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of human immunodeficiency virus type-i (HIV-1) and tat of HJV-2 was studied in frozen sections of lymph nodes from HIV-1-infected individuals, and.

American Journal of Pathology, Vol 141, No. 5, November 1992 Copyright X) American Association of Pathologists

Epitopes of Human Immunodeficiency Virus Regulatory Proteins tat, net, and rev Are Expressed in Normal Human Tissue Henk K. Parmentier,* Dick F. van Wichen,* Frits H. J. Gmelig Meyling,t Jaap Goudsmit, and Henk-Jan Schuurman* From the Division of Histochemist-y and Electron Microscopy, Departments of Pathology and Internal Medicine,* and Clinical Immunology, t University Hospital, Utrecht, and the Human Retroviral Laboratory, Academic Medical Center, Amsterdam, The Netherlands*

The expression of regulatory proteins tat, rev, and nef of human immunodeficiency virus type-i (HIV-1) and tat of HJV-2 was studied in frozen sections of lymph nodes from HIV-1-infected individuals, and various tissues from uninfected persons. In HIV-1positive lymph nodes, monoclonal antibodies to HIV-1-tat stained solitary cells in the germinal centers and interfollicular zones; and vascular endothelium. Staining by an anti-nef monoclonal antibody was restricted to follicular dendritic cells, whereas anti-rev antibody bound to fibriohistiocytes and high endothelial venules. The antibodies used labeled several cell types in tissues from uninfected individuals. Anti-HIV-i -tat antibodies labeled blood vessels and Hassall's corpucles in skin and thymus; goblet cells in intestinal tissue and trachea; neural cells in brain and spinal cord; and zymogen-producing cells in pancreas. Anti-rev antibody stained high endothelial venules, Hassall's corpuscles and histiocytes. One anti-nef antibody solely stained follicular dendritic cells in spleen, tonsil, lymph node and Peyer's patches, whereas two other anti-nef antibodies bound to astrocytes, solitary cells in the interfollicular zones of lymph nodes, and skin cells. The cur-

gag and env in thymus' and lymph nodes2'3 from HIV-1 infected patients. In lymph nodes, the HIV-1 antigens were predominantly localized in the germinal center,24 presumably in the form of immune complexes attached to follicular dendritic cells (FDC). This was supported by the presence of these proteins on isolated FDC.3 The expression of HIV-1 structural antigens in the germinal centers from HIV-1-infected individuals corresponded with the ultrastructural demonstration of virions in/on FDC,97 and expression of HIV-1 env mRNA by these cells.2'3'8 In some cases, endothelial cells showed a pronounced expression of gag antigens.2 We and others found staining of tissue from non-HIV-1-infected individuals by MAbs to structural proteins; eg, epithelium of noninfected involuted thymus expressed epitopes of gag

proteins.1'9 The HIV regulatory proteins tat (14 kd) and rev (20 kd) are supposed to have a critical role in the viral life cycle on the level of primary mRNA transcription.10 1 1 The nef protein (35 kd) was originally claimed to be involved in the down-regulation of virus replication by preventing activation of the proviral genome.10 Furthermore, nef protein may down-regulate CD4-antigen expression in HIVinfected cells.12 The cellular expression of these regulatory viral proteins thus is expected to provide information on the state of infection, ie, viral replication (tat, rev), or viral latency (nef). There are no data in the literature on the expression of these regulatory proteins in tissue. This prompted us to analyze the tissue localization of HIV-1 tat, rev, and nef and HIV-2 tat proteins, with focus on the expression in lymph nodes.

