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Type I Interferon Production Is Profoundly and Transiently Impaired in Primary HIV-1 Infection

  1. Isabelle Kamga1,
  2. Sandrine Kahi1,a,
  3. Leyla Develioglu1,
  4. Miriam Lichtner1,a,
  5. Concepción Marañón1,
  6. Christiane Deveau3,
  7. Laurence Meyer3,
  8. Cécile Goujard4,
  9. Pierre Lebon2,
  10. Martine Sinet5 and
  11. Anne Hosmalin1
  1. 1Institut Cochin, Département d’Immunologie, INSERM U567, Centre National de la Recherche Scientifique, UMR 8104, IFR 116, Université Paris V René Descartes, and
  2. 2Faculté de Médecine, IFR 116, Université René Descartes, Paris, and
  3. 3INSERM U569, Cohorte PRIMO–Agence Nationale de Recherche contre le Sida,
  4. 4Service de Médecine Interne, Hôpital de Bicêtre, and
  5. 5Unité INSERM E0109, Immunité antivirale systémique et cérébrale, Kremlin-Bicêtre, France
  1. Reprints or correspondence: Dr. Anne Hosmalin, Immunology Dept., Institut Cochin, INSERM U 567, 27 rue du Fg St-Jacques, Bât G. Roussy, 8è étage, 75014 Paris, France (hosmalin{at}cochin.inserm.fr)
 
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Abstract

BackgroundSuccessful immunological control of human immunodeficiency virus (HIV) infection is achieved only in rare individuals. Plasmacytoid dendritic cells (DCs) are mostly responsible for the production of strong antiviral factors—that is, type I interferons (IFNs)—in response to viruses. Their natural IFN production is impaired in chronic HIV infection, in correlation with viral load and disease progression, but it has not been tested during the critical stage of primary infection, when a balance is set between host immune responses and viral replication

MethodsWe longitudinally studied 26 patients during the primary stage of HIV infection. Fifteen patients received highly active antiretroviral therapy (HAART) for 12 months

ResultsAt the time of inclusion into the cohort, median type I IFN production in response to herpes simplex virus type 1 stimulation was dramatically impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients, compared with that in PBMCs from 31 uninfected donors (180 vs. 800 IU/mL; P<.0001). Median circulating plasmacytoid DC counts were also significantly decreased (7300 vs. 13,500 cells/mL; P=.001). Twelve months later, IFN production returned to normal, and the data suggest that HAART may help in the recovery of IFN production by plasmacytoid DCs

ConclusionsThese data underline the potential for early antiretroviral treatment and IFN-α treatment to enhance viral control in a larger proportion of patients during the critical stage of primary infection

Innate immunity is the first line of defense against HIV infection [1]. Type I interferons (IFNs) are important players in innate immunity, through their antiviral activity against HIV [2] and through their enhancement of T cell stimulation [3, 4]. Two main types of leukocytes are involved in type I IFN production [5]. Monocytes produce IFN in response to Sendai virus and other enveloped viruses. In HIV infection, their IFN production decreases late and is not correlated with opportunistic infections [6 –8]. Natural IFN-producing cells are ∼50 times less frequent in peripheral blood than are monocytes, but they can produce 100 times more IFN per cell [6, 9 –11]. They produce type I IFN in vitro in response to a broad range of enveloped viruses, including HIV, and to naked viruses complexed with antibodies [12 –15]. These cells have been identified as plasmacytoid dendritic cells (DCs) [10, 16]. HIV itself induces IFN secretion from plasmacytoid DCs, not from myeloid DCs [9, 15, 17]. Natural IFN-producing cells are progressively lost during HIV infection, in association with progression to disease and occurrence of opportunistic infections and Kaposi sarcoma [7, 8, 10, 18 –22]

