|
|
|
|
|
|
|
||
Original Article |
smoir{at}niaid.nih.gov
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Key Words: HIV-1 • B cell • viral reservoir • complement • CD21
HIV-mediated perturbations of B cell functions have been well described 1112 and are largely thought to reflect indirect effects of HIV replication. Several direct interactions between HIV and B cells have been suggested from in vitro studies, (for review see references 13, 14), yet in vivo correlates of these observations are lacking. Furthermore, perturbations of B cell function resulting from direct HIV infection of B cells have been suggested from numerous in vitro studies 1516; however, few in vivo correlates have been identified.
It has been suggested that one of the major modes of interaction between HIV and FDCs in vivo involves binding of HIV IC to complement receptors expressed on FDCs 9. Interestingly, B cells also express complement receptors, traffic through follicles where HIV RNA signal is most intense 1718, migrate to the periphery of follicles for interaction with T cells 19, and bind HIV in vitro through IC–CD21 interactions 20. In this study, we demonstrate that replication-competent virus binds directly to B cells isolated from lymphoid tissues and/or peripheral blood of patients chronically infected with HIV-1. This phenomenon was consistently demonstrated in chronically infected patients who have plasma viral loads >10,000 copies of HIV RNA per ml. By cell sorting, virus displacing, and complement-based capture assays we demonstrate that the association between HIV and B cells occurs through interactions between CD21 expressed on the surface of B cells and C3 fragments bound to HIV particles.
Antibodies.
Cell Preparations.
Introduction
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
HIV-1 replicates predominantly in activated CD4+ T cells. However, numerous other cell types contribute to HIV infection by acting as reservoirs or carriers for the virus. Intracellular reservoirs of HIV that have been well described include macrophages and latently infected resting CD4+ T cells, and extracellular sources of virus include dendritic cells (DCs) and follicular dendritic cells (FDCs; for review see references 123). Recently, the HIV capturing and transporting properties of DCs have been clarified with the identification of DC-SIGN, a lectin-based membrane protein that is uniquely expressed on DCs and demonstrates a specific capacity to interact with HIV envelope 4. Direct binding and stabilization of virions on cells that are not susceptible to infection have also been proposed to involve interactions between integrins expressed on the cell surface and adhesion molecules acquired by HIV-1 5. In contrast, the demonstration of HIV-trapping on FDCs has relied on ultrastructural analyses of germinal center sections stained for gag proteins or HIV-RNA 678, and in vitro reconstitution of HIV trapping on FDCs via immune complexes (ICs; 9, 10).
Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
Study Subjects.
23 HIV-1–infected patients were studied; 19 were chronically viremic and 4 were recently viremic after interruption of antiretroviral therapy that previously had suppressed viremia successfully 21. Of the 19 chronically viremic individuals studied, patients 4, 7, 16, and 17 were antiretroviral drug naive, and the remaining patients were either not fully compliant with their antiretroviral regimens or were failing therapy, thus explaining the presence of detectable viremia. All protocols were carried out in accordance to the Institutional Review Board of the National Institute of Allergy and Infectious Diseases.
FITC- or PE-conjugated mAbs specific for CD19, CD20, CD21, CD3, and CD14 were purchased from Becton Dickinson, and, in the case of CD4, CD1a, IgM, IgG, and CD32, from BD PharMingen. The C3-displacing anti-CD21 mAb FE8 was provided by Dr. W.M. Prodinger (University of Innsbruck, Innsbruck, Austria). The negative control, isotype-matched anti-CD21 mAb BL13, was purchased from Beckman Coulter. Rabbit anti–human C3d antibody, which recognizes native C3, C3b, iC3b, C3d, and C3dg, was purchased from Dako. Normal rabbit serum was obtained from Caltag Laboratories.