Materials and Methods

rent results hamper the immunohistochemical study for pathogenetic and diagnostic use of HIV regulatory protein expression in infected tissue specimens or cells. (Am JPathol 1992, 141:1209-1216)

The current study included normal tonsils obtained at tonsillectomy from young children, and FDC isolated from

Monoclonal antibodies (MAbs) are useful tools to demonstrate viral antigens in tissues or cells from human immunodeficiency virus (HIV)-infected patients. We previously described the presence of HIV-1 structural proteins

Supported by the Dutch Ministry of Health, as part of the National Program on AIDS Research, RGOMWVC grant no. 88-79/89005. Accepted for publication May 13, 1992. Address reprint requests to Dr. H.-J. Schuurman, Division of Histochemistry and Electron Microscopy, Department of Pathology, University Hospital, P.O. Box 85.500, 3508 GA Utrecht, The Netherlands.

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these tissues according to methods published by us elsewhere.13 Thymus, lymph node, spleen, liver, skin, kidney, diaphragm, ileum, colon, duodenum, thyroid, testis, aorta, trachea, brain, spinal cord, pancreas, heart, esophagus, adrenal gland, lung, and bone marrow were taken from two uninfected patients at autopsy. Three lymph nodes from HIV-1-infected individuals with persistent generalized lymphadenopathy were chosen on the basis of HIV-1 gag antigen p17 and p24 expression in the germinal centers and in solitary cells in the interfollicular zone.2 The lymph nodes were characterized by disrupted and fragmentated germinal centers as visualized by staining with the FDC-specific MAb DRC-1. The proportions of CD4-positive lymphocytes were low, and the mantles surrounding the germinal centers varied in size from almost absent to a small corona. In the lymph nodes, gp41 env antigen manifested in solitary cells in the interfollicular zones and occasionally also weakly in germinal centers.2'3 The following MAbs to tissue cells and HIV regulatory proteins were applied: anti-FDC (DRC-1, Dakopatts, Glostrup, Denmark); CD4 (anti-Leu-3a), and CD22 (antiLeu-14, Becton Dickinson, Mountain View, CA); antiHIV-1 tat, rev, and nef antibodies, and anti-HIV-2 tat antibody14 provided by the Medical Research Council (MRC, London, UK), American Biotechnologies (ABT, Cambridge, MA), and the AIDS Research and Reference Program, Division of AIDS, NIAID, NIH, (Rockville, MD), respectively. Some reagents supplied by NIH were polyclonal rabbit antisera. The optimal dilutions of the antiHIV-1 regulatory protein antibodies for immunohistochemistry were determined on cytocentrifuge preparations of H9 cells (provided by Dr. M. Schutten, Laboratory for Immunobiology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands) in the state of persistent infection, or infected with the HIV-1 IIIB strain 3 days before harvest. Also peripheral blood leukocytes (PBL) from three HIV-seropositive patients were studied. Peripheral blood leukocytes from uninfected individuals and uninfected H9 cells showed no labeling. Six-micron thick frozen tissue sections or cytocentrifuge preparations were fixed for 10 minutes in acetone at room temperature. After incubation with MAb, an incubation was done with rabbit anti-mouse immunoglobulins conjugated to horseradish peroxidase (RAM/PO) (Dakopatts) 1:120 diluted in phosphate-buffered saline, pH 7.4, supplemented with 10% heat-inactivated human AB serum. This was followed by 1 :100 diluted swine antirabbit immunoglobulins conjugated to PO (SwAR/PO) (Dakopatts). Staining was performed using 3-amino-9ethylcarbazole and hydrogen peroxide as substrate. Incubation with primary rabbit antibodies to HIV regulatory proteins was followed by SwAR/PO diluted 1:20. Controls included the omission of primary antibody

(mouse MAb or rabbit antiserum) or the replacement of primary antibody by an irrelevant one. In this condition there was no immunolabeling product observed. The only coloring product was that produced by endogenous peroxidase activity of polymorphonuclear granulocytes, when present.