Circulating plasmacytoid and myeloid DC counts, measured by flow cytometry ex vivo and by rare-event analysis, are decreased in HIV chronic infection [20, 21, 23 –28]. Several studies have found a correlation between circulating plasmacytoid DC counts and IFN production from peripheral blood mononuclear cells (PBMCs) in vitro [20, 21, 26, 28] and an inverse correlation with disease progression [20, 21]. In a cohort of patients treated with highly active antiretroviral therapy (HAART), restoration of type I IFN production was correlated with viral load reduction and was even found to be an earlier recovery marker than CD4+ T cell count [22]. We have shown that, during the primary stage of HIV infection, which is critical for the establishment of a balance between viral replication and the immune system, circulating plasmacytoid DC counts are already decreased [29]. Furthermore, a pilot study of a few patients treated with HAART during primary infection indicated that plasmacytoid DC recovery during treatment may predict viral load immunological control if HAART is interrupted [30]. However, to our knowledge, IFN production in vitro has never been tested during primary infection. Here, we show that this function is dramatically impaired during primary infection and then recovers 1 year later and that antiretroviral treatment may play a role in this recovery

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Subjects, Materials, and Methods

Patients and control subjects Peripheral blood was collected in heparin from 26 patients with HIV primary infection, aged 23–56 years (median, 37 years), from the prospective Agence Nationale de Recherche contre le Sida PRIMO cohort, approved by the local Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale (Paris, France). Primary infection was diagnosed by (1) an indeterminate Western blot (WB) result, (2) a positive p24 antigenemia or detectable plasma HIV RNA with a negative or weakly positive ELISA result, or (3) a positive ELISA result after a negative result <3 months earlier. Infection date was estimated as (1) the date of symptom onset minus 15 days, (2) the date of an indeterminate WB result minus 1 month, or (3) the date halfway between those of the negative and the positive ELISA results. Patients were then included in the cohort, after giving informed consent, at different times but no later than 6 months after infection. In this observational cohort, the decision to initiate HAART was made by the physicians on the basis of the clinical status of each patient. Patients were tested at inclusion, before any treatment, and 12 months later. Peripheral blood from 48 uninfected individuals, aged 19–58 years (median, 39 years) was collected in heparin by the Etablissement de Transfusion Sanguine of La Pitié-Salpêtrière Hospital (Paris, France), in accordance with ethics guidelines of the Etablissement. PBMCs were separated by Ficoll density gradient. Part of the PBMCs was tested fresh for in vitro type I IFN production, and part was cryopreserved in fetal calf serum (FCS; Dutscher)–10% dimethyl sulfoxide (Sigma) before DC labeling. Some samples were tested only for IFN or for plasmacytoid DC counts

Flow cytometry Cells were preincubated for 15 min at 4°C in normal decomplemented AB human serum and incubated with monoclonal antibodies for 30 min in the dark at 4°C in RPMI (Invitrogen/Gibco) containing 10% FCS. Plasmacytoid DCs were quantified using the following antibodies from BD Pharmingen: anti–HLA-DR–peridin chlorophyll protein (L243; diluted 1:20); lineage–fluorescein isothiocyanate cocktail (diluted 1:10) composed of anti-CD3 (SK7), anti-CD14 (MP9), anti-CD16 (3G8), anti-CD19 (SJ25C1), anti-CD20 (L27), and anti-CD56 (NCAM 16-2); and anti–CD123-phycoerythrin (PE) (9F5; diluted 1:10). Cells were then washed twice in 2 mL of PBS (Gibco) with 2% FCS-EDTA (5 mmol/L) and fixed in 200 μL of PBS–1% paraformaldehyde (Sigma). Flow-cytometric analysis was performed using a FACScalibur and CellQuest (version 3.3; Becton Dickinson). All data were collected using identical instrument settings. For rare-event analysis of DCs, we acquired at least 100,000 events corresponding to PBMCs according to their forward/side scatter characteristics. After exclusion of lineagehigh cells, plasmacytoid DCs were gated as CD123high–HLA-DR+, high (figure 1). The absolute numbers of plasmacytoid DCs per milliliter of blood (counts) were calculated as described elsewhere [29]. Plasmacytoid DC frequencies were determined as the percentage of PBMCs that were identified as plasmacytoid DCs: (number of events in gate R3/number of events in gate R1)×100

