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Loss of viral control in early HIV-1 infection Is temporally associated with sequential escape from CD8+ T cell responses and decrease in HIV-1-specific CD4+ and CD8+ T cell frequencies

  1. Annette Oxenius1,
  2. David A. Price3,
  3. Alexandra Trkola2,
  4. Charles Edwards4,
  5. Emma Gostick4,
  6. Hua-Tang Zhang4,
  7. Philippa J. Easterbrook6,
  8. Tin Tun4,
  9. Andrew Johnson7,
  10. Anele Waters6,
  11. Edward C. Holmes5 and
  12. Rodney E. Phillips4
  1. 1Institute for Microbiology, Eidgenössische Technische HochschuleZurich, Switzerland
  2. 2Division of Infectious Diseases, University HospitalZurich, Switzerland
  3. 3Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesda, Maryland
  4. 4Nuffield Department of Clinical Medicine, John Radcliffe Hospital and Peter Medawar Building for Pathogen ResearchOxford
  5. 5Department of Zoology, University of OxfordOxford
  6. 6Department of HIV and Genito-Urinary Medicine, Guy's, King's, and St. Thomas' School of MedicineLondon
  7. 7AvidexAbingdon, United Kingdom
  1. Reprints or correspondence: Dr. Annette Oxenius, Institute for Microbiology, ETH Zurich, LFV B31, Schmelzbergstr. 7, 8092 Zurich, Switzerland (oxenius{at}micro.biol.ethz.ch).
 
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Abstract

The outcome of human immunodeficiency virus type 1 (HIV-1) infection is related to the set-point plasma virus load (pVL) that emerges after primary HIV-1 infection (PHI). This set-point pVL generally remains stable but eventually increases with progression to disease. However, the events leading to loss of viremic control are poorly understood. Here, we describe an individual who presented with symptomatic PHI and subsequently progressed rapidly, after an initial period of 1 year during which viral replication was well controlled. Escalation of viral replication in this atypical case was preceded by the emergence of escape variants in many epitopes targeted by dominant CD8+ T cell responses and a marked decrease in HIV-1-specific CD4+ and CD8+ T cell frequencies. There were no changes in viral tropism, replication kinetics, or neutralizing antibody titers. These findings demonstrate the temporal relationship between viral escape from CD8+ T cell activity, decrease in HIV-1-specific T cell frequencies, and loss of control of viral replication.

Substantial evidence indicates that the adaptive immune system plays a major role in containing viral replication during HIV-1 infection [1, 2]. In particular, HIV-1-specific CD8+ T cell responses are thought to mediate the decrease in the initial viremia during primary HIV-1 infection (PHI) [3, 4]. After PHI, a setpoint plasma virus load (pVL) emerges that, in general, remains relatively stable throughout the chronic asymptomatic phase of infection. The magnitude of this setpoint pVL, which is likely determined by early interactions between the virus and the immune system, is inversely related to the rate of progression to AIDS [5]. However, the factors that are responsible for the maintenance of the established set-point pVL are less well defined, and it is not clear which events eventually lead to loss of control of viremia. Identification of such events requires longitudinal and comprehensive analysis of adaptive immune responses and viral evolution in patients with untreated HIV-1 infection.

Here, we studied the natural course of HIV-1 infection over a period of 2 years in an individual who presented with symptomatic PHI. Initially, viral replication was well controlled (during the first 410 days after the onset of symptoms); subsequently, pVL escalated dramatically, such that initiation of antiretroviral therapy became mandatory. This initial control and subsequent viral breakthrough offered a unique opportunity to analyze the immunologic and virologic events associated with both effective suppression of viral replication and the subsequent loss of control of viremia over time.

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Patients, Materials and Methods

Patient. Patient SC21 (37 years old, homosexual, white) presented with PHI after a recent, well-documented high-risk sexual exposure; the clinical features of his seroconversion illness included fever, myalgia, generalized rash, and oral candidiasis, for a period of 6 weeks. The time points of analysis refer to the reported start of the seroconversion illness. Written, informed consent was obtained, and the study was approved by the local ethics committee.

