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1 Institute for Virus Research, Laboratory of Primate Model, Experimental Research Center for Infectious Disease, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
2 Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
3 National Institute of Infectious Disease, Tokyo 162-8640, Japan
Correspondence
Masanori Hayami
mhayami{at}virus.kyoto-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Mellors et al., 1995; Schacker et al., 1996). Therefore, data obtained from the early phase of infection would help to define the pathogenesis of HIV-1.
Several non-human primate models have been used to investigate the early phase of HIV-1 infection (Joag et al., 1997; Lu et al., 1998). In some studies using macaques inoculated with Simian immunodeficiency virus (SIV) or an SIV/HIV-1 chimeric virus (SHIV) by a mucosal route (i.e. oral, rectal or vaginal), the virus spread to the systemic lymphoid tissues within 3–7 days post-inoculation (p.i.) following replication for a period of time in the local region (Couëdel-Courteille et al., 1999, 2003; Hirsch et al., 1998; Spira et al., 1996; Stahl-Hennig et al., 1999). However, recent studies have shown that the virus can spread more rapidly to the systemic tissues. Hu et al. (2000) detected SIV-infected cells in draining lymph nodes within 18 h of intravaginal exposure. Milush et al. (2004) showed that SIV spread to systemic lymphoid tissues 1–2 days after oral inoculation. Miller et al. (2005) showed that the dissemination of SIV infection to systemic lymphoid tissues occurred within 1–3 days of vaginal inoculation, although virus production at this site was established later. Furthermore, Veazey et al. (1998) reported that the intestinal tract was one of the major sites of SIV replication and CD4+ T cell depletion in the early phase of infection. In a study using SHIV, Harouse et al. (1999) suggested that SHIV using CCR5 as co-receptor for virus entry caused a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion in peripheral CD4+ T cells, whereas infection with SHIV using CXCR4 caused a profound loss in peripheral T cells that was not paralleled in the intestine.
The goals of the present study were to investigate the distribution of pathogenic virus in systemic tissues early after mucosal infection and to determine whether these tissues produced infectious virus, which is considered to play a major role in the spread of virus in the body. A pathogenic molecular clone, SHIV-C2/1-KS661c (Shinohara et al., 1999), which uses two major chemokine receptors, CCR5 and CXCR4, as co-receptors for virus entry, was used to inoculate rhesus macaque monkeys intrarectally. Proviral DNA and infectious virus were quantified by quantitative PCR and infectious plaque assay, respectively. Virus load in the infected individuals has usually been quantified by the copy number of virus RNA or DNA using PCR or by the immunodetection of core protein, p24 or p27 (Chun et al., 1997; Sei et al., 1994; Zhang et al., 1999). However, these methods do not differentiate between infectious and non-infectious virus. The infectious plaque assay used in this study quantified infectious virus only (Kato et al., 1998; Miyake et al., 2004). Our results show that the virus spread rapidly to the systemic tissues soon after intrarectal infection. Thereafter, infectious virus was actively produced in the lymphoid tissues, but decreased significantly after the peak of viraemia. In the intestinal tract, lower levels of infectious virus were produced than in lymphoid tissues throughout the infection.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). SHIV-C2/1-KS661c is a molecular clone constructed from the consensus sequence of SHIV-C2/1 (GenBank accession no. AF217181
[GenBank]
). SHIV-C2/1-KS661c can infect macaque monkeys by intravenous and intrarectal routes and cause precipitous viraemia and drastic CD4+ cell depletion. Virus stock was prepared from supernatant of a human lymphoid cell line, CEMx174, and stored in liquid nitrogen (–190 °C) until use. The TCID50 of the virus stock was measured in CEMx174; 20 TCID50 was equivalent to one 50 % macaque infectious dose (MID50).
Monkeys and virus inoculation.
