Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

Increased Risk of Invasive Aspergillosis in Immunocompromised Patients With Persistent SARS-CoV-2 Viral Shedding >8 Weeks, Retrospective Case-control Study.

Background: Immunocompromised patients now represent the population most at risk for severe coronavirus disease 2019. Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral shedding was reported in these patients ranging from several weeks up to 9 months. We conducted a bicentric retrospective case-control study to identify risk and prognostic factors associated with persistent viral shedding in immunocompromised patients. Material and Methods: Symptomatic immunocompromised adults with persistent SARS-CoV-2 viral shedding >8 weeks were retrospectively included between 1 March 2020 and 24 April 2022 at 2 university hospitals in Paris, France, and matched with a control group consisting of symptomatic immunocompromised patients without persistent viral shedding. Results: Twenty-nine immunocompromised patients with persistent viral shedding were compared with 40 controls. In multivariate analysis, fever and lymphocytopenia (<0.5 G/L) were associated with an increased risk of persistent viral shedding (odds ratio [OR]: 3.3; 95% confidence interval [CI], 1.01-11.09) P = .048 and OR: 4.3; 95% CI, 1.2-14.7; P = .019, respectively). Unvaccinated patients had a 6-fold increased risk of persistent viral shedding (OR, 6.6; 95% CI, 1.7-25.1; P = .006). Patients with persistent viral shedding were at risk of hospitalization (OR: 4.8; 95 CI, 1.5-15.6; P = .008), invasive aspergillosis (OR: 10.17; 95 CI, 1.15-89.8; P = .037) and death (log-rank test <0.01). Conclusions: Vaccine coverage was protective against SARS-CoV-2 persistent viral shedding in immunocompromised patients. This new group of immunocompromised patients with SARS-CoV-2 persistent viral shedding is at risk of developing invasive aspergillosis and death and should therefore be systematically screened for this fungal infection for as long as the viral shedding persists.

Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child.

We describe an unvaccinated child at risk for life-threatening COVID-19 due to an inherited deficiency of IRF9, which governs ISGF-3-dependent responses to type I and III interferons (IFN). She was admitted, with a high nasal SARS-CoV-2 load on day 1 of upper respiratory tract infection. She was viremic on day 2 and received casirivimab and imdevimab. Her clinical manifestations and viremia disappeared on days 3 and 4, respectively. Circulating SARS-CoV-2 virus induced the expression of IFN-stimulated genes in leukocytes on day 1, whereas the secretion of blood type I IFNs, which peaked on day 4, did not. Antibody-mediated SARS-CoV-2 neutralization is, therefore, sufficient to overcome a deficiency of antiviral IFNs.

A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control.

OBJECTIVE: The main aim of this study was to determine whether HIV replication can be controlled following interruption of treatment started early in the course of infection (CD4 >350 cells/µl and viral load <50 000 copies/ml), but not during the primary infection. METHODS: Patients enrolled in a multicenter trial of treatment interruption (ANRS 116 SALTO) with CD4 above 450 cells/µl and viral load below 400 copies/ml at treatment interruption were selected for this second analysis. We determined the proportion of patients whose plasma HIV-RNA load remained below 400 copies/ml during the first 12 months of treatment interruption, and baseline factors predictive of time to loss of viral control. Viral load rebound was defined as two successive values above 400 copies/ml, or as one value above 400 copies/ml, followed by treatment resumption. RESULTS: We studied 95 patients with a median CD4 nadir of 382 cells/µl (340-492). At treatment interruption, the median CD4 cell count and HIV-DNA load were 813/µl (695-988) and 206 copies/10 peripheral blood mononuclear cells (PBMCs) (53-556). Twelve months after treatment interruption, seven patients still had viral load below 400 copies/ml (Kaplan-Meier estimate 7.5%, 95% confidence interval 3.7-14.6), and four of them still had viral load below 400 copies/ml at 36 months. A multivariable Cox proportional-hazards model showed that time to loss of viral control was more shorter in patients with HIV-DNA at least 150 copies/10 PBMCs at treatment interruption (hazard ratio 2.1, 95% confidence interval 1.3-3.3, P = 0.002) than in those with HIV-DNA below 150 copies/10 PBMCs. CONCLUSION: Patients who have low HIV-DNA levels at antiretroviral treatment interruption are more likely to maintain viral control for long periods.

Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis.

OBJECTIVE: To compare performance of testing for human immunodeficiency virus (HIV)-1 DNA and HIV-1 RNA for diagnosis of HIV-1 infection in infants receiving preventive antiretroviral therapy. STUDY DESIGN: This substudy of the French multicenter prospective cohort of neonates born to HIV-infected mothers, included 1567 infants tested for HIV with polymerase chain reaction (PCR) in a single laboratory, receiving post-natal prophylaxis, not breastfed, and having simultaneous HIV-1 DNA and RNA results before 45 days. The performance of PCR was assessed in reference to the 6-month HIV-1 RNA result. RESULTS: Specificity of both HIV-1 RNA and HIV-1 DNA PCR was 100% at all ages (except 99.8% for DNA at birth); sensitivity was 58% (RNA) and 55% (DNA) at birth, and 89% at 1 month, 100% at 3 months for both, and 100% at 6 months (DNA). Concordance between HIV-1 DNA and RNA results was 0.78 and 0.81 (Kappa) at birth and 1 month and 100% at 3 and 6 months. Type of maternal and neonatal prophylaxis had no effect on sensitivity, but influenced viral load. CONCLUSION: The performances of testing for HIV-1 DNA and RNA were similar with 100% sensitivity at 3 months. At 1 month during prophylaxis, 11% of infected children had negative PCR results.

A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption, independently of the CD4 nadir.

This study aimed to evaluate the safety of antiretroviral treatment interruption (TI) in HIV-infected patients who started treatment based on earlier guidelines, and to identify baseline factors predictive of the time to reach fixed criteria for treatment resumption. Prospective, open-label, multicenter trial. Patients were eligible if they had a CD4 cell count >350/mm(3) and plasma HIV RNA <50,000 copies/ml when they first started antiretroviral therapy (ART); and if they had a CD4 count >450/mm(3) and stable plasma HIV RNA <5,000 copies/ml for at least 6 months prior to enrollment. The criteria for ART resumption were a CD4 cell count <300/mm(3) and/or a CDC stage B or C event. 116 patients had received ART for a median of 5.3 years. The median CD4 cell count and plasma HIV RNA values at inclusion were 809/mm(3) and 2.6 log copies/ml, respectively. Median HIV DNA load at inclusion was 2.3 log copies/10(6) peripheral blood mononuclear cells (PBMCs). Thirty-six months after TI, 63.9% of the patients had not yet reached the criteria for ART resumption, and 55.9% of patients had not resumed ART. In Cox multivariable analysis, a high HIV DNA level at TI, a low CD4 nadir, and pre-existing AIDS status were the only significant risk factors for reaching the criteria for ART resumption (hazards ratio: 2.15 (1.02-4.53), 4.59 (1.22-17.24), and 5.74 (1.60-20.56), respectively). Patients who started ART with a CD4 cell count above 350/mm(3) were able to interrupt treatment for long periods without a high absolute risk of either AIDS or severe non-AIDS morbidity/mortality. A high PBMC HIV DNA level at TI was a strong predictor for more rapid treatment resumption.

Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy.

UNLABELLED: Persistent immune activation plays a central role in driving Human Immunodeficiency Virus (HIV) disease progression. Whether CD4+CD25+ regulatory T cells (Tregs) are harmful by suppressing HIV-specific immune responses and/or beneficial through a decrease in immune activation remains debatable. We analysed the relationship between proportion and number of regulatory T cells (Tregs) and immune activation in HIV-infected patients interrupting an effective antiretroviral therapy (ART). Twenty-five patients were included in a substudy of a prospective multicenter trial of treatment interruption (TI) (ANRS 116). Proportions and numbers of Tregs and the proportion of activated CD4 and CD8 T cells were assessed at baseline and month 12 (M12) of TI. Specific anti-HIV CD4 and CD8 responses were investigated at baseline and M12. Non parametric univariate analyses and multivariate linear regression models were conducted. At baseline, the proportion of Tregs negatively correlated with the proportion of HLA-DR+CD8+T cells (r=-0.519). Following TI, the proportion of Tregs increased from 6.3% to 7.2% (p=0.029); absolute numbers of Tregs decreased. The increase in the proportion of HLA-DR+CD38+CD8+T cells was significantly related to the increase in proportion of Tregs (p=0.031). At M12, the proportion of Tregs did not negatively correlate with CD8 T-cell activation. Nevertheless, Tregs retain a suppressive function since depletion of Treg-containing CD4+CD25+ cells led to an increase in lymphoproliferative responses in most patients studied. Our data suggest that Tregs are efficient in controlling residual immune activation in patients with ART-mediated viral suppression. However, the insufficient increase in the proportion and/or the decrease in the absolute number of Tregs result in a failure to control immune activation following TI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00118677.