HLA typing. The HLA class I and II genotype was determined by polymerase chain reaction (PCR) with sequencespecific primers [6].

Determination of pVL. pVL was quantified from cryopreserved plasma by use of the b-DNA (Chiron) or Amplicor reverse-transcriptase PCR (Roche) kits.

Assessment of HIV-1-specific CD8+ and CD4+ T cell responses. Comprehensive screening for HIV-1-specific CD8+ and CD4+ T cell responses was performed ex vivo by use of interferon (IFN)-γ ELISPOT analysis with pooled overlapping peptides and baculovirus-expressed recombinant proteins, as described elsewhere [7]. For further analysis of CD8+ T cell responses, single 8–11-mer peptides were tested at 0.02 µmol/ L, and 20-mer peptides were tested at 1 µmol/L, unless specified otherwise. Phytohemagglutinin (5 µg/mL) was used as the positive control, and medium alone was used as the negative control; baculovirus supernatant was used as an additional control in all CD4+ T cell assays. Spot quantification was automated by use of an ELISPOT plate reader (AID).

Tetrameric complexes. Phycoerythrin (PE)-conjugated peptide/HLA class I tetrameric complexes were used to track antigen-specific CD8+ T cell responses physically, as described elsewhere [8].

Cell staining and fluorescence-activated cell sorter analysis. Cells were stained with PE-labeled tetramers for 15 min at 37°C, followed by anti-CD8-Tricolor (Caltag) for 20 min at 4°C, and then analyzed on a FACSCalibur flow cytometer with Cellquest software (Becton Dickinson).

Neutralization assay. Autologous virus was isolated by coculturing CD4+ T cells from the patient with peripheral blood mononuclear cells (PBMCs) from a healthy donor [9]. The TCID50 and coreceptor usage of the virus stocks were determined as described elsewhere [10]. Serum neutralization activity was analyzed in a neutralization assay using mitogenstimulated PBMCs, as described elsewhere [10]. Sensitivity of the virus isolates to monoclonal antibodies 2F5 [11], 2G12 [12], and IgG1b12 [13] and the tetrameric CD4 molecule CD4-IgG2 [14] were evaluated similarly.

Plasma virus RNA sequencing. RNA was extracted from plasma (NucleoSpin; Macherey-Nagel GmbH) and reverse transcribed by use of random decamers (ABgene). Primary and nested PCR amplification was performed as described elsewhere [15]. PCR products were gel purified, cloned (pCR4-TOPO; Invitrogen), and sequenced (ABI BigDye Terminator Cycle; Applied Biosystems).

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Results

HIV-1-Specific CD8+ T Cell Response

Sequential induction of functional CD8+ T cell responses. Patient SC21 presented with symptomatic acute PHI and exhibited good control of pVL (median, 11,115 copies/mL) and total CD4+ T cell counts (median, 544 cells/mm3) during the first 13 months after PHI. However, after 410 days, pVL increased, reaching 326,098 copies/mL by day 635. Comprehensive screening for CD8+ T cell responses identified 14 peptides (table 1) that induced positive responses on at least 1 occasion. Autologous epitope-containing viral genome regions were sequenced at days 52–66; the corresponding peptides were synthesized and used for analysis of longitudinal samples. CD8+ T cell responses were induced sequentially. At day 60, responses specific for RPM, DPN, ILR, and ITK were >1500 spot-forming cells (sfcs)/106 peripheral blood lymphocytes (PBLs); responses specific for SLF, IPR, IPL, ATE, VPV, EAE, and AEW ranged from 50 to 1000 sfcs/106 PBLs; and responses specific for VPL, DRL, and ANP were <50 sfcs/106 PBLs (figure 1A). All of the early induced responses and most of the later-induced responses increased up to day 297. The total HIV-1-specific CD8+ T cell response to all targeted epitopes combined decreased at day 410 (before the increase in pVL) to 37% and at day 523 to 18% of the total peak response (figure 1A).

Figure 1.
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Figure 1.

