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Engagement of Adhesion Molecules (Cdt8, Cdtta, CD45, CD44, and CD58) Enhances Human Immunodeficiency Virus Type T Replication In

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Engagement of Adhesion Molecules (Cdt8, Cdtta, CD45, CD44, and CD58) Enhances Human Immunodeficiency Virus Type T Replication In 54 Engagement of Adhesion Molecules (CDt8, CDtta, CD45, CD44, and CD58) Enhances Human Immunodeficiency Virus Type t Replication in Monocytic Cells through a Tumor Necrosis Factor-Modulated Pathway Robin J. Shattock, Gian Paolo Rizzardi,* Peter Hayes, Divisions ofInfectious Diseases and Oncology, St. George's Hospital and George E. Griffin Medical School, London, United Kingdom Engagement of monocytic cell membrane proteins was shown to enhance human immunodefi­ ciency virus type 1 (HIV-1) replication in monocytic cells. Cross-linking of CD18, CDlla, or CD45 by immobilized antibodies produced up to an ll-fold enhancement of HIV-1 release in the OM10.1 monocytic cell line in a tumor necrosis factor-a (TNF-a)-dependent manner. In addition, adhesion Downloaded from https://academic.oup.com/jid/article/174/1/54/959003 by guest on 29 September 2021 ofOM10.1 cells to immobilized intercellular adhesion molecule-I (ligand for CDl8/CDlla) induced similar TNF-a-dependent enhancement of HIV-l replication. After phenotypic differentiation of OMlO.l cells, engagement of cell membrane proteins CD18, CD1la, CD44, CD45, or CD58 by soluble antibodies enhanced HIV-1 replication in a TNF-a-dependent manner. These data suggest that cross-linkage of monocytic cell membrane proteins during cell-cell interaction and specifically during antigen presentation to CD4 T cells may enhance HIV-1 replication, facilitating infection of adjacent cells. Human immunodeficiency virus type 1 (HIV-l)-infected HIV-1 replication in infected peripheral blood monocytes. We macrophages are a persistent reservoir ofvirus in tissue during have previously demonstrated for monocytes that adhesion per all stages ofHIV-I infection [1,2], and migration of such cells se, a phenotypic change associated with differentiation, to tis­ is likely to facilitate dissemination of HIV -1 throughout the sue culture plastic and endothelial cells enhances HIV -1 tran­ body. It is well established that replication of HIV-1 in mono­ scription [8]. In addition, our preliminary studies on cellular cytic cells is dependent on the state of cellular differentiation adhesion suggested that cross-linkage ofCD18 enhanced HIV­ [3] and correlates with nuclear translocation of the transcrip­ 1 replication in monocytic cells [9]. These observations have tional activator nuclear factor (NF)-KB and subsequent binding recently been confirmed by other studies [10, 11] in which ofthis factor to the enhancer region ofthe HIV -1 long terminal antibody blocking experiments demonstrated that CD 18 plays repeat sequence. Small numbers ofperipheral blood monocytes a role in the enhancement of HIV -1 replication induced by have been shown to harbor latent HIV-1 infection (positive for adhesion of infected monocytic cells to endothelium. Thus, proviral DNA without detectable release of HIV-l virions), engagement of monocyte adhesion molecules through interac­ while considerably larger numbers of latently infected macro­ tion of monocytes or macrophages with other cells clearly has phages have been demonstrated in lymph nodes and bronchoal­ the potential to enhance HIV -1 replication. veolar lavage fluid from lungs of asymptomatic HIV-1-in­ Monocyte adherence is known to induce mRNA production fected patients [4- 7]. Control ofHIV-1 production and release for several protooncogenes and monokines, including tumor from such cells is likely to play a crucial role in progression necrosis factor-a (TNF-a) and interleukin (IL)-8, both ofwhich ofHIV-1 disease. Thus, stimuli that induce monocyte differen­ contain NF-KB binding sites in their promoter regions [12, 13]. tiation and activation have the potential to enhance HIV-1 repli­ More specifically, engagement of CDI8/CDlla (lymphocyte cation. function-associated antigen [LFA]-I), CD58, CD44, and CD45 Infectious virus can be isolated from infected peripheral on monocyte membranes induces secretion ofIL-l, TNF-a, and blood monocytes on physical interaction with activated T cells with the exception of LFA-I, macrophage colony-stimulating [4, 5], suggesting that monocyte-T cell interactions induce factor (M-CSF), which all enhance HIV-l replication [14-17]. Thus, engagement of specific monocyte adhesion molecules has the potential to directly influence HIV -1 production in infected monocytes through NF-KB-dependent mechanisms. Received 20 November 1995; revised 5 March 1996. In this study, we have investigated the effects of engagement Financial support: Medical Research Council, UK (G9228196PB to R.J.S., P.H., G.E.G.), and Istituto Superiore di Sanita, Rome (G.P.R.). of specific monocyte adhesion molecules on HIV-1 replication Reprints or correspondence: Dr. Robin Shattock, Division ofInfectious Dis­ to define