The majority of human immunodeficiency virus type 1 particles present within splenic germinal centres are produced locally

Marie-Jeanne Dumaurier{dagger}, Sophie Gratton, Simon Wain-Hobson and Rémi Cheynier{ddagger}

Unité de Rétrovirologie Moléculaire, Institut Pasteur, Paris, France

Correspondence
Rémi Cheynier
remi{at}pasteur.fr


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In most stages of human immunodeficiency virus (HIV) infection, cell-free viral particles can be detected in germinal centres (GCs) that are principally retained, in the form of immune complexes, on the surface of follicular dendritic cells (FDCs). The source of this virus remains unknown, although it is agreed that the FDCs themselves are not infected productively. By sequencing HIV viral DNA, genomic RNA and spliced mRNA isolated from individual splenic white pulps, it was shown here that the majority of HIV-1 viral particles are produced locally within the supporting lymphoid structure and do not result from trapping of circulating viruses or immune complexes. These findings underline the exquisite spatial organization of HIV-1 replication in vivo, suggesting a local origin for viruses trapped in splenic GCs.

{dagger}Present address: CNRS/UNSA UMR 6097, IPMC, 660 Route des Lucioles, 06560 Valbonne, France.

{ddagger}Present address: Unité des Virus Lents, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris cedex 15, France.


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Following human immunodeficiency virus (HIV) seroconversion, cell-free viral particles and immune complexes are found in the germinal centres (GCs) of the secondary lymphoid organs (Armstrong & Horne, 1984; Fox et al., 1991; Le Tourneau et al., 1986; Spiegel et al., 1992; Tenner-Racz et al., 1985), the load increasing over time (Tenner-Racz & Racz, 1995). Changes that occur in GC architecture include hyperplasia and infiltration of activated CD8+CD45RO+ T cells (Janossy et al., 1985; Racz et al., 1990; Rosenberg et al., 1998; Tenner-Racz et al., 1998), including anti-HIV cytotoxic T lymphocytes (Hosmalin et al., 2001). As infection progresses, GC degeneration and atrophy are noted until very late-stage disease, when the follicular dendritic cell (FDC) network is virtually non-existent (Zhang et al., 1998).

Lymphoid-tissue CD4+ T lymphocytes are the major producers of virus (Stahl-Hennig et al., 1999; Tenner-Racz et al., 1998; Veazey et al., 1998; Zhang et al., 1999). Moreover, a greater proportion of CD4 T cells harbour provirus than interdigitating dendritic cells or macrophages (McIlroy et al., 1995, 1996). Viral proliferation is sustained in the immunocompetent structures of secondary lymphoid organs (i.e. GC and T-cell zones in lymph nodes, GCs and periarteriolar lymphoid sheath in the spleen) as a consequence of antigen-specific CD4+ T-cell activation (Cheynier et al., 1998; Ostrowski et al., 1998). Activation-dependent viral proliferation leads to local development of viral quasispecies in GCs, such that a unique viral population characterizes each splenic white pulp (Cheynier et al., 1994; Gratton et al., 2000).

The origin of viruses in GCs is unknown. They are not produced by FDCs, as this cell type is not permissive for HIV infection (Embretson et al., 1993; Grouard & Clark, 1997; Reinhart et al., 1997; Schmitz et al., 1994; Tsunoda et al., 1996). Two hypotheses present themselves: virus, mainly in the form of circulating immune complexes, may be deposited on the FDC surfaces; this hypothesis has some support from murine experiments (Heath et al., 1995). This may be referred to as a ‘peripheral origin’. Another possibility is that virus may be produced locally by HIV-infected antigen-specific T cells within GCs and deposited on the FDC surfaces. This may be termed a ‘local origin’.

Although the two hypotheses are not mutually exclusive, how might it be possible in a natural setting to distinguish between the two, or, more precisely, to determine which is the more important? The enormous genetic variation of HIV-1 needs no reminder. More to the point, it varies considerably in space (Delassus et al., 1992), so much so that different splenic white pulps (Cheynier et al., 1994) and even 10 µm sections through splenic GCs (Gratton et al., 2000) exhibit different sequences. This suggests an experimental approach to distinguishing the above alternative.