A, Sequential induction of HIV-1-specific CD8+ T cells. The upper graph shows total CD8+ T cell counts (white symbols, left Y-axis) and plasma virus load (black circles, right Y-axis), from days 37 to 635. HIV-1-specific CD8+ T cell responses were analyzed ex vivo by use of interferon (IFN)-γ ELISPOT, with the indicated autologous CD8+ T cell epitopes for stimulation. Epitope sequences and HLA restriction are shown in table 1. Frequencies of epitope-specific CD8+ T cells are given in spot-forming cells (sfcs) per 106 peripheral blood lymphocytes (PBLs). Induction and evolution of epitope-specific CD8+ T cell frequencies are shown in 3 graphs; responses are grouped according to the temporal order in which they appeared. Only responses detected at ⩾1 time point are plotted. B, Comparative physical and functional evolution of CD8+ T cell populations specific for the epitopes RPM, ITK, SLF, and IPR. In each panel, the frequencies of CD8+ tetramer+ T cells (black symbols, left Y-axis) and the number of IFN-γ- secreting CD8+ T cells (white symbols, right Y-axis) for the same epitope are plotted over time.

Figure 2.
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Figure 2.

Serial sequence analysis of targeted CD8+ T cell epitopes. Plasma virus RNA was sequenced at multiple time points after infection. Autologous sequences of all targeted CD8+ T cell epitopes are shown; nos. indicate the no. of clones with the indicated sequence.

Figure 3.
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Figure 3.

Recognition profiles of index and variant epitopes by autologous CD8+ T cells directly ex vivo. Functional avidities for index (black squares) and variant epitopes (white symbols) were determined by peptide titration experiments. Peripheral blood lymphocytes (PBLs) from days 207, 297, and 635 were stimulated with serial dilutions of the relevant index and variant peptides, and the frequencies of interferon-γ producing CD8+ T cells were determined by use of ELISPOT analysis. sfcs, spot-forming cells.

Figure 4.
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Figure 4.

HIV-1-specific CD4+ T cell responses and neutralizing antibody response against autologous virus isolates. A, HIV-1-specific CD4+ T cell responses were analyzed between days 52 and 635 by use of interferon-γ ELISPOT. Fresh CD8-depleted peripheral blood lymphocytes (PBLs) were incubated with HIV-1-derived antigens, as shown. Results are shown as spot-forming cells (sfcs) per 106 CD8-depleted PBLs. The upper graph shows plasma virus load (pVL) (black circles, right Y-axis) and total CD4+ T cell counts (white circles, left Y-axis). B, Serial plasma samples from days 60 to 565 were tested for neutralizing antibody titers against autologous virus isolated from day 255 (upper graph) and from day 565 (lower graph). Titers for 50% (circles), 70% (squares), and 90% (triangles) in vitro neutralization are shown.

Table 1.
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Table 1.

Targeted CD8+ T cell epitopes.

Sequential appearance of CD8+ T cell populations. Tetrameric class I peptide/HLA complexes were generated to allow the physical detection of antigen-specific CD8+ T cell populations. Overall, the dynamics of sequential induction of specific CD8+ T cell populations observed in the functional assays were reflected by the physical presence of the respective CD8+ T cell populations (figure 1B).