Late postnatal HIV infection in children born to HIV-1-infected mothers in a high-income country.

OBJECTIVE: To evaluate the risk of late postnatal HIV-1 infection in nonbreastfed children enrolled in the French ANRS Cohort CO01 (EPF). METHODS: The EPF cohort has prospectively enrolled HIV-infected mother/child pairs with a low proportion of known breastfeeding (<0.2%). Children were followed until they were 24 months old, with HIV-1 DNA/RNA PCR tests performed at birth, M1, M3 and M6 and a late serology at 18-24 months. This substudy included 4539 children who were uninfected at the age of 6 months in 1984-2005. RESULTS: Five children were late diagnosed with HIV-1 infection despite negative PCR tests until 6 months. In three cases, the infection was diagnosed between 14 and 18 months. The other infections were diagnosed at 10 and 12 years of age because of AIDS-defining symptoms; their last (negative) serologies were performed at 19 and 9 months, respectively. A phylogenetic study performed in the latest case revealed a strong homology between the mother and child strains. No known mode of viral transmission (including breastfeeding or use of premasticated food) could be found. However, we observed previously reported risk factors for intrafamilial HIV-1 transmission: poor socioeconomic backgrounds and sustained HIV-1 viremia in the mothers during the follow-up of their children. CONCLUSION: Late postnatal HIV-1 infection can rarely be diagnosed in the absence of known breastfeeding in high-income countries. Our results highlight the need for a maintained close follow-up of the noninfected children even after 6 months, especially when there are risk factors for intrafamilial viral transmission.

In untreated HIV-1-infected children, PBMC-associated HIV DNA levels and cell-free HIV RNA levels are correlated to distinct T-lymphocyte populations.

BACKGROUND: Clinical studies support biologically independent roles of cell-free HIV particles and HIV-infected cells in disease progression. The associations between the level of infected cells and immune markers have been poorly studied, particularly in perinatally infected children. OBJECTIVE: We tested the hypothesis that independent roles of cell-free virus and infected cells in HIV pathogenesis should be revealed by different associations between each of them and specific immune markers. METHODS: Levels of HIV RNA and DNA, HIV-specific CD8 T lymphocytes, activated and naive/memory T lymphocytes were determined in 44 untreated HIV-1-infected children. Pearson partial correlation coefficients were used to assess associations between the variables. RESULTS: Here we provide new information, by showing a direct correlation between the percentages of CD4HLA-DR lymphocytes and HIV DNA levels. Furthermore, higher HIV-specific CD8 T-lymphocyte frequencies were associated with lower HIV DNA levels. In contrast, CD838 lymphocytes and memory CD4 lymphocytes were correlated only to the HIV RNA level. All correlations were independent of age and CD4 depletion. CONCLUSIONS: Several immune markers were correlated to either the HIV RNA or the HIV DNA level, but never to both of them, supporting the concept that cell-free virus and infected cells play different roles in HIV-1 immunopathogenesis.

Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome.

BACKGROUND: Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. PATIENTS AND METHODS: We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. RESULTS: Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%): drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available) and in newborn lymphocytes (6/8) suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10) and neonatal lymphocytes (2/8) suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. CONCLUSION: This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%), drug resistance was archived in the cellular reservoir and persisted during infancy, with or without antiretroviral treatment. This finding stresses the need for effective antiretroviral treatment of pregnant women.