If the majority of virus present within the white pulps is of peripheral origin, the sequence of genomic RNAs from different white pulps should be generally similar. In that case, one should expect that DNA- and RNA-derived sequences from the same white pulps will be different, as the infiltrating cells might have been infected earlier during the course of disease development. If, on the other hand, virus is derived mainly from infected T cells within the white pulp, then different sequence sets should characterize HIV-1 virions between two white pulps. Equally, some degree of correspondence should exist between viral DNA-, genomic RNA- and spliced mRNA-derived sequences.

Spleens of three HIV-1 patients who underwent surgery for non-treatable thrombocytopenia or suspicion of Burkitt's lymphoma were studied. Their peripheral blood CD4+ T-cell counts were all >200 µl–1. Immediately after surgery, spleens were cut into pieces (2–3 cm3) and splenic white pulps were dissected under a binocular microscope (magnification x10).

The first spleen analysed was from patient B, who was not on therapy at the time of splenectomy (5900 RNA copies ml–1, 583 CD4 µl–1). Total DNA and RNA were extracted independently from three white pulps by using a Master Pure extraction kit (Epicentre). To avoid contamination, PCR was performed in a DNA-free room. In order to amplify viral DNA sequences, PCR for the V1V2 hypervariable env region was performed by using the LV15/LV13 and SK122/123 primer pairs (Cheng et al., 1994; Delassus et al., 1992) on DNA extracts. For viral and mRNA amplifications, cDNA synthesis was performed on RNA extracts by using the LV13 primer. The LV15 primer served as 5' primer for full genomic RNA, whilst an outer 5' primer, LTR-SD (5'-TCTCTCGACGCAGGACTCGGCTTG-3'), mapping 42 bp 5' to the major splice leader for HIV-1 Lai, was used for spliced env mRNA. For the nested reaction, SK122/123 primers were used. Accordingly, RT-PCR amplification using oligonucleotides specific for spliced mRNA detects intracellular spliced mRNA specifically. To control for the absence of residual DNA in RNA preparations, PCR was performed on purified RNA (without the RT step), using env V1V2-specific primers. No preparations proved positive.

For each white pulp, PCR products were cloned in M13mp18; approximately 20 sequences were established from DNA, total RNA and env mRNA and are given in the form of an unrooted phylogenetic tree (Fig. 1), compiled by using the SplitsTree2 program (Bandelt & Dress, 1992; http://bibiserv.techfak.uni-bielefeld.de/splits/). The majority of sequences were clustered into three groups based on their spatial origin. A predominant form was invariably accompanied by a collection of variants. Whether they were derived from DNA, total RNA or env mRNA, the major forms were identical or very similar to one another. For two white pulps, B2 and B3, the predominant DNA sequences (D) were identical to that derived from genomic RNA (R). For the third white pulp, B1, there were two point mutations between the predominant forms. A comparable situation pertained to the DNA and spliced mRNA (Rs) collections of sequences. Only for B2 was there complete coincidence of the predominant DNA, RNA and mRNA forms. The difference between two sequences from the same white pulp was always smaller than the distances between the three white pulps (Fig. 1). A small number of sequences did not conform to this distribution based on lymphoid architecture. For example, one of 40 sequences from B2, four of 53 from B1 and four of 51 from B3 mapped in a spatially discordant manner. Hence, it may be concluded that the majority (>90 %) of genomic RNA is produced in situ.



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Fig. 1. Phylogenetic analysis of env V1V2 sequences derived from splenic white pulps. DNA (D), RNA (R) and mRNA (Rs) were derived, by PCR, cloning and sequencing, from splenic white pulps (B1–B3). The frequency of sequences present in more than one copy in a given sample is indicated (e.g. x10). Distances are proportional to the number of mutations separating sequences.

 
A comparable approach was applied to an analysis of five white pulps (P1–P3, P5–P6) from the spleen of patient P (AZT-treated, 290 CD4+ cells µl–1, 320 pg p24 ml–1). Overall intra-P sequence variation was more extensive than for patient B. Eleven distinct amino acid sequence motifs (A–K), defined by two to seven distinct amino acid substitutions, could be discerned (Table 1). Four sequence motifs (A–D) accounted for 79 % of a total of 241 sequences. In each white pulp, one motif dominated the collection of DNA-, genomic RNA- and spliced env mRNA-derived sequences. Even for the minor forms (E–K), there was a degree of correspondence between the categories, again supportive of a local origin.