Ten adult (5- to 8-year-old) rhesus macaques (Macaca mulatta), which were of Chinese origin, were used in this study. All monkeys used were treated in accordance with the institutional regulations approved by the Committee for Experimental Use of Non-human Primates in the Institute for Virus Research, Kyoto University. Eight monkeys were anaesthetized by intramuscular injection of ketamine chloride and inoculated intrarectally with 2x103 TCID50 SHIV-C2/1-KS661c. All intrarectal inoculations were done with a paediatric feeding catheter 10 cm from the anus. The catheter was inserted carefully to avoid causing trauma. Two monkeys were euthanized at each of 3 (animals MM301 and MM307), 6 (MM300 and MM309), 13 (MM313 and MM334) and 27 (MM308 and MM310) days p.i. Two monkeys (MM244 and MM314) were used as uninfected controls.
Sample collection.
Blood was collected periodically from all monkeys. Peripheral blood mononuclear cells (PBMCs) and plasma were separated from heparinized blood by Percoll (Lymphocyte Separation Solution; Nacalai Tesque) density-gradient centrifugation. Plasma was frozen at –80 °C until use. Complete sets of organs were obtained at the time of euthanasia. Parts of the samples were frozen directly at –80 °C until further use (i.e. quantification of proviral DNA). Residual samples of spleen, thymus, and axillary, inguinal and mesenteric lymph nodes were minced and filtered through a 40 µm nylon filter (Becton Dickinson). Samples of jejunum and rectum were washed in Dulbecco's modified Eagle's medium (DMEM) containing 0·45 mM dithiothreitol, cut into 1 cm2 pieces and agitated in DMEM medium containing 5 % fetal calf serum (FCS) for 1 h at room temperature. After short sedimentation, supernatants and tissue fragments were processed to give intraepithelial lymphocytes (iEL) and lamina propria lymphocytes (LPL), respectively. The supernatants (containing iEL) were filtered through columns containing packed glass wool and centrifuged at 1600 r.p.m. for 7 min; pellets were then suspended in 30 % Percoll (Pharmacia) and centrifuged at 1800 r.p.m. for 20 min. The resulting pellets were resuspended in 44 % Percoll, layered on 70 % Percoll and centrifuged at 1800 r.p.m. for 20 min. Cells at the interface between the 44 and 70 % Percoll layers were collected. The residual tissue fragments were agitated in Hanks' buffer containing 5 mM EDTA for 10 min at room temperature and the supernatants were removed. This step was repeated three times. The fragments were suspended in RPMI 1640 medium (Gibco) containing 10 % FCS and, after agitation for 30 min at room temperature, the supernatants were removed. The fragments were resuspended in RPMI 1640 medium containing 10 % FCS and type II collagenase (0·2 mg ml–1; Sigma) and agitated for 90 min at room temperature. The suspensions (containing LPL) were filtered through glass-wool columns and cells were enriched by Percoll density-gradient centrifugation as described above for iEL. The cells obtained from each organ were used immediately in the infectious plaque assay and flow-cytometry analysis.
Quantification of plasma viral RNA.
The viral RNA loads in plasma were determined by quantitative RT-PCR (Suryanarayana et al., 1998). Total RNAs were prepared from plasma with a QIAamp Viral RNA kit (QIAGEN). RT-PCR was performed with a Taqman EZ RT-PCR kit (Perkin Elmer) for the SIV gag region using the following primers: SIV2-696F (5'-GGAAATTACCCAGTACAACAAATAGG-3') and SIV2-784R (5'-TCTATCAATTTTACCCAGGCATTTA-3'). A labelled probe, SIV2-731T (5'-Fam-TGTCCACCTGCCATTAAGCCCG-Tamra-3'; Perkin Elmer), was used for detection of the PCR products. These reactions were performed with a Prism 7700 Sequence Detector (Applied Biosystems) and analysed by using the manufacturer's software. For each run, a standard curve was generated from dilutions whose copy numbers were known and the RNA in the plasma samples was quantified based on the standard curve.
Quantification of proviral DNA.