Viral Sequence Variation and Evolution within Targeted CD8+ T Cell Epitopes

Emergence of epitope mutations and effects on CD8+ T cell recognition. The decrease in HIV-1-specific CD8+ T cell responses before and concomitant with the increase in pVL suggested that antigenic variation within targeted epitopes might have evolved. Therefore, all HIV-1 genome regions containing targeted epitopes were sequenced from plasma virus RNA at different time points: (1) days 52-66 (baseline); (2) days 172, 297, 327, and 369 (intermediate); and (3) day 635 (late). Six of 14 epitopes showed substantial sequence variation between baseline and intermediate or late samples; the remaining 8 epitopes showed no significant variation (figure 2). To address the question of whether autologous T cell recognition of the variants differed with respect to the index epitopes, all major variant epitopes were synthesized and tested by use of IFN-γ ELISPOT analysis (figure 3). In general, all variant epitopes were less potent at inducing production of IFN-γ, compared with the index peptides. In particular, at lower peptide concentrations, more likely reflecting the in vivo situation, reduced agonistic activity was clearly apparent for emerging variants of the index peptides IPL, DPN, RPM, and SLF. For the DRL epitope, 20-mer peptides were used for analysis, precluding an exact avidity assessment of the index and variant peptides. The appearance of the variant epitopes occurred in multiple stages (figure 2). DRL was completely replaced by a variant between days 66 and 327. VPL and RPM were either largely or completely replaced by variant epitopes between days 172 and 635. SLF was completely replaced by variants between days 327 and 635. Overall, the variant epitopes were 0%–80% as efficient as the index epitopes, with respect to specific induction of IFN-γ, when tested on PBLs before their in vivo appearance (figure 3). Interestingly, the relative efficiency of the variant epitopes increased when tested on PBLs after their in vivo appearance. However, the magnitude of the response generated against the variants was always substantially lower than the responses initially directed against the index peptides. The epitopes IPL and DPN evolved sequentially into different variants. IPL was replaced by a first variant between days 297 and 369 (exhibiting 40% of the index agonistic potential), which was subsequently replaced by 2 further variants, which completely lacked agonistic activity, between days 369 and 635 (figure 3).

Emergence of epitope mutations and effects on CD8+ T cell recognition. The decrease in HIV-1-specific CD8+ T cell responses before and concomitant with the increase in pVL suggested that antigenic variation within targeted epitopes might have evolved. Therefore, all HIV-1 genome regions containing targeted epitopes were sequenced from plasma virus RNA at different time points: (1) days 52-66 (baseline); (2) days 172, 297, 327, and 369 (intermediate); and (3) day 635 (late). Six of 14 epitopes showed substantial sequence variation between baseline and intermediate or late samples; the remaining 8 epitopes showed no significant variation (figure 2). To address the question of whether autologous T cell recognition of the variants differed with respect to the index epitopes, all major variant epitopes were synthesized and tested by use of IFN-γ ELISPOT analysis (figure 3). In general, all variant epitopes were less potent at inducing production of IFN-γ, compared with the index peptides. In particular, at lower peptide concentrations, more likely reflecting the in vivo situation, reduced agonistic activity was clearly apparent for emerging variants of the index peptides IPL, DPN, RPM, and SLF. For the DRL epitope, 20-mer peptides were used for analysis, precluding an exact avidity assessment of the index and variant peptides. The appearance of the variant epitopes occurred in multiple stages (figure 2). DRL was completely replaced by a variant between days 66 and 327. VPL and RPM were either largely or completely replaced by variant epitopes between days 172 and 635. SLF was completely replaced by variants between days 327 and 635. Overall, the variant epitopes were 0%–80% as efficient as the index epitopes, with respect to specific induction of IFN-γ, when tested on PBLs before their in vivo appearance (figure 3). Interestingly, the relative efficiency of the variant epitopes increased when tested on PBLs after their in vivo appearance. However, the magnitude of the response generated against the variants was always substantially lower than the responses initially directed against the index peptides. The epitopes IPL and DPN evolved sequentially into different variants. IPL was replaced by a first variant between days 297 and 369 (exhibiting 40% of the index agonistic potential), which was subsequently replaced by 2 further variants, which completely lacked agonistic activity, between days 369 and 635 (figure 3).

The remaining 8 targeted CD8+ T cell epitopes in patient SC21 did not show significant sequence variation over the entire period of analysis (see figure S1, in Appendix A, in the online version of this article, available at http://www.journals.uchicago.edu/JID/journal/issues/v190n4/32384/32384.html). Five of these (VPV, ATE, EAE, ANP, and AEW) were low-frequency responses at most time points of analysis (mostly <1000 sfcs/106 PBLs). ITK-specific CD8+ T cells were present at high numbers already at day 60; in fact, this response was strongest early during infection. However, at day 635, this response had decreased to only 13% of the initial magnitude. Similarly, the ILR-specific response was completely abrogated at day 635. Only the IPR-specific response showed a less-dramatic reduction from days 369 to 635 and represented the only high-frequency CD8+ T cell response with no epitope variation at day 635 (for details, refer to figure S1, in Appendix A, in the online version of this article, available at http://www.journals.uchicago.edu/JID/journal/issues/v190n4/32384/32384.html).