Results Using the antibodies from MRC, NIH, and ABT, HIV-1 regulatory proteins were visualized in H9 cells in a state of continous infection, or infected with the HIV-1 IIIB strain 3 days before harvest. Anti-HIV-1-tat and especially antirev MAbs, exhibited a polar cytoplasmic staining of infected H9 cells (Figure 1). This indicates that tat and rev expression may not be restricted to the nucleus or nucleolus as has been reported in the literature.15'16 Both NIH anti-nef antibodies intensely labeled the cytoplasm of infected H9 cells, whereas ABT-anti-nef antibody showed a patchy staining pattern in the cytoplasm and on the cell membrane. Most (approximately 70%) of PBL from HIVinfected patients were labeled by anti-rev antibody, but not by anti-tat or anti-nef antibodies. The expression of nef by HIV-infected and actively HIV-producing H9 cells indicates that nef expression itself may not reflect latency. Uninfected H9 cells, and PBL from uninfected individuals, were not stained by any of the antibodies to HIV regulatory proteins. Various tissues from HIV-1-infected and uninfected individuals were studied for the presence of HIV-1 and HIV-2 regulatory proteins. In tissues from uninfected individuals (Table 1), anti-HIV-1 -tat antibodies stained vascular endothelial cells, Hassall's bodies in thymus, goblet cells in intestinal and tracheal epithelium, stratum granulosum and pigmented melanophages in skin, and dendritic cells in brain (Figure 2), spinal cord, and adrenal gland. Hassall's corpuscles, tracheal epithelium, and stratum corneum in skin of uninfected individuals were stained by anti-HIV-2 tat antibody. Rev-expression was found on fibroblastic reticulum in skin and lymph nodes, high endothelial venules (HEV), and endothelial cells in tissues from uninfected patients (Figure 3). Follicular dendritic cells in germinal centers in lymph nodes and tonsils from uninfected individuals showed an intense membranous and cytoplasmic staining by anti-nef antibody from ABT (Figure 4). This labeling was solely and consistently restricted to germinal centers in various lymphoid organs (Table 2). The FDC nature of nef-positive cells was confirmed by the staining of FDC isolated from normal tonsils (Figure 5). The anti-nef antibodies obtained from NIH did not stain FDC in lymph nodes nor FDC in other lymphoid tissue from uninfected persons, but labeled occasionally solitary cells in the in-

HIV-Epitope Expression in Normal Human Tissues 1211 AJP November 1992, Vol. 141, No. 5

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MN 1 tat (MRC) antibody (a), anti-MN-i rev (ART) antibody Figure 1. Labeling of M9 cells in persistent infection ith MN-i IIIB by antiH (b), and anti-MIV-i nef (ART) antibody (C). Labeling ofperipheral blood leukocytesfr-om a MNV-i seropositive patient by anti-MWV-i rev (ART) antibody (d). Three-step immunoperoxidase, counterstaining with hematoxylin. Magnification X380. Figure 2. Labeling of neural cells in brain tissue of an MNV-i uninfected patient by anti-MNV-i tat (ART) antibody. Three-step immunoperoxidase, counterstaining withhetoxyin. Magnflctio X iSC

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Table 1. Tissue Specimens and Staining by Anti-HIV-tat and rev Antibodies 1tat-1 (ABTt) ltat-1 (MRC*) Tissue Thymus

Lymph node Tonsil Spleen Liver

Skin

Endothelium Hassall's corpuscles Endothelium Endothelium Cryptoepithelium (focal) Endothelium Endothelium Bile ducts Endothelium Melanophages

Endothelium Hassall's corpuscles

2tat-2 (NIHt) Hassall's corpuscles

(ABTI")

Hassall's corpuscles

Histiocytes HEV Cryptoepithelium (focal) HEV

Endothelium

Endothelium Stratum

rev

Stratum

Histiocytes

corneum

granulosum

Kidney Diaphragm Ileum Colon Duodenum Thyroid Testis Aorta Trachea Brain Spinal cord Pancreas Heart Esophagus Adrenal gland Lung Bone marrow