Proviral DNA loads in tissues were determined by quantitative PCR. DNA samples were extracted directly from frozen tissues with a Qiagen DNeasy Tissue kit. PCR was performed with a Taqman PCR Reagent kit (Perkin Elmer) using the same primer set and probe used in RT-PCR. A standard curve was generated from a plasmid DNA sample containing the full genome of SHIV-NM-3rN, which was quantified with a UV spectrophotometer.
Infectious plaque assay.
Infectious virus was quantified and isolated by using an infectious plaque assay (Kato et al., 1998). An agarose-gel bilayer containing RPMI 1640 medium was made in plastic culture dishes with a diameter of 100 mm; the lower layer consisted of 12 ml 1·2 % agarose (Agarose NA; Pharmacia) and the upper layer consisted of 12 ml 0·4 % low gelling-temperature agarose (SeaPlaque Agarose; FMC). Dishes were incubated at 37 °C in 5 % CO2 overnight. The following day, 2x106 cells of each sample and 8x106 M8166 cells (Clapham et al., 1987) were suspended in 3 ml 0·4 % low gelling-temperature agarose solution containing the culture medium and the mixture was immediately overlaid on the agarose-gel layer prepared previously. After the gel had hardened, plates were covered with 12 ml culture medium and incubated at 37 °C in 5 % CO2 for 10 days. The medium over the plates was replaced with fresh medium every day. After removal of the medium on day 10, plates were stained with 2 ml 0·7 % MTT for 2 h to count the number of plaques.
Flow-cytometry analysis.
The frequencies of CD4+ single-positive and CD4CD8 double-positive T cells in PBMCs and various tissues were examined by flow cytometry. Lymphocytes were treated with anti-CD3 (FN-18–fluorescein isothiocyanate; Biosource), anti-CD4 (Nu-TH/I–phycoerythrin; NICHIREI) and anti-CD8 (SK1–PerCP; Becton-Dickinson) monoclonal antibodies and examined on a FACScan analyser (Becton Dickinson). The absolute number of lymphocytes in the blood was determined by using an automated blood-cell counter (F-820; Sysmex).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). The plasma viral RNA load of these monkeys reached peak levels, about 108 to 5x109 copies ml–1, at 13 days p.i. and then decreased, reaching 106 copies ml–1 at 27 days p.i. CD4+ T-cell counts in peripheral blood of these monkeys started to decrease from day 6 p.i. and were lower than 500 cells µl–1 by 13 days p.i. (Fig. 2). These low counts of CD4+ T cells remained at the same levels until 27 days p.i.
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). It was also detected in non-lymphoid tissues (kidney and lung; data not shown) at low levels [<20 copies (µg DNA)–1]. These results show that the virus spread quickly to the systemic tissues after intrarectal inoculation. In both monkeys that were examined at 6 days p.i. (MM300 and MM309), proviral DNA was detected in PBMCs as well as other lymphoid tissues (Fig. 3), suggesting that detectable levels of infected cells had drained to the peripheral bloodstream by this time. However, the titres of proviral DNA in these tissues were less than about 102 copies (µg DNA)–1 and proviral DNA was not detected in some tissues at 6 days p.i. In monkeys examined at 13 days p.i. (MM313 and MM334), when viraemia reached peak levels, proviral DNA was detected in all tissues examined and virus titres in each tissue were much higher than those determined at 6 days p.i. In most of the lymphoid tissues and the intestinal tract, proviral DNA was detected at >103 copies µg–1 (Fig. 3). In the non-lymphoid tissues of these monkeys, including lung, liver, kidney and brain, proviral DNA was detected at about 10–103 copies µg–1 (data not shown). The titres of proviral DNA in all tissues of the monkeys examined at 27 days p.i. (MM308 and MM310) were still >103 copies µg–1 (MM310) or 102 copies µg–1 (MM308) (Fig. 3). These results show that virus infections in various tissues were amplified from 6 to 13 days p.i. and then decreased, but virus remained detectable in each tissue until 27 days p.i.