Evolutionary analysis of CD8+ T cell escape mutations. To determine whether the mutations fixed within CD8+ T cell epitopes conferred a selection advantage to the virus, we undertook a phylogenetic analysis. This analysis revealed the action of positive selection on 4 of the 6 variant epitopes (DRL, DPN, IPL, and SLF) see table S1, in Appendix B, in the online version of this article, available at http://www.journals.uchicago.edu/JID/journal/issues/v190n4/32384/32384.html). In these cases, the observed time to fixation of individual escape mutations within the viral population was significantly shorter than the neutral prediction (i.e., the estimated fixation time assuming the random sampling process of genetic drift). In the case of the VPL and RPM epitopes, there was no evidence for positive selection by use of this approach, mainly because, in both cases, 2 variants with roughly similar frequencies coexisted at day 635. However, both variants were weaker agonists than were the index epitopes; thus, their equity of effect may have prevented identification of 1 variant site as subject to positive selection (for details, refer to table S1, in Appendix B, in the online version of this article, available at http://www.journals.uchicago.edu/JID/journal/issues/v190n4/32384/32384.html).

HIV-1-Specific CD4+ T Cell Responses and Neutralizing Antibody Response against Autologous Virus Isolates

The evolution of the HIV-1-specific CD4+ T cell response was analyzed by use of serial IFN-γ ELISPOT analysis with fresh CD8-depleted PBLs. From day 52 to 369, patient SC21 exhibited strong responses to recombinant gp120 Env, p24 Gag, and Nef proteins (figure 4A). Fine-mapping studies showed that the p24 Gag response was specific for peptide NPPIPVGEIWKRWIILGLNK and that the Nef response was specific for peptide KAAVDLSHFLKEKGGLEGLI; antibody-blocking experiments demonstrated that both responses were HLA DP restricted. In both targeted epitopes, longitudinal variation in antigen sequence was observed, which could have contributed to the decrease in HIV-1-specific CD4+ T cell frequencies (data not shown). At day 297, HIV-1-specific CD4+ T cell frequencies started to decrease, concurrent with a transient increase in pVL. By day 410, all HIV-1-specific CD4+ T cell responses had disappeared, despite the maintenance of a relatively stable total CD4+ T cell count.

Next, we isolated autologous virus from PBMCs, at days 255 and 565.We found no indication of a shift of in vitro replication kinetics or CCR5 coreceptor usage between these isolates (data not shown). We evaluated the neutralizing activity against the 2 isolates from the patient, in plasma samples obtained between days 60 and 565 (figure 4B). Overall, only low neutralizing activity against both autologous virus isolates was observed, with the exception of plasma obtained at day 255, in which a transient general increase was evident. Furthermore, the general sensitivity of the virus isolates to neutralization with 3 potent neutralizing antibodies (2F5, 2G12, and IgG1 b12) and the tetrameric CD4 molecule CD4-IgG2 was assessed, and both viruses were found to be comparably sensitive to neutralization (data not shown). Taken together, the neutralization data indicate that the loss of control of viremia cannot be attributed to either a change in overall sensitivity to neutralization or escape from autologous neutralizing activity.

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Discussion

A major determinant of the rate of progression to AIDS is the set-point pVL that is established within ∼6 months after seroconversion [5, 16]. Many factors contribute to the level of pVL reached at equilibrium; these include virologic factors, such as replication rate, and host factors, both immunologic and genetic [17, 18]. The patient in the present study exhibited a more rapid disease progression than would have been expected from his set-point pVL, with a sudden increase in viremia after day 410. This provided a rare opportunity to study changes in immunologic and virologic factors associated with loss of control of viremia, within a uniformgenetic background.