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Table 1. Distribution of env V1V2 sequences derived from splenic white pulps from patient P

HIV env V1V2 sequences were obtained from five splenic white pulps from patient P by PCR, cloning and sequencing. The observed sequences for each white pulp were segregated on the basis of characteristic amino acid motifs and named A–K. Bold type highlights the major forms (>25 %) among DNA, RNA and mRNA sequences.

 
In total white pulps, genomic RNA is composed of a mixture of both extracellular viral RNA and intracellular full-length mRNA. In order to confirm that viral particles and colocalized cells indeed contain similar HIV sequences, freshly dissected white pulps from a third patient (patient C, untreated, 250 CD4 cells µl–1) were dissociated by using collagenase VII (40 U ml–1; Sigma) and DNase I (20 U ml–1; Sigma) treatment for 30 min at 37 °C. Extracellular viruses were separated from cells by pancreatic trypsin digestion (1 U ml–1, 0·5 U per sample, 10 min at 37 °C; Eurobio), followed by addition of aprotinin (12 U ml–1; Sigma). After such treatment, the supernatant should only contain free virions, whilst the infected cells should be in the pellet. Cell-free viral RNA was amplified by RT-PCR on the supernatant, whilst standard PCR was performed on the cell pellet to analyse the intracellular DNA.

The sequences could be resolved into five distinct clades, differing from each other by a minimum of 18 mutations (Fig. 2). In white pulp C19, there was close concordance between extracellular viral RNA-derived and cell (proviral or non-integrated viral DNA)-derived sequences for clusters A and B. Other sequences were derived from either DNA or RNA fractions (clades C and D). For white pulp C18, both RNA- and DNA-derived sequences were essentially clustered into two clades (D and E) with only two of 30 (6·6 %) being scattered across the other three clades.



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Fig. 2. Phylogenetic analysis of env V1V2 sequences derived from trypsin-treated splenic white pulps. Two splenic white pulps (18 and 19) from patient C were trypsin-treated to separate extracellular viral RNA from intracellular viral DNA. The RNA-derived (R) and DNA-derived (D) sequences were grouped into five clades (A–E) according to this phylogenetic analysis. Phylogenetic analyses of both the complete population and each clade are shown. The frequency of sequences present in more than one copy in a given sample is indicated (e.g. x10). Distances are proportional to the number of mutations separating sequences.

 
The concordance in HIV-1 DNA, genomic RNA and spliced mRNA sequences (Fig. 1, Table 1) excludes the hypothesis of an exogenous origin for the viruses present in the GCs and strongly supports their local production. This conclusion fits well with previous findings of viral founder effects in microdissected splenic white pulps based on an analysis of viral DNA (Cheynier et al., 1994). As the CD4+ T cell is the predominantly infected cell type in the spleen (McIlroy et al., 1995, 1996), tonsillar GCs (Røsok et al., 1997; Stahl-Hennig et al., 1999) and other lymphoid organs (Veazey & Lackner, 2003; Zhang et al., 1999), it may be supposed that extracellular HIV is derived from activated CD4 lymphoblasts.

FDCs are unique to lymphoid follicles of secondary lymphoid organs. They are of non-haematopoietic origin and play a critical role in the maturation of immunoglobulin-producing cells and establishment of specific B-cell memory (Klaus et al., 1980; MacLennan & Gray, 1986; Tew et al., 1990). The ability of FDCs to retain native antigens in the form of immune complexes on their surface for considerable periods of time is essential to efficient immune responses within B-lymphoid follicles (Mandel et al., 1980). The quantity of virus on the FDC surfaces of functional GCs is approximately 10–50-fold greater than that of mRNA (Haase, 1999; Haase et al., 1996). Accordingly, sequence sets derived from RT-PCR amplification of total RNA effectively correspond to the FDC-borne virus and those derived from spliced mRNA reflect cell-associated mRNA. Hence, it may be concluded that the major fraction of RNA amplified from collagenase-treated cells is indeed coming from FDC-associated virions produced locally.