PBMCs were obtained from lymphopheresis or standard blood draws by Ficoll-Hypaque density gradient centrifugation. Excisional inguinal lymph node biopsies were performed on a subset of patients to obtain lymph node mononuclear cells (LNMCs). LNMCs were obtained by gentle mechanical manipulation of the tissue. B cells were isolated by negative selection using a column-based purification technique (StemCell Technologies). Purity of B cell preparations was verified by flow cytometry (EPICS XL Flow cytometer; Beckman Coulter), with a panel of mAbs against CD19, CD20, and CD21. Typically these markers accounted for >95% percent of the cell suspensions, with the remainder of the cells expressing neither CD14 nor CD1a, nor coexpressing CD3 and CD4. CD4+ T cell populations were prepared by depleting PBMCs or LNMCs of CD8+ cells by magnetic bead depletion (Dynal); CD19+ cells were also removed for the data collected from patient 2 in Fig. 1 and all patients in Table (see below).
|
|
Replication-competent virus associated with each cell preparation was evaluated by coculturing 106 cells with 106 anti-CD3 stimulated HIV-negative PBMCs depleted of CD8+ T cells (indicator T cells). Surface-bound virus was removed by pronase (Roche Molecular Biochemicals) pretreatments as previously described 23, with the modification that 20 mg/ml of pronase was used in the assay. Productive infection was evaluated by ELISA determination of HIV-1 p24 (Beckman Coulter). Virus collected at the peak of replication in cocultures was analyzed for coreceptor usage by exposure to the human glioma cell lines U87/CD4 expressing the chemokine receptors CCR5 or CXCR4 (provided by D.R. Littman, New York University Medical Center, New York, NY).
B Cell Subset and Ligand-displacing Analyses.
Fresh or thawed PBMCs from HIV-infected individuals were depleted of CD2- and CD14-expressing cells using magnetic bead separation protocols, then sorted on a EPICS ELITE cell sorter (Coulter) into one of the following subset pairs: CD20+/CD21+ and CD20+/CD21– or CD20+/CD32+ and CD20+/CD32–. In other experiments, B cells prepared by negative selection (StemCell Technologies) were depleted of surface IgG– or surface IgM–expressing cells by incubation with biotinylated anti-IgG or anti-IgM antibodies (BD PharMingen), followed by incubation with streptavidin-conjugated magnetic beads (Dynal) and separation on a magnet. Subsets of B cells were tested for the presence of replication-competent HIV by coculturing equal numbers of B cells from each fraction with indicator T cells. For displacement of HIV-bound C3 fragments, B cells were isolated from PBMCs of HIV-infected patients by negative selection. The cells were incubated with 2 µg/ml of anti-CD21 C3 fragment–displacing mAb FE8 or control anti-CD21 mAb BL13 for 1 h at 37°C, washed once, incubated a second time with 2 µg/ml mAb for 30 min at 37°C, washed twice, and cocultured with indicator T cells. HIV virions displaced by FE8 were captured by sequential incubations with rabbit anti-C3d antibodies and sheep anti–rabbit–conjugated magnetic beads (Dynal), followed by separation of unbound virions by magnetic bead separation. Levels of HIV RNA in each fraction, including samples of FE8-displaced virus incubated with normal heat-inactivated rabbit serum (negative control), were determined by branched DNA assay (limit of detection, 50 copies of HIV-1 RNA; Chiron Corp.).
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Detailed Characterization of B Cell–associated HIV-1 in the Peripheral Blood of Chronically Infected Patients.