There is substantial evidence that the CD8+ T cell response to HIV-1 is central to the control of viremia in infected individuals [1, 2], and the ability of the CD8+ T cell response to select for virus variants in vivo attests to the antiviral capacity of this form of immunity [19, 20]. In the present study, sequence variation occurred in 6 of 14 targeted CD8+ T cell epitopes; 50% of the total HIV-1-specific CD8+ T cell response at day 297 was directed against these 6 epitopes. Furthermore, epitope variants were generated and predominated in vivo either before (DRL, DPN, and IPL) or concurrent with (RPM, VPL, and SLF) the loss of control of viremia, suggesting that the accumulation of these mutations was causally related to escalation of viral replication. Somevariant peptides (in particular SLF and DRL) retained some agonistic activity, suggesting that sequence variation might not necessarily lead to complete abrogation of CD8+ T cell recognition. However, reduced agonistic activity of variant peptides was most pronounced at low concentrations, more likely reflecting the in vivo situation. Furthermore, even small decreases in T cell recognition might be sufficient to confer a relative survival advantage in vivo. Positive selection for CD8+ T cell escape mutations, occurring at different times during the infection, could be identified in 4 of 6 epitopes. All variant epitopes were weaker agonists than the index peptide, when tested on PBLs before their in vivo appearance. However, when they were tested on PBLs after their in vivo appearance, the relative agonistic potential changed in favor of the variant epitope in all cases except 1. These findings suggest some flexibility within epitope-specific CD8+ T cell populations that allows for modulation of the overall specificity in favor of emerging new variants. Furthermore, HIV-1-specific CD8+ T cell frequencies specific for all epitopes, whether they showed variation or not, decreased before pVL increased. The reason for this general decrease in HIV-1-specific CD8+ T cell frequencies could be a lack of HIV-1-specific CD4+ T cell help, or this decrease may, perhaps, reflect that viral escape from some epitopes leads to more “strain” on the other responses, which, in turn, become more susceptible to exhaustion [21].

Functional HIV-1-specific CD4+ T cells are thought to be important components of effective adaptive immunity to HIV- 1 infection [22]. Indeed, the decrease in CD4+ T cell responses to undetectable levels before the loss of control of viremia, in patient SC21, suggests that these responses are involved in antiviral immunity. Possible reasons for this decrease include mutational escape within CD4+ T cell epitopes [23] and preferential infection of HIV-1-specific CD4+ T cells, leading to selective ablation of this T helper cell response [24]. In contrast, the loss of control of viremia after day 410 was not associated with changes in neutralizing antibody titers.

In summary, the early loss of control of viremia was associated with, and preceded by, the positive selection of viral escape mutations within many epitopes targeted by dominant HIV- 1-specific CD8+ T cell responses, a decrease in overall frequencies of HIV-1-specific CD8+ T cells, and the complete loss of HIV-1-specific CD4+ T cells. These observations provide strong support for a role of HIV-1-specific cellular immune responses in the natural control of HIV-1 replication in vivo.

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Acknowledgments

We would like to thank patient SC21 for exceptional cooperation, Jonathan M. Boulter for technical expertise, Hermann Katinger (University of Agriculture, Institute of Applied Microbiology, Vienna, Austria) for monoclonal antibodies (MAbs) 2F5 and 2G12, Dennis Burton (Scripps Research Institute, La Jolla, CA) for MAb IgG1 b12, and Paul Maddon (Progenics Pharmaceuticals, Tarrytown, NY) for the CD4-IgG2 molecule.

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Footnotes

  • Financial support: Wellcome Trust (support to R.E.P., H.T.Z., C.E., T.T., and E.C.H.); Schweizerische Stiftung für Medizinisch Biologische Stipendien (support to A.O.); Roche Research Fund for Biology (support to A.O.); Swiss National Science Foundation (support to A.T.); Medical Research Council (MRC) (support to E.G. and D.A.P.). D.A.P. is a MRC (United Kingdom) Clinician Scientist Fellow. Recombinant proteins and peptides were provided by the European Union program European Vaccine against AIDS/MRC Centralized Facility for AIDS Reagents, National Institute for Biological Standards and Control, United Kingdom (grants QLK2-CT- 1999-00609 and GP828102).

  • Received January 15, 2004.
  • Accepted March 9, 2004.
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  1. J Infect Dis. (2004) 190 (4): 713-721. doi: 10.1086/422760
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