 22% (n = 37) for 3TC + TDF + ritonavir-boosted PI (P = 0.002; Fisher's exact test). The use of lamivudine versus emtricitabine (P = 0.001), non-nucleoside reverse transcriptase inhibitors versus ritonavir-boosted PIs (P = 0.01) and the level of viral load at the time of virological failure (P = 0.01) were associated with selection of the M184V/I mutation (logistic regression analysis). CONCLUSIONS: Emtricitabine and lamivudine showed differing resistance profiles when administered in combination with tenofovir disproxil fumarate and either efavirenz or a ritonavir-boosted PI. The prevalence of the M184V/I resistance mutation was significantly lower in patients who received emtricitabine and tenofovir disoproxil fumarate than in those who received lamivudine and tenofovir disoproxil fumarate.

Outcome of patients with diabetes with negative percutaneous bone biopsy performed for suspicion of osteomyelitis of the foot.

AIMS: To assess the outcome of patients with diabetes with suspicion of osteomyelitis of the foot who had undergone a percutaneous bone biopsy that yielded negative microbiological results, with focus on the occurrence of osteomyelitis at the biopsied site. METHODS: Medical charts of adult patients with diabetes with a negative percutaneous bone biopsy were reviewed. Patients' outcome was evaluated at least 2 years after the initial bone biopsy according to wound healing, the results of a new bone biopsy and bone imaging evaluation when applicable. RESULTS: From January 2001 to January 2008, 41 patients with diabetes (30 men/11 women; mean age 58.1 ± 9.6 years; mean diabetes duration 15.8 ± 6.7 years) met study criteria. Osteomyelitis was suspected based on combined clinical and imaging diagnostic criteria. On follow-up at a mean duration of 41.2 ± 22.5 months post-bone biopsy, 16 patients had complete wound healing (39.0%). Of the 25 other patients, 15 had a new bone biopsy performed, six of which yielded positive microbiological results, and among the 10 patients who neither healed nor underwent bone biopsy, comparative radiography of the foot showed a stable aspect of the biopsied site in six of them, for whom the data were available. Finally, osteomyelitis of the foot at the site where the initial bone biopsy had been performed was confirmed during follow-up in six patients (14.6%) and was suspected in four additional patients (9.7%). CONCLUSIONS: The results of the present study suggest that, of patients with diabetes with the suspicion of osteomylelitis and a negative percutaneous bone biopsy, only one out of four will develop osteomyelitis within 2 years of the biopsy.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

[Bacteremia and French computerized disease surveillance system: financial valorisation of an infectious diseases specialist in a hospital]. / Bactériémies et Programme de médicalisation des systèmes d'information : valorisation financière de l'infectiologue à l'hôpital.

OBJECTIVE: Bacteremia surveillance is a mission assumed by the referent person for antimicrobial therapy. We propose an original financial valorization of this activity, using the computerized disease surveillance system (CDSS). MATERIAL AND METHODS: A database collecting community-acquired and care-associated bacteremia was created on January 1, 2009 at the Bethune Hospital, France, using EPI-Info software (EPI Data). This database was used to complete missing data (presence of bacteremia, origin [community-acquired or care-associated], site of infection) in CDSS codes of patients hospitalized in surgical and medical wards (410 beds) during 2009. Financial benefit was assessed by the difference of funds allocated on the basis of CDSS, before and after completion of the missing data. RESULTS: In 2009, 383 out of the 35,000 patients presented with bacteremia. When missing CDSS codes were added, a financial gain of 229,291 euros was obtained, concerning 64 patients. CONCLUSION: Bacteremia surveillance is a transversal task based on quality of care, which may have a positive financial impact. This study may be helpful for clinicians with transversal activities, for whom financial valorization is difficult to implement in the CDSS, particularly without hospitalization beds. The lack of complete notification in the CDSS may cause a substantial financial loss.

[Usefulness of PCR test for the management of a Mycoplasma pneumoniae outbreak in Bethune Hospital (Pas-de-Calais, France)]. / Importance de la PCR dans la gestion d'une épidémie àMycoplasma pneumoniae au centre hospitalier de Béthune (Pas-de-Calais).