Figure 1
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Figure 1

Rare-event analysis of plasmacytoid dendritic cells (DCs) in 1 donor, by flow cytometry. Peripheral blood mononuclear cells were selected in the R1 gate, excluding debris (A). Lineage− or lineagelow cells were selected in the R2 gate (B). In the combination of gates R1 and R2, plasmacytoid DCs were quantified as CD123high-HLA-DR+, high events, in gate R3 (C). FITC, fluorescein isothiocyanate; FSC, forward scatter characteristic; Lin, lineage; PE, phycoerythrin; PerCP, peridin chlorophyll protein; SSC, side scatter characteristic

In vitro type I IFN production PBMCs (400,000 cells/well) were cultured for 18 h at 37°C, with 5% CO2, in 24-well plates in RPMI 1640–10% FCS in the presence or absence of herpes simplex virus (HSV) at an MOI of 0.25. Cells were removed by centrifugation, and supernatants were stored at −80°C. Type I IFN titrations were performed using a biological assay, as described elsewhere [12]. After inactivation of HSV at pH 2, supernatants were serially diluted 2-fold in a 96-well plate with MEM–10% FCS; 3000 Madin Darby bovine kidney (MDBK) cells/well were added and incubated for 18 h at 37°C, with 5% CO2. The medium was then discarded, and the cells were infected with vesicular stomatitis virus at an MOI of 0.1 in MEM without FCS. Cytopathic effects were scored by use of a microscope 18 h later. A laboratory reference of human IFN-α standardized with National Institutes of Health Ga 023-902-530 was included with each titration. One international unit represents the reciprocal of the dilution that results in 50% of cell destruction, corrected for the value obtained with the IFN standard. MDBK cells are of bovine origin, and the test is sensitive to human IFN-α [31]; they do not respond to IFN-γ and respond poorly to IFN-β

Statistical analysis Data are summarized as medians and ranges. Statistical comparisons between control subjects and HIV-infected patients were performed using the nonparametric Mann-Whitney U test, longitudinal analysis was performed using the Wilcoxon test, and correlations (ρ) were evaluated using Spearman’s test. P<.05 was considered to be significant. SPSS (version 11.0) was used for statistical analyses

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Results

Study subject characteristics Twenty-six HIV-positive patients with primary infection were included into the PRIMO cohort 16–159 days (median, 51 days) after the presumed date of infection. Of these patients, 2 received diagnoses during acute infection (i.e., during symptomatic infection before seroconversion), and 24 received diagnoses during early infection [32]. At the time of inclusion (table 1), tests were performed before any treatment was given: the primary infection viral load was found to be high in almost all of the patients (median, 5.0 log copies of HIV-1 RNA/mL), and CD4+ T cell counts were low (median, 470 cells/μL). Fifteen patients were treated as follows, from the time of inclusion (day 0) until month 12: 10 patients received 2–3 nucleoside reverse-transcriptase inhibitors (NRTIs) and 1 protease inhibitor (PI); 3 patients received 2 NRTIs and 1 nonnucleoside reverse-transcriptase inhibitor (NNRTI); 1 patient received 3 NRTIs; and 1 patient received 2 NRTIs, 1 PI, and 1 NNRTI. Two additional patients were treated at day 0 but had treatment interruptions, and 1 patient initiated HAART only at month 10. These 3 patients were excluded from the analysis of the effect of HAART between day 0 and month 12. As shown in table 1, the decision to treat was made for patients with lower median CD4+ T cell counts (Mann-Whitney P=.001, treated vs. untreated patients at day 0); viral loads also appeared to be higher in these patients, but the difference was not significant (Mann-Whitney P=.08). After 1 year, untreated patients did not experience a decrease in their viral loads, whereas HAART-treated patients had efficient viral replication control: 11 of 15 had loads <50 copies of HIV-1 RNA/mL (Wilcoxon P<.0001) (table 1). Untreated patients had CD4+ T cell counts at month 12 that were not statistically different from those at day 0, whereas HAART-treated patients improved theirs (from 370 to 660 cells/μL; Wilcoxon P=.001, day 0 vs. month 12). These data are consistent with those previously described for patients from the PRIMO cohort [33]