Factors influencing peripheral blood mononuclear cell-associated HIV-1 DNA level after long-term suppressive antiretroviral therapy in 236 patients.

OBJECTIVE: The objectives of this study were to determine whether peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA level in patients on long-term suppressive antiretroviral therapy (ART) was associated with plasma HIV-1 RNA level, CD4 cell count, and therapeutic factors throughout patient history. DESIGN: Patients receiving triple or dual therapy with plasma HIV-1 RNA below detection limit for more than 3 years were recruited in a multicentric, cross-sectional study within the eight virology laboratories of the Agence Nationale de Recherche sur le SIDA et les Hépatites virales HIV quantification working group, each one in relation with a clinical center. METHODS: PBMC-associated HIV-1 DNA was quantified using a standardized real-time PCR method in all laboratories. RESULTS: A total of 236 patients was included. Median HIV-1 DNA was 2.8 log10 copies/10 PBMCs (interquartile range 2.4-3.0). Univariate analysis showed PBMC HIV-1 DNA level to be related to pre-ART immuno-virologic status (plasma HIV-1 RNA zenith and CD4 cell count nadir) and to current CD4 T-cell count. HIV-1 DNA was lower in patients receiving ART with inferior virologic efficacy, as they also had a higher CD4 nadir and a lower HIV-1 RNA zenith than other patients. PBMC HIV-1 DNA level was not related to therapy duration, to time spent with undetectable HIV-1 RNA or to occurrence of a blip. Plasma HIV-1 RNA zenith and CD4 cell count nadir remained predictive of HIV-1 DNA level in the multivariate model which was associated with 22% of its variability. CONCLUSION: Whatever the duration of treatment, HIV-1 DNA level during ART gives a picture of the intensity of viral replication and immune deficiency reached before starting therapy.

LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in HAART area (ANRS CO 01).

HIV-1 diagnosis in babies born to seropositive mothers is one of the challenges of HIV epidemics in children. A simple, rapid protocol was developed for quantifying HIV-1 DNA in whole blood samples and was used in the ANRS French pediatric cohort in conditions of prevention of mother-to-child transmission. A quantitative HIV-1 DNA protocol (LTR real-time PCR) requiring small blood volumes was developed. First, analytical reproducibility was evaluated on 172 samples. Results obtained on blood cell pellets and Ficoll-Hypaque separated mononuclear cells were compared in 48 adult HIV-1 samples. Second, the protocol was applied to HIV-1 diagnosis in infants in parallel with plasma HIV-RNA quantitation. This prospective study was performed in children born between May 2005 and April 2007 included in the ANRS cohort. The assay showed good reproducibility. The 95% detection cut-off value was 6 copies/PCR, that is, 40 copies/10(6) leukocytes. HIV-DNA levels in whole blood were highly correlated with those obtained after Ficoll-Hypaque separation (r = 0.900, P < 0.0001). A total of 3,002 specimens from 1,135 infants were tested. The specificity of HIV-DNA and HIV-RNA assays was 100%. HIV-1 infection was diagnosed in nine infants before age 60 days. HIV-DNA levels were low, underlining the need for sensitive assays when highly active antiretroviral therapy (HAART) has been given. The performances of this HIV-DNA assay showed that it is adapted to early diagnosis in children. The results were equivalent to those of HIV-RNA assay. HIV-DNA may be used even in masked primary infection in newborns whose mothers have received HAART.

Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort.