There exists also a temporal component to the distribution of HIV in GCs. Following multidrug therapy, most FDC-bound HIV decays with a half-life of 1·7 days (Cavert et al., 1997; Hlavacek et al., 1999). As the majority of this virus is produced in situ, this dynamic process may be accompanied by an equally rapid turnover of CD4 T cells. To this can be added strong immune responses, notably HIV-specific cytotoxic T cells (CTLs), which infiltrate white pulps and GCs (Blancou et al., 2001; Devergne et al., 1991; Hosmalin et al., 2001; Racz et al., 1990). As the majority of infected cells are depleted before they can produce viruses (Haase, 1999; Pelletier et al., 1995), it may well be that, within a GC, viral DNA is turning over faster than viruses on FDC surfaces. In fact, FDC-trapped HIV particles can remain infectious in vivo for more than 9 months (Smith et al., 2001).

In this respect, inspection of the sequences is revealing. Sequence identity was not always found between the DNA and genomic RNA (e.g. B1, Fig. 1; C19, Fig. 2). Why should this be, given that transcription is less error-prone than reverse transcription (Mansky & Temin, 1994, 1995)? The probability of RNA sequences differing from those of the parent DNA provirus is next to nil. A possible explanation is that viral DNA and genomic RNA are indeed turning over at different rates, such that the provirus that gave rise to FDC-bound HIV had been cleared by the time of sampling. Equally, viral DNA detected could reflect recently immigrated T cells harbouring HIV DNA that are not yet producing virions. The distribution of a fraction of RNA- and DNA-derived sequences in white pulp C19 might well reflect the stark dynamics of infiltration and CTL destruction of infected cells. However, in general, there was correspondence between the dominant RNA- and DNA-derived sequences for all of the white pulps studied.

The findings highlight the very dynamic, yet compartmentalized, nature of HIV replication within lymphoid structures. It follows that models, essential to illuminating such a dynamic process, should take this into account (Grossman et al., 1999, 2002).


   ACKNOWLEDGEMENTS
 
We would like to thank Drs Eric Oksenhendler and Thierry Debord for access to patient samples. This work was supported by grants from the Institut Pasteur and l'Agence Nationale pour la Recherche sur le SIDA (ANRS). M.-J. D. was supported by a fellowship from the ANRS.


   REFERENCES
Top
ABSTRACT
MAIN TEXT
REFERENCES
 
Armstrong, J. A. & Horne, R. (1984). Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet ii, 370–372.

Bandelt, H. J. & Dress, A. W. (1992). Split decomposition: a new and useful approach to phylogenetic analysis of distance data. Mol Phylogenet Evol 1, 242–252.[CrossRef][Medline]

Blancou, P., Chenciner, N., Cumont, M.-C., Wain-Hobson, S., Hurtrel, B. & Cheynier, R. (2001). The infiltration kinetics of simian immunodeficiency virus-specific T cells drawn to sites of high antigenic stimulation determines local in vivo viral escape. Proc Natl Acad Sci U S A 98, 13237–13242.[Abstract/Free Full Text]

Cavert, W., Notermans, D. W., Staskus, K. & 11 other authors (1997). Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960–964.[Abstract/Free Full Text]

Cheng, S., Fockler, C., Barnes, W. M. & Higuchi, R. (1994). Effective amplification of long targets from cloned inserts and human genomic DNA. Proc Natl Acad Sci U S A 91, 5695–5699.[Abstract/Free Full Text]

Cheynier, R., Henrichwark, S., Hadida, F., Pelletier, E., Oksenhendler, E., Autran, B. & Wain-Hobson, S. (1994). HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes. Cell 78, 373–387.[CrossRef][Medline]

Cheynier, R., Gratton, S., Halloran, M., Stahmer, I., Letvin, N. L. & Wain-Hobson, S. (1998). Antigenic stimulation by BCG vaccine as an in vivo driving force for SIV replication and dissemination. Nat Med 4, 421–427.[CrossRef][Medline]

Delassus, S., Cheynier, R. & Wain-Hobson, S. (1992). Nonhomogeneous distribution of human immunodeficiency virus type 1 proviruses in the spleen. J Virol 66, 5642–5645.[Abstract]

Devergne, O., Peuchmaur, M., Crevon, M. C., Trapani, J. A., Maillot, M. C., Galanaud, P. & Emilie, D. (1991). Activation of cytotoxic cells in hyperplastic lymph nodes from HIV-infected patients. AIDS 5, 1071–1079.[Medline]

Embretson, J., Zupancic, M., Ribas, J. L., Burke, A., Racz, P., Tenner-Racz, K. & Haase, A. T. (1993). Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362.[CrossRef][Medline]