Figure 2
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Figure 2

Dramatically low type I interferon (IFN) production by peripheral blood mononuclear cells (PBMCs) after in vitro stimulation in primary HIV infection. A Type I IFN production by PBMCs from control subjects, patients with HIV primary infection at initiation of the study (day 0), and patients 1 year later (month 12). Horizontal bars indicate median values. The Mann-Whitney test was used for statistical comparison between groups. Untreated patients are indicated by gray dots. B Longitudinal follow-up of type I IFN production by PBMCs from treated (n=13) and untreated (n=8) patients. Bars represent median values. The Wilcoxon signed-rank test was used for within-group comparison

Figure 3
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Figure 3

Circulating plasmacytoid dendritic cell (DC) count decrease during primary HIV infection. A Plasmacytoid DC counts in control subjects and in patients with HIV primary infection at day 0 and at month 12. Untreated patients are indicated by gray dots. B Longitudinal follow-up of plasmacytoid DC counts in treated (n=13) and untreated (n=7) patients. Statistical tests were used as described in figure 2

Table 1
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Table 1

Patient plasma viral loads and CD4+ T cell counts at inclusion into the cohort (day 0) or 1 year later (month 12)

Dramatic impairment of type I IFN production during HIV primary infection, followed by an increase 1 year later We investigated type I IFN production of PBMCs in response to HSV-1 stimulation in vitro. This function was profoundly impaired in patients with primary infection at the time of inclusion into the cohort, compared with that in control subjects (median, 180 vs. 800 IU/mL; Mann-Whitney P<.0001) (figure 2A ). There was no correlation with the putative time elapsed since infection. After 1 year, median IFN production increased significantly (from 180 to 400 IU/mL; Mann-Whitney P = .03, day 0 vs. month 12) and became statistically undistinguishable from that of the control subjects (figure 2A ). We investigated the effect of HAART administration on IFN production (figure 2B ). The median baseline IFN production values at day 0 were not statistically different between HAART-treated patients and untreated patients (110 vs. 200 IU/mL; Mann-Whitney P=.20). The median level of IFN production at month 12 was 500 IU/mL in the HAART-treated group and 350 IU/mL in the untreated group, and the median IFN production variation between month 12 and day 0 was +425 IU/mL in HAART-treated patients and 0 IU/mL in untreated patients, but this difference was not significant. However, when we followed each patient longitudinally, we observed a significant increase from day 0 to month 12 in the HAART-treated patients (Wilcoxon P=.02) but not in the untreated patients (P=.50). These data indicate that HAART may help to restore type I IFN production after the profound impairment that results from HIV primary infection. In addition, in untreated patients, type I IFN production appeared to be linked to viral control, since changes in viral load and IFN production between day 0 and month 12 were inversely correlated (n=8; ρ=-0.82; P=.02); this was not the case for patients who received HAART (n=13; ρ=0.26; P=.38)