To establish the scope of patients whose B cells harbor HIV, we performed in depth analyses of peripheral blood B cells isolated from 19 chronically viremic patients (Table , patients 1–19) and 4 recently viremic patients (Table , patients 20–23). A parallel CD4+ T cell fraction was prepared from each patient studied by depleting PBMCs of CD8 and CD19 cells. For all patients studied, the level of HIV RNA associated with each cell fraction lysate was determined by NASBA analysis (Table ). The B cell–associated HIV-1 RNA levels ranged from undetectable to 1,700 copies/105 cells (median: 460 copies/105 cells), whereas T cell–associated HIV-1 RNA ranged from undetectable to 8,100 copies/105 cells (median: 2,000 copies/105 cells). The mean ratio of HIV RNA between B and CD4+ T cells was 0.23. To establish the cellular localization of the HIV RNA signal, we performed a qualitative in situ NASBA analysis for HIV-1 gag sequences. The B cell–associated HIV-1 RNA localized to the surface of the cells, as suggested by the staining pattern that was largely restricted to the periphery of the cells (Fig. 2A and Fig. B) and reduction of staining to background level (Fig. 2 E) when cells were treated with pronase before NASBA (data not shown). In contrast, the T cell–associated HIV-1 RNA was found to be dispersed throughout the cytoplasm (Fig. 2C and Fig. D) and largely insensitive to pronase treatment (data not shown). Varying degrees of brightness were observed throughout the B cell population (Fig. 2 A), ranging from rare bright green ring-like patterns to dimmer specks of green on the contour of the cells, indicated by arrows. This spectrum of HIV RNA staining could also be observed at higher magnification for a single B cell (Fig. 2 B), contrasting sharply with the dense intracellular staining associated with T cells (Fig. 2 D). These data suggest a nonuniform mode of interaction between HIV particles and B cells through molecules that are either unevenly expressed or vary in binding affinities.
|
Sensitivity of B and T Cell–associated HIV to Proteolytic Treatment of Cell Surfaces.
Inter-patient comparison of the capacities of B and T cells to pass virus to indicator T cells (B–T and T–T respectively) revealed that, overall, passage of virus was more efficient in T–T than B–T cocultures. However, the kinetics of passage of virus from input B cells to indicator T cells were surprisingly rapid considering the fivefold difference in RNA levels between CD4+ T cells and B cells. Based on these observations and the location of the pronase-sensitive RNA signal revealed by in situ NASBA (Fig. 2), we hypothesized that the HIV RNA detected on B cells represented readily available and infectious viral particles, whereas the signal in the T cells represented genomic or messenger RNA. To directly test this hypothesis, B and T cell suspensions from eight of the patients described in Table were treated with pronase before cocultivation. In all eight patients, as shown by three representative graphs in Fig. 3 A, proteolysis completely abrogated the passage of virus from the B cells to the indicator T cells, whereas the CD4+ T cell preparations were unaffected by pronase treatment. In seven out of eight patients a dramatic decrease in the levels of B cell–associated HIV-1 RNA, but not T cell–associated HIV-1 RNA as measured by NASBA, was also observed after pronase treatment (data not shown). Taken together, these data strongly suggest that the HIV-1 RNA associated with B cells of chronically HIV-1–infected patients is in the form of surface-bound virions that can readily initiate a spreading infection when placed in proximity to activated CD4+ T cell targets. Conversely, the HIV-1 RNA associated with T cells largely reflects pronase-insensitive intracellular HIV-1 RNA.
|
Mechanism of Interaction between HIV and B Cells.
To investigate the mechanism of interaction between HIV and B cells in vivo, we performed extensive B cell subset analyses using surface markers that have been associated with HIV binding to B cells in vitro 202728, and/or with trapping of immune-complexed virus by FDCs in vivo 8910. Accordingly, binding to HIV envelope–specific surface Ig was addressed by depleting the surface IgG– and IgM–expressing B cells of patients 8, 11, and 19; virus was passed to indicator T cells with kinetics similar to those described in Table (data not shown). The possibility that HIV binds B cells through Fc receptor interactions was addressed by sorting the B cells of patients 11, 13, and 19 into CD32+ and CD32– fractions; virus was passed to indicator T cells with kinetics similar to those described in Table ; data for patient 19 are shown in Fig. 3 C. The possibility that HIV binds B cells through IC–complement receptor interactions was addressed by sorting the B cells of patients 6, 11, 13, 16, 17, and 19 into CD21+ and CD21– fractions (typical FACSTM staining shown in Fig. 3 B). In all six patients, as shown by three representative graphs in Fig. 3 C, replication-competent virus in the CD21-depleted fractions was either absent or showed dramatically reduced replication kinetics compared with the CD21-enriched fractions. Finally, verification of surface markers after pronase treatment revealed a dramatic suppression of CD21 expression on B cells of HIV-infected patients (representative data shown in Fig. 3 D), providing a mechanistic explanation for the initial observation made in Fig. 3 A on the sensitivity of B cell–bound virus to pronase. We found no cosegregation of the CD21+ fraction with markers such as surface IgD/G/M that may be involved in superantigenic binding of HIV envelope to VH3 27 or CD4 (data not shown), suggesting that HIV-1 preferentially interacts with B cells through IC binding to CD21. However, there remained the possibility that HIV binds B cells through another CD21-cosegregating receptor, such as CD35, or a novel B cell marker.