OBJECTIVE: To identify factors associated with mother-to-child HIV-1 transmission (MTCT) from mothers receiving antenatal antiretroviral therapy. DESIGN: The French Perinatal Cohort (EPF), a multicenter prospective cohort of HIV-infected pregnant women and their children. METHODS: Univariate analysis and logistic regression, with child HIV status as dependent variable, were conducted among 5271 mothers who received antiretroviral therapy during pregnancy, delivered between 1997 and 2004 and did not breastfeed. RESULTS: The MTCT rate was 1.3% [67/5271; 95% confidence interval (CI), 1.0-1.6]. It was as low as 0.4% (5/1338; 95% CI, 0.1-0.9) in term births with maternal HIV-1 RNA level at delivery below 50 copies/ml. MTCT increased with viral load, short duration of antiretroviral therapy, female gender and severe premature delivery: 6.6% before 33 weeks versus 1.2% at 37 weeks or more (P < 0.001). The type of antiretroviral therapy was not associated with transmission. Intrapartum therapy was associated with four-fold lower MTCT (P = 0.04) in case of virological failure (> 10 000 copies/ml). Elective cesarean section tended to be inversely associated with MTCT in the overall population, but not in mothers who delivered at term with viral load < 400 copies/ml [odds ratio (OR), 0.83; 95% CI, 0.29-2.39; P = 0.37]. Among them, only duration of antenatal therapy was associated with transmission (OR by week, 0.94; 95% CI, 0.90-0.99; P = 0.03). CONCLUSIONS: Low maternal plasma viral load is the key factor for preventing MTCT. Benefits in terms of MTCT reduction may be expected from early antiretroviral prophylaxis. The potential toxicity of prolonged antiretroviral use in pregnancy should be evaluated.

Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study.

HIV-specific T cell responses play a critical role in the control of infection. We evaluated the impact of immune-based interventions in patients first treated during primary HIV-1 infection (PHI). Forty-three patients were randomized within three groups, to receive either interleukin-2 (IL-2 group), or boosts of ALVAC-HIV (vCP1433) and LIPO-6T followed by interleukin-2 (Vac-IL2 group), compared with no immune intervention (control group), and were monitored for T cell responses. Impact of strategies on viral replication was subsequently assessed during long-term treatment interruption. HIV-specific CD4(+) T cell responses did not change during the study period in immunized patients relative to controls, and vaccination had only a transient effect on interferon-gamma-producing CD8 responses. Viral rebound after treatment interruption was similar in immunized patients and controls. Forty percent of patients had HIV RNA values <10,000 copies/ml 12 weeks after interruption. The cumulative time off treatment represented almost half the total follow-up period. Immunological and virological status during PHI and HIV DNA load at interruption were predictive of the level of viral rebound after treatment interruption, whereas HIV RNA level during PHI and HIV DNA level at interruption were predictive of the time off treatment. Treatment interruption is safe in patients treated early after primary HIV infection. On the basis of this pilot study, HIV immunizations and interleukin-2 appear to have no supplementary benefit.

Impact of HIV-1 genetic diversity on plasma HIV-1 RNA Quantification: usefulness of the Agence Nationale de Recherches sur le SIDA second-generation long terminal repeat-based real-time reverse transcriptase polymerase chain reaction test.

The high genetic diversity of HIV-1 has a major impact on the quantification of plasma HIV-1 RNA, representing an increasingly difficult challenge. A total of 898 plasma specimens positive for HIV-1 RNA by commercial assays (Amplicor v1.5; Roche Diagnostic Systems, Alameda, CA or Versant v3.0; Bayer Diagnostics, Emeryville, CA) were tested using the Agence Nationale de Recherches sur le SIDA second-generation (G2) real-time reverse transcriptase polymerase chain reaction (RT-PCR) test: 518 samples containing HIV-1 of known subtype, including 88 from 2 subtype panels and 430 harboring B (n = 266) and non-B (n = 164) group M HIV-1 subtypes from patients followed up in 2002 through 2005 at Necker Hospital (Paris, France), and 380 samples from 10 different countries (Argentina, Cambodia, Cameroon, Central African Republic, France, Ivory Coast, Madagascar, Morocco, Thailand, and Zimbabwe). HIV-1 RNA values obtained by G2 real-time PCR were highly correlated with those obtained by the Amplicor v1.5 for B and non-B subtypes (R = 0.892 and 0.892, respectively) and for samples from diverse countries (R = 0.867 and 0.893 for real-time PCR vs. Amplicor v1.5 and real-time PCR vs. Versant v3.0, respectively). Approximately 30% of specimens harboring non-B subtypes were underquantified by at least -0.51 log10 in Amplicor v1.5 versus 5% underquantified in G2 real-time PCR. Discrepant results were also obtained with subtype B samples (14% underquantified by Amplicor v1.5 vs. 7% by G2 real-time PCR). Similar percentages were observed when comparing results obtained with the G2 real-time PCR assay with those obtained using the Versant assay. Addressing HIV-1 diversity, continual monitoring of HIV-1 RNA assays, together with molecular epidemiology studies, is required to improve the accuracy of all HIV RNA assays.