Circulating plasmacytoid DC counts Median plasmacytoid DC counts in peripheral blood were lower in patients with primary infection at inclusion than in control subjects (7300 vs. 13,500 cells/mL, Mann-Whitney P=.001; 0.33% vs. 0.55%, Mann-Whitney P=.001) (figure 3A ). Baseline median plasmacytoid DC counts were statistically different between patients who initiated HAART at the time of inclusion and those who did not, but this difference was not found between plasmacytoid DC frequencies among PBMCs (5700 vs. 11,000 cells/mL, Mann-Whitney P=.04; 0.31% vs. 0.33%, Mann-Whitney P = .7). After 1 year, median plasmacytoid DC counts were higher than at day 0 but not statistically different, and they were still lower than those in control subjects (10,200 vs. 13,500 cells/mL; Mann-Whitney P=.03). The difference from control subjects that was observed for plasmacytoid DC absolute counts was not found for plasmacytoid DC frequencies among PBMCs (0.37% vs. 0.55%; Mann-Whitney P=.13), but it is consistent with the low plasmacytoid DC counts found in other studies of chronically HIV-infected patients [20, 21, 25 –28]. In HAART-treated patients, the median plasmacytoid DC count was 10,100 cells/mL; in untreated patients, it was 11,000 cells/mL (Mann-Whitney P=.15, for treated and untreated patients vs. control subjects; DC frequency in HAART-treated patients, 0.63% [P = .75 vs. control subjects]; DC frequency in untreated patients, 0.35% [P=.05 vs. control subjects]). A longitudinal analysis showed an increase in plasmacytoid DC frequencies (Wilcoxon P=.04), but not in absolute counts, between day 0 and month 12. The effect of HAART administration was studied longitudinally (figure 3B ). Other than 1 atypical patient, discussed below, patients receiving HAART experienced increases in their median plasmacytoid DC counts between day 0 and month 12, although with borderline statistical significance (from 5900 to 10,100 cells/mL, Wilcoxon P = .048; frequency, from 0.31% to 0.63%, Wilcoxon P=.047), whereas untreated patients did not (11,000 cells/mL at both time points, Wilcoxon P=.31; frequency, from 0.33% to 0.35%, Wilcoxon P=.12). Moreover, 13 of 15 HAART-treated patients had a positive circulating plasmacytoid DC count variation between month 12 and day 0, and the median circulating plasmacytoid DC variation was +2900 cells/mL in HAART-treated patients and −830 cells/mL in untreated patients (Mann-Whitney P = .02). This indicates that HAART may help plasmacytoid DC counts to recover after the profound initial loss at the onset of primary infection

Correlation between plasmacytoid DC counts and type I IFN production Because plasmacytoid DCs are the main type I IFN producers during viral infection, we assessed correlations between plasmacytoid DC counts and IFN production. As expected, we found a strong positive correlation between IFN production and circulating plasmacytoid DC counts in the control group (n=16; ρ=0.8; P<.001). However, this correlation was abolished in the patients at inclusion into the cohort: all had low IFN production with different plasmacytoid DC counts (n=25; ρ=0.29; P=.16). The correlation was restored at month 12 (n=22; ρ=0.66; P=.001). Further analysis showed that it was then restricted to the HAART-treated group (ρ=0.93; P<.0001 in the treated group vs. ρ=0.07; P=.88 in the untreated group). The median ratio of IFN production per plasmacytoid DC was significantly lower in patients at inclusion (0.07 IU/plasmacytoid DC) than in control subjects (0.20 IU/plasmacytoid DC) (Mann-Whitney P = .002). HAART-treated patients experienced significant increases in their IFN production per plasmacytoid DC, whereas untreated patients did not (treated group, from 0.04 to 0.21 IU/plasmacytoid DC, Wilcoxon P=.02; untreated group, from .07 to .11 IU/plasmacytoid DC, Wilcoxon P=.50). Altogether, these results suggest that HAART given during primary infection improves the type I IFN–secreting ability of plasmacytoid DCs

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Discussion

The present study shows—for the first time, to our knowledge—that in vitro production of type I IFN in HIV-infected patients is profoundly impaired during primary infection. It also confirms that plasmacytoid DC counts are low during this stage of the disease [29]. The loss of in vitro IFN production from natural IFN-producing cells/plasmacytoid DCs was previously known only in chronically infected patients and was predictive of the occurrence of opportunistic infections or Kaposi sarcoma [7, 10, 18 –22]