Displacement of HIV-1 Particles from B Cells with a C3-displacing Anti-CD21 mAb.
To directly address the role of CD21 in HIV binding to B cells, we preincubated the B cells of six HIV-infected patients with the anti-CD21 mAb FE8, which has been shown to block and displace the binding of C3 fragment (C3d/C3dg, iC3b)–coated particles 29. In parallel, B cells were also preincubated with an isotype-matched, anti-CD21 mAb BL13, known to bind outside the ligand-binding domain for C3 fragments 30. In agreement with the sorting data, pre-incubation with FE8 but not BL13 either completely abrogated or dramatically reduced the levels of replication-competent HIV associated with the B cells of all six patients studied (Fig. 3 E shows three representative graphs). Furthermore, in order to demonstrate that the binding of HIV to CD21 was mediated by C3 fragments, we performed C3 capture assays on FE8-displaced virus using rabbit anti–human C3d and magnetized anti–rabbit IgG antibodies, followed by detection of HIV-1 RNA in the magnetic bead and soluble fractions. Although a high proportion of FE8-displaced HIV from the B cells of patients 9, 12, and 18 remained in the soluble fraction, anti–human C3d antibodies captured significant amounts of virus when compared with normal serum (Fig. 3 F). Considering that B cells incubated with the nondisplacing anti-CD21 mAb BL13 released undetectable levels of HIV RNA (data not shown), the virus released by FE8 but not captured by anti-C3d antibodies may represent a C3-independent mode of binding between HIV and CD21. Alternatively, virions may have become dissociated from C3 fragments during the incubation steps with FE8, or the HIV-C3 fragment association may have partially restricted recognition of the latter by anti-C3d. Nonetheless, these data confirm that C3 fragments contribute to the binding of HIV to CD21 on B cells.
This study has several implications for in vivo HIV pathogenesis, regarding direct effects of HIV on B cell function, enhancement of virus replication by complement products, and a potential role for B cells as a reservoir for HIV-1. CD21 has been directly associated with B cell activation 31, suggesting that the constant triggering of CD21 by HIV IC may contribute to the high levels of polyclonal B cell activation described in HIV disease and exacerbated when viremia is not controlled by antiretroviral therapy 32. Of note, CD21 expression on B cells of HIV-infected patients can be dramatically decreased compared with HIV-negative individuals (Table and Fig. 3 B; references 33, 34), suggesting a direct perturbation of B cells by HIV IC binding. Furthermore, in agreement with previous studies on HIV-mediated destruction of lymphoid tissues that are the major sites of HIV replication 781718, we demonstrate that HIV–B cell interactions are amplified in lymphoid tissues. Our findings suggest that, similar to the situation in which HIV trapped on FDCs serves as a source of infection of CD4+ T cells migrating into lymphoid tissue germinal centers 10, HIV can be presented to activated CD4+ T cell targets as B cell immune-complexed virus. Furthermore, since B cells circulate through peripheral blood and migrate within lymphoid tissues to the border of follicles for cognate B–T interactions 19, they may have even greater opportunities than FDCs to transmit virus to T cells.