the mechanism by which monocyte interaction with eases, St. George's Hospital Medical School, Cranmer Terrace, SWl7 ORE, other cells might induce HIV -1 replication. London, UK. * Present affiliation: Istituto di Medicina Intema, Malettie Infettive e Immu­ nopathologia, Universita di Milano, Milan, Italy. Materials and Methods The Journal of Infectious Diseases 1996; 174:54-62 © 1996 by The University of Chicago. All rights reserved. Cell culture. The OMI0.1 cell line, a derivative of the HL60 0022-1899/96/7401-0007$01.00 myelomonocytic leukemia cell line containing a single integrated JID 1996; 174 (July) Monocyte Adhesion and HIV Replication 55 copy of HIV-I L A v provirus [18], was donated by S. Butera and specific cytokines. The following antibodies were used: anti-TNF­ T. Folks (COC, Atlanta). Cells were maintained in RPMI 1640 a, CB0006 (25 j.Lg/mL; Celltech, Slough, UK); anti-TNF-a, C168 supplemented with 2 roM glutamine, 100 U/mL penicillin, and 0.1 cA2 (25 j.Lg/mL, > 50X concentration required to neutralize 1 ng/ mg/mL streptomycin (Sigma, Poole, UK) and 5% heat-inactivated mL TNF as stipulated by manufacturer; Centocor, Malvern, PA); fetal calfserum (ICN Flow, High Wycombe, UK). For experimen­ anti-IL-Ia, S76/BM (111000, lOx concentration required to neu­ tation, cells were used in the log phase of growth and before use tralize 100 pg ofIL-la; National Institute for Biological Standards were washed three times with PBS to remove exogenous virus. and Control, Potters Bar, UK); anti-IL-I,B, S77/BM (1/500, 5X In some experiments, OMIO.l cells were treated with 10- 8 M concentration required to neutralize 100 pg of IL-I,B as stipulated 1,25 dihydroxycholecalciferol (1,25(OH)2D3) for 24 h before ex­ by supplier; National Institute for Biological Standards and Con­ perimentation. After 24 h, I,25(OH)2Drtreated cells were washed trol); and anti-M-CSF, BL-MCP (10 j.Lg/mL, concentration re­ three times in PBS directly before experimentation and resus­ quired to neutralize 5 ng of M-CSF as stipulated by supplier; IO~8 pended in fresh culture medium containing M 1,25(OHhD3. Genzyme, Boston). In some experiments, cells were incubated in Downloaded from https://academic.oup.com/jid/article/174/1/54/959003 by guest on 29 September 2021 Cross-linking of cell membrane proteins by immobilized anti­ the presence of 1 j.Lg/mL IL-l receptor antagonist (IL-IRA; Na­ bodies. Microtiter plates (3590; 96-well; Costar, Cambridge, tional Institute for Biological Standards and Control). MA) were coated with a primary Ftab"), fragment of goat mono­ Measurement of RT activity. RT activity was determined by clonal antibody (MAb) against the Fc portion of mouse immuno­ e2p]dTTP incorporation as described [20]. Samples of cell-free globulins by incubating antibody (50 p,L/well; 10 j.Lg/mL in PBS) tissue culture supernatant (5 j.LL) were added to 25 j.LL of RT at 4°C overnight. Plates were then washed twice with PBS, 50 j.LLI cocktail (4 j.Lg/mL polyadenylic acid, 1.26 j.Lg/mL pd[T] 12-18 [Oligo well of 1% bovine serum albumin (BSA) in PBS was added to (dT); Pharmacia, Milton Keynes, UK], 10 j.LCi/mL thymidine 5' each well, and the plates were incubated for 1 h at room tempera­ [a-32P]triphosphate triethylammonium salt [Amersham, Amer­ ture. This step blocked free protein binding sites not occupied by sham, UK], and 0.01% NP-40) and incubated at 37°C for 1.5 h. goat MAb. Plates were subsequently washed and incubated for 1 RT reaction mixture (5 j.LL) was then dotted onto DE81 paper h at room temperature with one of a panel of secondary mouse (Whatman, Maidstone, UK), air dried, and washed four times in MAbs (50 j.LLlwell; 10 j.Lg/mL) directed against specific cell mem­ 2X standard saline citrate and twice in absolute ethanol. 32p activity brane proteins. The use of a primary Ftab"), anti-mouse MAb was then determined using a direct beta plate reader (Canberra ensured that all secondary antibodies were bound to microtiter Packard, Pangbourne, UK). plates via their Fe portion, ensuring that no Fe portions were able Measurement of TNF-a and IL-1,B in culture supernatant. to interact with Fe receptors on the surface of monocytic cells. Supernatant TNF-a and IL-1,B levels were measured by ELISA The following secondary mouse MAbs were used in experi­ according to the manufacturer's protocols (R&D Systems, Oxon, ments: anti-C018 (MHM23), anti-CDlla (MHM24), anti-CDIlb UK). The lower limit of sensitivity of the TNF -a assay was 4.4 (M74l), anti-CDIlc (M732), anti-C045 (T29/33), anti-C04 pg/mL and of the IL-1,B assay was 0.3 pg/mL. Bioactive TNF (MT3l0), IgG 1a (X 931) and IgG2a (X 943) control antibodies concentrations were measured using the previously described bio­ (Dako, High Wycombe, UK), anti-intercellular adhesion mole­ assay involving the WEHI 164 cell line [20a]. 6 cule-I (ICAM-l; 84HlO), anti-major histocompatibility complex Flow cyto metry. Cells (10 ) were harvested for each test and (MHC)-II (DWHC54), anti-CD44 (F 10-44-2), anti-CD58 (BRIC­ pelleted by centrifugation at 400 g for 5 min.
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