During primary HIV infection, when a balance between viral replication and immune responses is set, this loss of type I IFN production may be very detrimental. Indeed, a role for IFN in HIV replication control in patients is indicated by the negative correlations between viral load and IFN production or plasmacytoid DC counts [20 –22, 29]. Correlations are not found uniformly throughout all studies [26, 27], probably because multiple parameters help to control HIV replication [32, 35 –37]. In the present study, there was no significant correlation between viral load and IFN production or plasmacytoid DC counts at a given time point, either at day 0 or month 12. However, in the untreated patients, changes in viral load and IFN production during the year-long follow-up were inversely correlated. The mechanisms of action of type I IFNs against viral replication may be either direct [2] or indirect by inducing infected cell lysis by NK cells, specific cytotoxic T cells, or T helper type 1 cells [3]. Type I IFNs enhance the survival of plasmacytoid DCs themselves [38, 39]. They also enhance MHC class I expression, which is down-modulated by the HIV Nef protein [40]. They may favor monocyte differentiation into potent antigen-presenting DCs during viral infections [41]. In addition, they enhance cross-presentation [42], which is a quantitatively optimal HIV presentation pathway, compared with direct presentation [43]

This longitudinal study was performed using the same methods as originally set up during the first year [29]. The plasmacytoid DC counts in control subjects (median, 13,500 DCs/mL; 0.55% among PBMCs) allow internal comparison with those obtained in patients. However, they are higher than those found in many other laboratories [20, 21, 25 –28, 34]. Factors influencing DC counts include anticoagulant solution; Ficoll density gradient separation; freezing, thawing, and washing protocols; antibody labeling strategies; and flow-cytometric gating (data not shown) [34]. It is likely that single platform tests using fresh whole blood will be less biased than other tests [34]. Because many studies have indicated that DC counts are of potential interest in clinical immunology, a standardization between the different laboratories involved is urgently needed

Type I IFN production is mainly due to plasmacytoid DCs, as assessed by the correlation found with plasmacytoid DC counts [28, 44]. The loss of this correlation at day 0 reflects the fact that some patients with relatively high plasmacytoid DC counts had low IFN production, as in the patient with the third highest plasmacytoid DC count (16,300 cells/mL), whose PBMCs had IFN production of only 12 IU/mL. Some patients with relatively high IFN production, at 400 IU/mL, also had some of the lowest plasmacytoid DC counts (4400 and 4000 cells/mL). This indicates that, at this stage, either the few plasmacytoid DCs remaining in some patients or other cells are responsible for IFN production [5 –8]. Intracellular labeling should be used to discriminate between these hypotheses [45]. IFN production or plasmacytoid DC counts have also been related to the course of other infectious diseases: low plasmacytoid DC counts and/or IFN production have been found in hepatitis C virus infection [28, 44], and low plasmacytoid DC counts have been linked to the severity of dengue virus and HSV infection [46, 47]

One atypical patient among the HAART-treated patients had a substantial decline in IFN production (from 400 to 2 IU/mL) and in plasmacytoid DC counts (from 14,200 to 3100 DCs/mL) (figures 2B and 3B ). However, at month 12, his viral load was controlled (from 5.4 log copies of HIV-1 RNA/mL at day 0 to undetectable at month 12), and his CD4+ T cell count was close to the median (from 459 cells/μL at day 0 to 624 cells/μL at month 12). This patient had the earliest postinfection inclusion into the cohort (16 days). In experimental simian immunodeficiency virus infection, macaques exhibit a peak in their IFN levels around day 10 after infection [48]. This patient may be within this very early IFN production peak, which is poorly explored in patients