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). Thereafter, the levels of infectious virus increased dramatically and high titres of infectious virus were detected in many lymphoid tissues of monkeys examined at 13 days p.i. (MM313 and MM334) (Fig. 4). In both of these monkeys, the highest numbers of infectious virus (119 and 100 p.f.u. per 106 cells, respectively) were detected in the mesenteric lymph nodes, suggesting that this is the main site of production of infectious virus. Levels of infectious virus in the axillary and inguinal lymph nodes of these monkeys were 55·5–100·0 p.f.u. per 106 cells. In MM313, levels of infectious virus in PBMCs and thymus (99·5 and 110·0 p.f.u. per 106 cells, respectively) were almost as high as those in the mesenteric lymph node. However, MM334 tissues had remarkably low numbers of infectious virus in PBMCs and thymus (24·0 and 3·5 p.f.u. per 106 cells, respectively). In the monkeys examined at 27 days p.i. (MM308 and MM310), infectious virus was detected at very low levels in lymphoid tissues (<19 p.f.u. per 106 cells) (Fig. 4), whereas proviral DNA was detected at the same levels as at 13 days p.i. (Fig. 3
). These results suggest that, after the peak of viraemia, high levels of virus existed in the lymphoid tissues, but most virus did not replicate there. In particular, PBMCs and thymus contained infectious virus at only 0–5 p.f.u. per 106 cells at 27 days p.i., suggesting that these tissues hardly contribute to the release of infectious virus after the peak of viraemia.
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). At 13 days p.i., some infectious virus was detected in the jejunum, but titres were much lower than those in the lymphoid tissues (4·5 and 12·5 p.f.u. per 106 cells in the jejuna of MM313 and MM334, respectively). These results show that virus replication was much lower in the intestinal tract than in the lymphoid tissues at the early phase of infection, although the virus reached the intestinal tract at the same time that it reached the lymphoid tissues.
Sequential changes in the proportion of CD4+ T cells in various tissues early after intrarectal infection
CD4+ T cells have been reported as the main target and source for amplification of the virus. To estimate the effect of virus replication on the proportion of CD4+ T cells existing in various tissues, sequential changes in the proportion of CD4+ T cells were examined in each tissue in which virus was detected at various loads by using flow cytometry. The mean percentages of CD4+ T cells in PBMCs, spleen, thymus, and inguinal, axillary and mesenteric lymph nodes of uninfected controls (MM244 and MM314) were 35, 26, 43, 59, 56 and 58 % of total lymphocytes, respectively (Fig. 5). The percentages of CD4+ T cells in PBMCs were higher in monkeys at 6 and 13 days p.i. (62 and 61 % of total lymphocytes, respectively) than in the uninfected normal controls, but then decreased to 12 % of total lymphocytes by 27 days p.i. In other lymphoid tissues, the percentages of CD4+ T cells remained at the level of uninfected normal controls until 6 days p.i. Between 6 and 27 days p.i., the percentages of CD4+ T cells decreased significantly to 9–14 % of whole lymphocytes in each tissue.
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, 2000a, b) and it was expected in the present study that the infection kinetics in iEL and LPL would differ. The mean percentages of CD4+ T cells in the jejuna of control monkeys were 10 % in iEL and 34 % in LPL, and those in the rectums were 5 % in iEL and 11 % in LPL (Fig. 5). CD4+ T cells in the intestinal tract remained at the same level as those in the uninfected controls until 13 days p.i. and then decreased to 1–2 % of whole lymphocytes by 27 days p.i. These sequential changes of CD4+ T cells were almost the same in iEL and LPL of the jejunum and rectum. Thus, SHIV-C2/1 caused marked CD4+ T-cell depletion both in peripheral blood and the intestinal tract. The extent of CD4+ T-cell depletion in intestinal tract and lymphoid tissues correlated with the extent of virus replication in each tissue.