Endothelium

Goblet cells Goblet cells Goblet cells Endothelium Endothelium

Goblet cells Goblet cells Goblet cells

Cilia Endothelium

Goblet cells Neural dendrites Neural dendrites Zymogen cells

Cilia

Cortex

ND

Zymogen cells

Goblet cells

Interstitial cells

Endothelium

Cilia Ventricle

ND

Endothelium

1 Denotes

antibody dilution 1:100. Antibody dilution 1:1000. * Anti-HIV-1 tat monoclonal antibody (Dr. J. Karn, ADP352, provided by the Medical Research Council). t Anti-HIV-1 tat monoclonal antibody (Cat. no 7001, American Biotechnologies). t Rabbit anti-HIV-2 tat antibody (National Institute of Health USA, AIDS Research and Reference Program). Anti-HIV-1 rev monoclonal antibody (Cat. no 6001, ABT). -, no labeling observed; ND, not done; HEV, high endothelial venules. 2

follicular zones of tonsils. These antibodies also labeled astrocytes in brain, and stratrum granulosum and histiocytes in skin (Table 2). In lymph nodes from HIV-1-infected patients, both anti-HIV-1 -tat antibodies stained solitary cells located in and outside germinal centers (Figure 6). Vascular endothelium was also positive. HIV-2-tat antibody stained solitary cells in the interfollicular areas. Rev expression was found on the same tissue components as those labeled in noninfected lymph nodes (eg, HEV and histiocytes). Solitary positive cells were observed in the germinal centers. Remnants of germinal centers in lymph nodes were stained by ABT anti-nef antibody. The anti-nef antibodies from NIH did not label any component in the infected lymph nodes.

Discussion The immunohistochemical application of anti-HIV antibodies offers the proviso to assess the state and tissue location of infected cells. This holds especially for those

situations in which cells are difficult to isolate, purify, or maintain in culture, thus preventing the determination of DNA/RNA sequences by other methods such as the polymerase chain reaction. Using such antibodies, we documented the presence of tat, rev, and nef proteins in HIV-1 IIIB-infected H9 cells. We were not able to establish the specificity of the antibodies by immunoblotting, but in enzyme-linked immunosorbent assay all antibodies specifically bound to recombinant proteins to which they were directed (data not shown). We were unable to perform radioimmunoprecipitation to further confirm the specificity of the reagents. A marked staining with antiHIV-1-tat, anti-nef, and anti-rev, and anti-HIV-2-tat antibodies was found in a variety of cell types in different organs from uninfected individuals. The frequency and intensity of this staining was such that is is impossible to unequivocally demonstrate HIV-encoded regulatory proteins in HIV-infected tissues. The labeling of non-HIVinfected tissues has been found previously with antiHIV-1 gag antibodies, but to a lesser extent than that using the present antibodies against regulatory proteins. A number of anti-gag p17 and p24 MAbs labeled epi-

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Figure 3. Staining ofhigh endothelial venules (a, arrows), andfibriohistiocytes in the interfollicular zone (b, IF) in a HIV-1 uninfected tonsil by anti-HIV-1 rev antibody (ABT). Three-step immunoperoxidase, counterstaining with hematoxylin. Magnification a: X90, b: X410a Figure 4. Labeling of a follicle germinal center (GC) in the lymph node of an HIV-1 uninfected patient by anti-HIV-1 nef (ABT) antibody. IF = interfollicular zone. Three-step immunoperoxidase, counterstaining by hematoxylin. Magnification x 10. Figure 5. Labeling offollicular dendritic cells purifiedjfrom a normal tonsil by anti-nef (ABT) antibody. Three-step immunoperoxidase, counterstaining with hematoxylin. Magnification X410. Figure 6. Labeling ofsolitary cells (arrows) in thegerminal center and interfollicular zone (asterisk), in the lymph nodefrom an HPV-infected patient by anti-HIV-I tat (ABT) antibody. Three-step immunoperoxidase, counterstained with hematoxylin. Magnification x410.