Fox, C. H., Tenner-Racz, K., Racz, P., Firpo, A., Pizzo, P. A. & Fauci, A. S. (1991). Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis 164, 1051–1057.[Medline]

Gratton, S., Cheynier, R., Dumaurier, M.-J., Oksenhendler, E. & Wain-Hobson, S. (2000). Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers. Proc Natl Acad Sci U S A 97, 14566–14571.[Abstract/Free Full Text]

Grossman, Z., Polis, M., Feinberg, M. B. & 10 other authors (1999). Ongoing HIV dissemination during HAART. Nat Med 5, 1099–1104.[CrossRef][Medline]

Grossman, Z., Meier-Schellersheim, M., Sousa, A. E., Victorino, R. M. & Paul, W. E. (2002). CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 8, 319–323.[CrossRef][Medline]

Grouard, G. & Clark, E. A. (1997). Role of dendritic and follicular dendritic cells in HIV infection and pathogenesis. Curr Opin Immunol 9, 563–567.[CrossRef][Medline]

Haase, A. T. (1999). Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol 17, 625–656.[CrossRef][Medline]

Haase, A. T., Henry, K., Zupancic, M. & 11 other authors (1996). Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989.[Abstract/Free Full Text]

Heath, S. L., Tew, J. G., Tew, J. G., Szakal, A. K. & Burton, G. F. (1995). Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377, 740–744.[CrossRef][Medline]

Hlavacek, W. S., Wofsy, C. & Perelson, A. S. (1999). Dissociation of HIV-1 from follicular dendritic cells during HAART: mathematical analysis. Proc Natl Acad Sci U S A 96, 14681–14686.[Abstract/Free Full Text]

Hosmalin, A., Samri, A., Dumaurier, M.-J., Dudoit, Y., Oksenhendler, E., Karmochkine, M., Autran, B., Wain-Hobson, S. & Cheynier, R. (2001). HIV-specific effector cytotoxic T lymphocytes and HIV-producing cells colocalize in white pulps and germinal centers from infected patients. Blood 97, 2695–2701.[Abstract/Free Full Text]

Janossy, G., Pinching, A. J., Bofill, M. & 7 other authors (1985). An immunohistological approach to persistent lymphadenopathy and its relevance to AIDS. Clin Exp Immunol 59, 257–266.[Medline]

Klaus, G. G., Humphrey, J. H., Kunkl, A. & Dongworth, D. W. (1980). The follicular dendritic cell: its role in antigen presentation in the generation of immunological memory. Immunol Rev 53, 3–28.[Medline]

Le Tourneau, A., Audouin, J., Diebold, J., Marche, C., Tricottet, V. & Reynes, M. (1986). LAV-like viral particles in lymph node germinal centers in patients with the persistent lymphadenopathy syndrome and the acquired immunodeficiency syndrome-related complex: an ultrastructural study of 30 cases. Hum Pathol 17, 1047–1053.[Medline]

MacLennan, I. C. & Gray, D. (1986). Antigen-driven selection of virgin and memory B cells. Immunol Rev 91, 61–85.[Medline]

Mandel, T. E., Phipps, R. P., Abbot, A. & Tew, J. G. (1980). The follicular dendritic cell: long term antigen retention during immunity. Immunol Rev 53, 29–59.[Medline]

Mansky, L. M. & Temin, H. M. (1994). Lower mutation rate of bovine leukemia virus relative to that of spleen necrosis virus. J Virol 68, 494–499.[Abstract]

Mansky, L. M. & Temin, H. M. (1995). Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69, 5087–5094.[Abstract]

McIlroy, D., Autran, B., Cheynier, R., Wain-Hobson, S., Clauvel, J.-P., Oksenhendler, E., Debré, P. & Hosmalin, A. (1995). Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients. J Virol 69, 4737–4745.[Abstract]

McIlroy, D., Autran, B., Cheynier, R., Clauvel, J.-P., Oksenhendler, E., Debré, P. & Hosmalin, A. (1996). Low infection frequency of macrophages in the spleens of HIV+ patients. Res Virol 147, 115–121.[CrossRef][Medline]

Ostrowski, M. A., Krakauer, D. C., Li, Y., Justement, S. J., Learn, G., Ehler, L. A., Stanley, S. K., Nowak, M. & Fauci, A. S. (1998). Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies. J Virol 72, 7772–7784.[Abstract/Free Full Text]