Other than the atypical patient, most of the HAART-treated patients experienced an increase in IFN production between day 0 and month 12, but this was not the case in untreated patients. The fact that the decision to initiate HAART was made in the interest of each patient and not as a randomized therapeutic study is reflected by the lower CD4+ T cell counts at day 0 in patients who had received HAART from day 0. Absolute plasmacytoid DC counts were also slightly lower in patients who had received HAART from day 0. However, viral loads and type I IFN production levels were not statistically different. The question of whether to initiate antiretroviral treatment as early as the primary stage of infection is a current dilemma [32]. Studies have shown that treatment during early infection may improve protection by developing anti-HIV CD4+ and CD8+ T cell responses [49 –51]. However, these results are controversial, because it was also shown that CD8+ T cell responses either decrease or cannot develop after therapy during primary infection [33, 52]. HAART started as early as primary infection might lead to compliance reduction, drug-resistance mutations, and exposure to long-term drug toxicity. In addition, HIV-specific T helper responses do not persist after HAART interruption, at least during chronic infection [53, 54]. In any case, no experimental evidence has yet shown long-term clinical benefits of early HAART. Conversely, our data suggest that initiating HAART at the time of diagnosis of primary infection may favor recovery of antiviral innate immunity. To further document the effect of HAART on IFN production recovery, it will be necessary to compare IFN production in treated and untreated patients with matched baseline values in a larger cohort

The present study also suggests that the defective IFN production during primary infection should perhaps be supplemented. It will be important to assess whether PEG-α-IFN treatment, which has already given promising results in preliminary studies [55], helps to control viral replication during primary infection and whether it acts on plasmacytoid DC numbers and function

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PRIMO Cohort Study Group Members