Sequential changes in the proportion of CD4 single-positive (SP) and CD4CD8 double-positive (DP) T cells in the jejunum and thymus
There were larger percentages of CD4CD8 DP T cells in the jejunum than in the lymphoid tissues, apart from the thymus. In the jejuna of the normal control monkeys, the mean percentages of CD4CD8 DP T cells in total CD4+ T cells were 64 % in iEL and 45 % in LPL, whereas in the lymphoid tissues, they were only 8–16 % (data not shown). The proportion of CD4 SP T cells in the jejunum remained at the level of uninfected controls until 13 days p.i. (15 and 34 % in jejunum iEL and LPL, respectively, at 13 days) and then dropped sharply to <0·3 % in both iEL and LPL by 27 days p.i. This sequential change in the proportion of CD4 SP T cells in the jejunum was the same as that observed for total CD4+ T cells. However, the proportion of CD4CD8 DP T cells started to decrease from day 3 p.i.; at 13 days p.i., it was <5 % in both iEL and LPL of the jejunum (Fig. 6).
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). These results suggest that there is a difference in the effect of virus infection on CD4 SP T cells, CD4CD8 DP T cells and CD3–CD4CD8 DP cells early after intrarectal infection.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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showed that SIV penetrated the vaginal mucosa of rhesus macaques within 60 min of intravaginal inoculation, infecting primarily intraepithelial dendritic cells (DCs), and that SIV-infected cells were detected in iliac lymph nodes within 18 h of inoculation. Because the epithelium of the rectum mucosa is just as rich in DCs as the vaginal mucosa, it appears that the virus is transported to the draining lymph nodes by DCs within several hours of intrarectal exposure in this study. Once the virus reaches the local lymphoid tissues, systemic dissemination might occur shortly thereafter.
Virus levels increased remarkably between 6 and 13 days p.i. and high levels of proviral DNA and infectious virus were detected in various lymphoid tissues at 13 days p.i., which was the time of peak viraemia. Among all the tissues examined, the mesenteric lymph node had the largest level of infectious virus. This result is consistent with a previous study that showed that mesenteric lymph nodes contain numerous SIV-infected cells in the early stages of SIV infection (Cantó-Nogués et al., 2001; O'Neil et al., 1999). The intestinal tract is constantly exposed to antigens in foods and pathogens. Therefore, the mesenteric lymph node, which is a draining lymph node of the intestinal tract, might have many more activated T cells than other lymphoid tissues. Because SIV/HIV-1 can replicate optimally in activated T cells, the mesenteric lymph nodes might release the largest numbers of infectious virus.
After the peak of viraemia, the titre of infectious virus in the lymphoid tissues decreased significantly. Around this time, it is generally recognized that adaptive immunity is induced in the host. Therefore, the induction of such acquired immunity might also result in the suppression of virus replication in the lymphoid tissues. Moreover, CD4+ T cells, which are the main target and source of amplification of the virus (Dalgleish et al., 1984; Klatzmann et al., 1984; Sattentau et al., 1988), were depleted in the lymphoid tissues by this time, thus resulting in the low level of virus production there. In contrast, significant proviral DNA remained in the lymphoid tissues after the peak of viraemia. The identity of the cells holding this proviral DNA was not clear, but they might represent a reservoir pool of virus until the development of AIDS.
In the intestinal tract, infectious virus was detected, but the virus load was much lower than in the lymphoid tissues. This is surprising because it was expected that the intestinal tract would have as many activated lymphocytes as the mesenteric lymph node and the virus replicates efficiently in those cells. Some reasons for the low titre of infectious virus in the intestinal tract were considered. Firstly, the sample of intestinal tract, which was separated as iEL and LPL, contains various types of cells and the percentage of CD4+ T cells there was much lower than in samples of lymphoid tissues, thus giving rise to a lower level of virus production in the intestinal tract. In addition, there is a possibility that the intestinal tract has a strong immunity. Following virus infection, the components of innate immunity might respond rapidly and provide time for the subsequent development of adaptive immunity. Natural killer (NK) cells, which are a critical component of innate immunity to virus infection, were reported to mediate suppression of HIV-1 replication by producing CC chemokines or causing cytotoxicity against HIV-1-infected cells (Baum et al., 1996; Fehniger et al., 1998; Kottilil et al., 2003; Levy, 2001; Oliva et al., 1998). In the monkeys used in this study, NK activity using K562 target cells was measured in PBMCs, intestinal tract and inguinal and mesenteric lymph nodes (K. Ibuki, N. Saito, Y. Enose, A. Miyake, H. Suzuki, R. Horiuchi, T. Miura & M. Hayami, unpublished data). Among these tissues, NK activity was much higher in the intestinal tract of both normal and infected monkeys. This result raises the possibility that NK activity in the intestinal tract contributed to the suppression of virus replication in the present study.