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Table 2. HPV-1 nef Epitope Expression in Normal Human Tissues Tissue 1NF2-B2 (NIH*) 2rabbit-anti nef (NlHt) Thymus Lymph node Tonsil

3nef (ABTt)

Solitary cells in medulla Endothelium Solitary cells in interfollicular zone

Solitary cells in interfollicular zone

Solitary cells in

Spleen

FDC FDC

FDC

red pulpa Liver Skin

Kidney Diaphragm Ileum Colon Duodenum Thyroid Testis Aorta Trachea Brain Spinal cord Pancreas Heart Esophagus Adrenal gland Lung Bone marrow

Stratum granulosum

Histiocytes

ND

ND Goblet cells Goblet cells

FDC in Peyer's patches

Endothelium Solitary cells in lamina propria ND

ND

Astrocytes

Astrocytes

ND

ND

Endothelium ND

ND

' Antibody dilution 1:50. Antibody dilution 1:1000. 3 Antibody dilution 1:100. * Anti-HIV-1 nef (NF2-B2)3' provided by the NIH. t Rabbit anti-HIV-1 nef provided by the NIH. t Anti-HIV-1 nef monoclonal antibody (Cat. no 2001, ABT). -, no labeling observed; ND, not done; FDC, follicular dendritic cells. 2

thelium in the subcapsular/medulla area and surrounding Hassall's bodies in uninfected involuted thymus;1 MAbs to HIV-1 gag p18 labeled epithelium of skin, thymus, and tonsils, as well as astrocytes in the brain9; and an antiHIV-1 gag p24 MAb stained proximal and distal tubuli of the kidney in seronegative patients (unpublished data). The present data for MAbs to HIV-1 -tat, rev, and nef proteins parallel the expression of gag or env antigens in lymph nodes from HIV-infected individuals. Tat expression showed a similar distribution as gp4l and env mRNA expression, as was localized in solitary cells in and outside germinal centers.21 Expression of a nef epitope corresponded with gag expression on FDC in the lymphoid germinal centers from HIV-infected individuals.238 The expression of HIV regulatory proteins in lymph nodes from HIV-1 infected patients showed only a quantitative increase with respect to that in noninfected lymph nodes. Therefore, we conclude that the currently used antibodies to HIV-regulatory proteins cannot be used for the immunohistochemical demonstration of HIV infection. As a consequence, we did not evaluate non-

lymphoid tissues from HIV-1-infected individuals and AIDS patients. Some hypotheses can be proposed to explain the labeling of normal human tissues or cells by antibodies to HIV regulatory proteins. The explanation on the basis of nonspecific reactivity is highly unlikely, because control experiments did not show any labeling product, the patterns of labeling varied considerably between different antibodies, and the connective tissues matrix known to be target for nonspecific binding was negative. The labeling observed might reflect expression of as yet unknown endogenous retroviral(-like) elements. The genome of humans,17'18 like other vertebrates such as mice19 and baboons,20 contains a considerable number of endogenous proretroviral or retrovirus-like sequences with homology to sequences of exogenous retroviruses. The origin and significance of these endogenous retroviral sequences are largely unknown, but some of them may be at least transcribed, eg, in placenta.21 Immature (type C) virions have been detected in various human tissues.21 In this respect, the expression of a nef epitope

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on FDC in normal germinal centers, a location where undefined virions have been repeatedly located,22 is noteworthy. Second, the apparent cross-reactivity may be based om molecular mimicry of conformational epitopes shared by viral and host molecules.2>25 This has been reported previously for HIV-1 structural proteins.2627 Support for this hypothesis comes from recently published data on the identification in HIV-1 tat of the highly conserved tripeptide sequence Arg-Gly-Asp (RGD), which characterizes sites for integrin-mediated cell adhesion.28 Conserved motifs have been established among RNAdependent polymerase encoding elements in various viruses.29 Their presence may be related to repetitive DNA sequences encoding a reverse transcriptase-related protein in various mammalian cells, which may be derived from a sequence with strong homology to RNAdependent DNA polymerase of viral origin.30 These together make it tempting to speculate that homology of HIV-1 and cellular proteins may rest on integration of human sequences in the viral genome. These sequences may have acquired a function in the viral life cycle, like adhesion mediated by RGD (tat) sequences. In conclusion, epitopes of HIV regulatory proteins are expressed in normal human tissues. This phenomenon should encourage the study of the possible expression, characteristics, and function of endogenous retroviral-like elements in human cells.