Pelletier, E., Saurin, W., Cheynier, R., Letvin, N. L. & Wain-Hobson, S. (1995). The tempo and mode of SIV quasispecies development in vivo calls for massive viral replication and clearance. Virology 208, 644–652.[CrossRef][Medline]

Racz, P., Tenner-Racz, K., van Vloten, F., Schmidt, H., Dietrich, M., Gluckman, J. C., Letvin, N. L. & Janossy, G. (1990). Lymphatic tissue changes in AIDS and other retrovirus infections: tools and insights. Lymphology 23, 85–91.[Medline]

Reinhart, T. A., Rogan, M. J., Viglianti, G. A., Rausch, D. M., Eiden, L. E. & Haase, A. T. (1997). A new approach to investigating the relationship between productive infection and cytopathicity in vivo. Nat Med 3, 218–221.[CrossRef][Medline]

Rosenberg, Y. J., Lewis, M. G. & Kosco-Vilbois, M. H. (1998). Enhanced follicular dendritic cell-B cell interaction in HIV and SIV infections and its potential role in polyclonal B cell activation. Dev Immunol 6, 61–70.[Medline]

Røsok, B., Brinchmann, J. E., Voltersvik, P., Olofsson, J., Bostad, L. & Åsjö, B. (1997). Correlates of latent and productive HIV type-1 infection in tonsillar CD4+ T cells. Proc Natl Acad Sci U S A 94, 9332–9336.[Abstract/Free Full Text]

Schmitz, J., van Lunzen, J., Tenner-Racz, K., Grossschupff, G., Racz, P., Schmitz, H., Dietrich, M. & Hufert, F. (1994). Follicular dendritic cells (FDC) are not productively infected with HIV-1 in vivo. Adv Exp Med Biol 355, 165–168.[Medline]

Smith, B. A., Gartner, S., Liu, Y. & 8 other authors (2001). Persistence of infectious HIV on follicular dendritic cells. J Immunol 166, 690–696.[Abstract/Free Full Text]

Spiegel, H., Herbst, H., Niedobitek, G., Foss, H. D. & Stein, H. (1992). Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol 140, 15–22.[Abstract]

Stahl-Hennig, C., Steinman, R. M., Tenner-Racz, K. & 7 other authors (1999). Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 285, 1261–1265.[Abstract/Free Full Text]

Tenner-Racz, K. & Racz, P. (1995). Follicular dendritic cells initiate and maintain infection of the germinal centers by human immunodeficiency virus. Curr Top Microbiol Immunol 201, 141–159.[Medline]

Tenner-Racz, K., Racz, P., Dietrich, M. & Kern, P. (1985). Altered follicular dendritic cells and virus-like particles in AIDS and AIDS-related lymphadenopathy. Lancet 1, 105–106.[CrossRef][Medline]

Tenner-Racz, K., Stellbrink, H. J., van Lunzen, J., Schneider, C., Jacobs, J. P., Raschdorff, B., Großschupff, G., Steinman, R. M. & Racz, P. (1998). The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of highly active antiretroviral therapy. J Exp Med 187, 949–959.[Abstract/Free Full Text]

Tew, J. G., Kosco, M. H., Burton, G. F. & Szakal, A. K. (1990). Follicular dendritic cells as accessory cells. Immunol Rev 117, 185–211.[Medline]

Tsunoda, R., Hashimoto, K., Baba, M., Shigeta, S. & Sugai, N. (1996). Follicular dendritic cells in vitro are not susceptible to infection by HIV-1. AIDS 10, 595–602.[Medline]

Veazey, R. & Lackner, A. (2003). The mucosal immune system and HIV-1 infection. AIDS Rev 5, 245–252.[Medline]

Veazey, R. S., DeMaria, M., Chalifoux, L. V. & 7 other authors (1998). Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431.[Abstract/Free Full Text]

Zhang, Z.-Q., Notermans, D. W., Sedgewick, G. & 14 other authors (1998). Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc Natl Acad Sci U S A 95, 1154–1159.[Abstract/Free Full Text]

Zhang, Z.-Q., Schuler, T., Zupancic, M. & 21 other authors (1999). Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357.[Abstract/Free Full Text]

Received 23 April 2005; accepted 18 September 2005.



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