In the lymphoid tissues, levels of CD4+ T cells decreased significantly from day 6 p.i. In contrast, in the intestinal tract, CD4+ T cells remained at the same level as in uninfected normal controls until 13 days p.i. These results clearly correlated with the extent of virus replication in the lymphoid tissues and intestinal tract. However, CD4+ T cells in the intestinal tract were finally depleted by 27 days p.i. In previous studies, it was reported that the target tissues or organs of the virus differed when using CXCR4 or CCR5 as co-receptors of virus entry (Harouse et al., 1999; Reyes et al., 2004). In the early phase of infection, CXCR4-utilizing SHIV causes rapid depletion of CD4+ T cells in the peripheral blood, but not in the intestinal tissues, whereas CCR5-utilizing SHIV causes rapid depletion of CD4+ T cells in the intestinal tissues, but not in the peripheral blood. Recent studies using SIV-infected monkeys showed a profound and selective loss of memory CD4+ CCR5+ T cells in the intestinal tract in the early phase of infection (Brenchley et al., 2004; Mehandru et al., 2004; Mattapallil et al., 2005; Li et al., 2005). Moreover, some HIV-1-carrier studies demonstrated that a significant and preferential depletion of mucosal CD4+ T cells that express CCR5 occurs compared with peripheral blood or lymphoid tissues (Veazey et al., 2000a, b; Centlivre et al., 2005). SIV and most primary isolated HIV-1 utilize CCR5 as co-receptor for entry, and target tissues of dual-tropic virus using both CXCR4 and CCR5 were unknown. In this study, it was shown that SHIV-C2/1 using both CXCR4 and CCR5 as co-receptors caused rapid CD4+ T-cell depletion in both peripheral blood and the intestinal tract.
Among the tissues examined, the thymus and intestinal tract had a large percentage of CD4CD8 DP T cells. Both tissues have been reported as sites of maturation of lymphocytes (Haynes et al., 1990; Lundqvist et al., 1995) and CD4CD8 DP T cells have been proposed to be immature T cells. A previous study reported that CD4CD8 DP T cells in the thymus were susceptible to HIV-1 infection (Schnittman et al., 1990). Moreover, CD4 SP and CD4CD8 DP T cells were found to decrease at the same time during acute SIV infection in rhesus macaques in the thymus (Rosenzweig et al., 2000) and intestinal tract (Mattapallil et al., 2000; Smit-McBride et al., 1998). In this study, however, CD4CD8 DP T cells started to decrease earlier than mature CD4 SP T cells in both the thymus and intestinal tract, suggesting that the resultant effect of virus infection is different between the mature and immature T cells in each tissue. CD4CD8 DP T cells were observed to decrease in both tissues before virus replication. This shows that the virus may indirectly kill CD4CD8 DP T cells. Moreover, CD3– CD4CD8 DP cells, which are precursors of CD3+ CD4CD8 DP cells (Hori et al., 1991), were also depleted in the thymus after the peak of viraemia. Further studies of the pathogenesis of virus infection in immature T cells of the thymus and intestinal tract may lead to better understanding of the mechanisms of CD4+ cell depletion in HIV-1-infected humans.
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ACKNOWLEDGEMENTS |
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Received 1 July 2005;
accepted 9 January 2006.
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