Poor recognition of HIV-1 Nef protein by CD8 T cells from HIV-1-infected children: impact of age.

Recognition of various HIV proteins by CD8 T cells from HIV-infected children was determined by two functional assays. First, using an Elispot assay, we show that 80% of patients recognized Gag, 77% recognized Pol, 61% recognized Env, 44% recognized Nef and 29% recognized Vif. Frequencies of Gag-, Pol-, and Env-specific IFN-gamma producing CD8 T cells were higher than frequencies of Nef and Vif-specific CD8 T cells. The poor recognition of Nef by ex vivo CD8 T cells was confirmed by CTL assays performed in HAART naïve children: 25% of children had positive response against Nef versus 44, 63 and 62% for Env, Gag, and Pol, respectively. Memory Gag-specific CTL were positively correlated with age, whereas Nef-specific CTL were negatively correlated with age. The poor Nef-specific CD8 T cell response in HIV-infected children contrasts with dominance of Nef-specific responses in infected adults.

Characteristics of HIV-infected children recently diagnosed in Paris, France.

Pediatric HIV-1 infections are still being diagnosed in France, despite the efficacy of prophylactic treatment to prevent mother-to-child transmission. To describe the characteristics and mode of infection of these children, we retrospectively analysed data of 59 children diagnosed with the HIV-1 infection between January 2000 and June 2005 in a Parisian university hospital. Twenty of these children had been born in France, and none had received appropriate prophylaxis (insufficient, not taken or given too late). Six received no preventive treatment due to failures in screening: three mothers were HIV-seronegative at the start of pregnancy and no test was carried out for the other three. At diagnosis, four had a severe immune deficiency (CD4 cells <15%). The 39 children born abroad were diagnosed at a median age of 3 years (range: 3 months-16 years), sometimes several years after their arrival in France. The clinical, virological and immunological status of these children was poorer than that of the children born in France: 18 had less than 15% CD4 cells. In contrast, the response to treatment of the children born in France was not as good as that of the children born abroad. The HIV-1 screening and prevention programme for pregnant women could be improved. Some children infected following the failure of prevention are at high risk of subsequent treatment failure. HIV-1 infection should be taken into consideration in children born in countries with a high prevalence of HIV, even if they have been living in France for several years and present no symptoms.

Structured treatment interruptions in primary HIV-1 infection: the ANRS 100 PRIMSTOP trial.

BACKGROUND: Whether structured treatment interruptions (STIs) can induce anti-HIV immune response and control HIV replication following discontinuation of highly active antiretroviral therapy (HAART) in patients with primary HIV infection is controversial. METHODS: In this multicenter, prospective trial, patients with early symptomatic primary HIV infection were given HAART continuously for 34 weeks. Afterward, patients with plasma viral load (PVL) <50 copies/mL entered the STI phase, which consisted of 3 consecutive periods of 2, 4, and 8 weeks off HAART, each separated by 12 weeks on HAART. HAART was permanently stopped at week 84 and patients were followed up for 24 weeks. The primary endpoint for definition of virologic success was a PVL <50 copies/mL during the 6 months following HAART discontinuation. RESULTS: Of the 29 patients enrolled, 26 completed the trial. Six months after HAART discontinuation, only 1 patient (3.8%, 95% CI: 0.1% to 19.6%) had PVL <50 copies/mL, whereas 6 of 26 (23.1%, 95% CI: 9.0% to 43.7%) had PVL <1000 copies/mL. Female gender was the only parameter significantly associated with a PVL <1000 copies/mL. No other parameter, either at baseline or before HAART discontinuation, predicted virologic success at week 108. A major protease inhibitor resistance mutation (L90M) developed in 3 patients. CONCLUSIONS: This trial failed to confirm that a significant proportion of patients with primary HIV infection can maintain suppression of viremia after a sequence of HAART/STIs followed by HAART discontinuation.