The members of the PRIMO Cohort study group are as follows: J. Beylot, P. Morlat, D. Malvy, M. Bonarek, and F. Bonnet (St André, Bordeaux); C. Caulin, E. Badsi, J. Cervoni, and V. Vincent (Lariboisière, Paris); J. M. Molina and D. Ponscarme (St Louis, Paris); A. P. Blanc and T. Allègre (Aix en Provence); J. F. Delfraissy, C. Goujard, and Y. Quertainmont (Bicêtre, Le Kremlin Bicêtre); F. Raffi, V. Reliquet, E. Billaud, and J. L. Esnault (Hôtel-Dieu, Nantes); F. Bricaire, C. Katlama, V. Zeller, H. Ait Mohand, C. Duvivier, and J. Ghosn (Pitié-Salpétrière, Paris); E. Rouveix, S. Morelon, and C. Dupont (A. Paré, Boulogne); J. Reynes, V. Baillat, and V. Lemoing (Montpellier); J. M. Livrozet, F. Jeanblanc, and P. Chiarello (E. Herriot, Lyon); R. Thomas, F. Souala, and C. Bouvier (Pontchaillou, Rennes); A. Cabié and S. Abel (Fort de France); J. L. Vildé, C. Jestin, and C. Jadand (Bichat, Paris); E. Pichard, P. Fialaire, and J. M. Chennebault (Angers); P. Henon, G. Beck-Wirth, and C. Beck (Emile Muller, Mulhouse); D. Sereni and C. Lascoux (St Louis, Paris); S. Herson and A. Simon (Pitié-Salpétrière, Paris); B. Dupont and J. P. Viard (Necker, Paris); A. Devidas, P. Chevojon, and P. Kousignian (Corbeil); P. Massip and M. Obadia (Purpan, Toulouse); J. Beytout and C. Jacomet (Hôtel Dieu, Clermont-Ferrand); H. Aumaître, B. Delmas, and M. Saada (Joffre, Perpignan); P. Yeni, E. Bouvet, I. Fournier, P. Campa, and S. Abgrall (Bichat, Paris); A. Sobel, P. Lesprit, and A. S. Lascaux (H. Mondor, Creteil); H. Gallais, I. Ravaux, and C. Tomei (La Conception, Marseille); R. Verdon and M. Six (Caen); C. Trepo and C. Augustin-Normand (Hôtel-Dieu, Lyon); G. Pialoux, W. Rosembaum, L. Slama, and P. Mariot (Tenon, Paris); P. Morel and F. Timsit (St Louis, Paris); B. Hoen and C. Drobacheff (St Jacques, Besançon); M. Kazatchkine, P. Castiel, and D. Batisse (HEGP, Paris); D. Sicard, D. Salmon, and A. Brunet (Cochin, Paris); P. Galanaud, F. Boué, and J. Polo de Veto (A. Béclère, Clamart); P. Veyssier and D. Merrien (Compiegne); P. M. Girard and D. Samanon-Bollens (St Antoine, Paris); M. Bentata and F. Rouges (Avicenne, Bobigny); J. P. Cassuto, C. Sohn, and E. Rosenthal (L’Archet, Nice); P. Dellamonica and S. Chaillou (L’Archet, Nice); J. M. Ragnaud and I. Raymond (Pellegrin, Bordeaux); P. Choutet, P. Nau, and F. Bastides (Tours); P. Canton and L. Boyer (Nancy); Y. Mouton and A. Dos Santos (Tourcoing); P. Chavanet and M. Buisson (Dijon); G. Dien, C. Daniel, and C. Devaurs (St-Brieuc); Y. Redelsperger, B. Ponge, and L. Fournier (Melun); J. Laffay and A. Greder Belan (A. Mignot, Le Chesnay); I. Lamaury and A. Cheret (Pointe à Pitre); M. Gayraud and L. Bodard (IMM Jourdan, Paris); J. C. Imbert and O. Picard (St Antoine, Paris); E. Oksenhendler and L. Gérard (St Louis, Paris); G. Huchon and A. Compagnucci (Hôtel-Dieu, Paris); P. Lagarde and F. David (Lagny); Ph. Vinceneux and M. Bloch (L. Mourier, Colombes); B. Audhuy and N. Plaisance (Colmar); O. Bletry and D. Zucman (Foch, Suresnes); L. Bernard and J. Salomon (R. Poincaré, Garches); M. Chousterman and V. Garray (Intercommunal, Créteil); A. Regnier (Vichy); M. Uzan and F. Saint-Dizier (Ducuing, Toulouse); J. J Girard (Loches); P. Moreau and O. Vaillant (Lorient); F. Grihon (Noyon); A. Lepretre (Eaubonne); D. Houlbert (Alençon); F. Caron and Y. Debab (Rouen); F. Trémolières and V. Perronne (Mantes la Jolie); A. Lepeu and B. Slama (Avignon); E. Brottier and L. Faba (La Rochelle); C. Miodovski (Paris); R. Armero and E. Counillon (Fréjus); G. Guermonprez and A. Dulioust (Briis sous Forges); P. Boudon and D. Malbec (Aulnay sous Bois); O. Patey and C. Semaille (Villeneuve St-Georges); J. Deville, G. Remy, and I. Beguinot (Reims); and G. Gonzalez and F. Sanlaville (Sens)

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Acknowledgments

We thank all the participating patients from the PRIMO cohort and their clinicians, as well as the staff from the Etablissement Français du Sang of La Pitié Salpêtrière. We thank Orly Amar for help in protocol design, Alejandra Urrutia and Audrey Rodollec for help in sample processing, Ilham Iraqui for providing patient clinical data, and Jérôme Pacanowski for critical reading of the manuscript

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Footnotes

  • ↵Presented in part: 12th International Congress of Immunology and 4th Annual Conference of the Federation of Clinical Immunology Societies, Montreal, Canada, 22 July 2004

    Financial support: Agence Nationale de Recherche contre le Sida; Ensemble contre le SIDA (Sidaction); Institut National de la Recherche Médicale (INSERM)

  • ↵Present affiliations: INSERM SC-10, Hôpital Paul Brousse, Villejuif, France (S.K.); Dipartimento Malattie Infettive e Tropicali, Policlinico Umberto 1-Universita di Roma la Sapienza, Rome, Italy (M.L.)

  • Received December 2, 2004.
  • Accepted February 10, 2005.
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  1. J Infect Dis. (2005) 192 (2): 303-310. doi: 10.1086/430931
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