SUBJECT: Molecular amplification (PCR) provides adequate rapid and specific diagnosis of Mycoplasma pneumoniae infection (first agent responsible for community-wide bacterial pneumonia in children above 5 years of age). METHOD: Positive (Chlamylège(®), Argène) PCR in nasopharyngeal aspirate, respiratory samples and nasopharyngeal swab and/or positive serological test (ELISA). RESULTS: Diagnosis of M. pneumoniae infection in 39 cases: 31 between September and December 2008 (30 children and one adult) and eight since June 2009 (three adults and five children). Children (mean age: 3.6years) were hospitalized in 88.6% of cases, mean hospitalization duration was 2.9 days for respiratory tract infections, mainly due to lack of response to ß-lactamines therapy (65.7%). Four adults (mean age: 29.5 years) presented a pneumonia, with hospitalization for three of them with one in intensive care unit. Twenty-eight PCR have proved positive (87%): without associated serology (13), eight negative serologies, IgG and IgM positive (five), and IgG alone (two). Seven patients had only serological test for diagnosis: IgM±IgG. For two children, IgM positive only in isolation, with a PCR probably false negative. CONCLUSION: The sensitivity of the serology in the diagnosis of mycoplasma infection is limited: IgM, which appear traditionally 1 week after clinical signs are mostly inexistent for adults and IgG rise at a later stage. Early diagnosis of child pneumoniae by PCR helped rapidly characterize this epidemic phenomenon and adapt the treatment.

Post-compression of high-energy femtosecond pulses using gas ionization.

We present a new optical post-compression technique designed for high-energy ultrashort pulses. A large spectral broadening is achieved through rapid ionization of helium by an intense pulse (>10(15) W/cm(2)) propagating in a capillary filled with low-pressure helium. The blueshifted pulses are re-compressed with chirped mirrors and silica plates. From a terawatt Ti:sapphire laser chain providing pulses of 40 fs, 70 mJ, we demonstrate the compression of pulses down to 11.4 fs (FWHM) with a total output energy of 13.7 mJ.

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

[Diagnosis of herpetic esophagitis in the immunocompetent subject by PCR (Herpès Consensus Générique-Argène). Report of six cases]. / Diagnostic d'oesophagite herpétique à HSV1 chez le sujet immunocompétent par PCR (Herpès Consensus Générique-Argène). A propos de six cas.

AIM OF THE WORK: We have researched and identified Herpes viruses on the esophageal biopsies taken during the period between September 2006 and March 2008 for 15 suspected patients. PATIENTS AND METHODS: The esophageal biopsies were transferred to the laboratory being conserved in physiological serum and frozen at -80 degrees C for PCR. A fragment was conserved for histopathological analysis. The specimen was defrozen and refrozen in liquid azote (to limit the inhibitors) and crushed to the powder form. Extraction was then done following the prerecognised protocol (Herpès Consensus Générique-"Argene"). That kit allows the amplification consensus of the viral genome of the most frequently encountered Herpes family virus: HSV1, HSV2, CMV, VZV, EBV and HHV6. The identification of the implicated virus was done by the Hybridowell Herpes Identification (Argene) kit in parallel with the migration of SDS gel of the obtained amplifications. RESULTS: HSV1 was identified in seven esophageal biopsies between the 15 studied. HHV6 and the association HHV6/EBV for two patients and only one biopsy had inconclusive. The endoscopy and the histopathological examination had confirmed ulcerated esophagitis with cytopathogene aspect in favour of viral infection for six patients. CONCLUSION: In absence of inhibitors, the adaptation of the extraction technique of the fragments of tissue for few millimetres and the amplifications by PCR had allowed rapid confirmation of the diagnosis of herpetic esophagitis secondary to HSV1 even before the results of the histopathological examination. Treatment by acyclovir entrained regression of the disease.

[HIV genetic diversity and its consequences]. / Diversité génétique des VIH et ses conséquences.

Human immunodeficiency viruses HIV-1 and HIV-2 are the results of multi-interspecies transmissions from simian virus to humans. HIV-1 viruses are very divergent and are classified in three groups: M, N and O. The group M is subdivided in nine subtypes and numerous Circulating Recombinant Forms. In 1996, protease inhibitors and HAART disposal have modified the prognostic of the HIV infection. However, one of the major problems is the emergence of antiretroviral resistance. A major advance from the last year is the access to antiretroviral in resources limited countries. On the other hand, the development of a vaccine is today hypothetic.

Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice.

The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(-/-) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(-/-) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.