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Acknowledgments The authors thank Drs. A. de Ronde and J. Dekker for performing immunoblotting and ELISA assays; Dr. S. T. Pals for stimulating discussions on this study; the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, and NIH for supplying the MAb to recombinant nef (No. NF2-B2), and rabbit antiserum to recombinant nef; Dr. Bryan Cullen for providing the antiserum to HIV-2-tat; and the Medical Research Council, London, UK, for supplying the antibody NT3 2D1 1 (ADP352, Dr. J. Kam, anti-HIV-1 tat).

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19. Kozak C: Retroviruses as chromosomal genes in the mouse. Adv Cancer Res 1985; 44:295-336 20. Cohen M, Rein A, Stephens R, O'Connell C, Gildman RV, Shure M, Nicolson MO, McAllister RM, Davidson N: Baboon endogenous virus genome: Molecular cloning and structural characterization of nondefective viral genomes from DNA of a baboon cell strain. Proc Natl Acad Sci USA 1981, 78:5207-5211 21. Johansen T, Holm T, Bjorklia E: Members of the RTLV-H family of human endogenous retroviral-like elements are expressed in placenta. Gene 1989, 79:259-267 22. O'Hara CJ, Groopman JE, Federman M: The ultrastructural and immunohistochemical demonstration of viral particles in lymph nodes from human immunodeficiency virus-related and non-human immunodeficiency virus-related lymphadenopathy syndromes. Hum Pathol 1988, 5:545-549 23. Fujinama RS: Virus-induced autoimmunity through molecular mimicry. Ann NY Acad Sci 1988, 540:210-217 24. Query CC, Keene JD: A human autoimmune protein associated with Ul RNA contain a region of homology that is crossreactive with p30 gag antigen. Cell 1987, 51:211-220 25. Purcell DFJ, Deacon NJ, McKenzie IFC: The human nonlineage antigen CD46 (HuLY-M5) and primate retroviral gp70 molecules share protein-defined antigenic determinants. Immunol Cell Biol 1989, 67:279-289 26. Beretta A, Grassi F, Pelagi M, Clivio A, Parravicini C, Giovinazzo G, Andronico F, Lopalco L, Verani P, Butto S, Titti F, Rossi GB, Viale G, Ginelli E, Siccardi AG: HIV env glycopro-

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tein shares a cross-reacting epitope with a surface protein present on activated human monocytes and involved in antigen presentation. Eur J Immunol 1987, 17:1793-1798 Golding H, Robey FA, Gates FT l1l, Linder W, Beining PR, Hoffman T, Golding B: Identification of homologous regions in human immunodeficiency virus gp4l and human MHC class 11 p 1 domain: I. Monoclonal antibodies against the gp4l-derived peptide and patients' sera react with native HLA class 11 antigens, suggesting a role for autoimmunity in the pathogenesis of acquired immune deficiency syndrome. J Exp Med 1988; 167:914-923 Brake DA, Debouck C, Biesecker G: Identification of an ArgGly-Asp (RGD) cell adhesion site in human immunodeficiency virus type 1 transactivation protein, tat. J Cell Biol 1990, 111:1275-1281 Poch 0, Sauvaget I, Delarue M, Tordo N: Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 1989, 8:3867-3774 Hattorri M, Kuhara S, Takenaka 0, Sakakie Y: Li family of repetitive DNA sequences in primates derived from a sequence encoding a reverse transcriptase-related protein. Nature 1986, 321:625-628 Kaminckik Y, Bashan N, Pinchasi D, Amit B, Sarver N, Johnston Ml, Fischer M, Yavin Z, Gorecki M, Panet A: Expression and biochemical characterization of human immunodeficiency virus type 1 nef gene product. J Virol 1990, 64:3447-3454

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