In summary, 23 out of 23 chronically HIV-1–infected patients with viral loads >10,000 copies of HIV-1 RNA per ml were found to have replication-competent, pronase-sensitive virus associated with their B cells that was readily transmitted to activated HIV-negative CD4+ T cells. The CD21-based sorting experiments and the C3-displacing assays performed on several patients indicate that HIV-1 interacts directly with B cells through CD21–IC interactions. These findings are underscored by the facts that a significant portion of virions circulate in the blood as ICs 35, and complement breakdown products increase with HIV infection 36. Furthermore, a recent in vitro study indicates that virions bound to B cells through IC interactions are far more infectious for T cells than are free virions 20. The role of HIV-specific antibodies in these ICs has not been addressed here; however, numerous studies suggest their presence contributes to the HIV-enhancing effects of complement 37383940. Thus, our findings provide new insights regarding the potential role of B cells as a unique extracellular reservoir for HIV.
|
Acknowledgments |
|---|
Submitted: 27 April 2000
Revised: 5 July 2000
Accepted: 14 July 2000
S. Moir and A. Malaspina contributed equally to this paper.
Yuexia Li's present address is VIRxSYS, Inc., Gaithersburg, MD 20877.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Burton G.F., Masuda A., Heath S.L., Smith B.A., Tew J.G. & Szakal A.K.. Follicular dendritic cells (FDC) in retroviral infectionhost/pathogen perspectives, Immunol. Rev., 156, 1997, 185–197.[Medline]
Chun T.W. & Fauci A.S.. Latent reservoirs of HIVobstacles to the eradication of virus, Proc. Natl. Acad. Sci. USA., 96, 1999, 10958–10961.
Haase A.T.. Population biology of HIV-1 infectionviral and CD4+ T cell demographics and dynamics in lymphatic tissues, Annu. Rev. Immunol., 17, 1999, 625–656.[Medline]
Geijtenbeek T.B., Kwon D.S., Torensma R., van Vliet S.J., van Duijnhoven G.C., Middel J., Cornelissen I.L., Nottet H.S., KewalRamani V.N. & Littman D.R.. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells, Cell., 100, 2000, 587–597.[Medline]
Liao Z., Roos J.W. & Hildreth J.E.. Increased infectivity of HIV type 1 particles bound to cell surface and solid-phase ICAM-1 and VCAM-1 through acquired adhesion molecules LFA-1 and VLA-4, AIDS Res. Hum. Retroviruses., 16, 2000, 355–366.[Medline]
Tenner-Racz K., Racz P., Bofill M., Schulz-Meyer A., Dietrich M., Kern P., Weber J., Pinching A.J., Veronese-Dimarzo F. & Popovic M.. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS, Am. J. Pathol., 123, 1986, 9–15.[Abstract]
Fox C.H., Tenner-Racz K., Racz P., Firpo A., Pizzo P.A. & Fauci A.S.. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA, J. Infect. Dis., 164, 1991, 1051–1057.[Medline]
Spiegel H., Herbst H., Niedobitek G., Foss H.D. & Stein H.. 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, 1992, 15–22.[Abstract]
Joling P., Bakker L.J., Van Strijp J.A., Meerloo T., de Graaf L., Dekker M.E., Goudsmit J., Verhoef J. & Schuurman H.J.. Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent, J. Immunol., 150, 1993, 1065–1073.[Abstract]
Heath S.L., Tew J.G., Szakal A.K. & Burton G.F.. Follicular dendritic cells and human immunodeficiency virus infectivity, Nature., 377, 1995, 740–744.[Medline]
Lane H.C., Masur H., Edgar L.C., Whalen G., Rook A.H. & Fauci A.S.. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome, N. Engl. J. Med., 309, 1983, 453–458.[Abstract]
Schnittman S.M., Lane H.C., Higgins S.E., Folks T. & Fauci A.S.. Direct polyclonal activation of human B lymphocytes by the acquired immune deficiency syndrome virus, Science., 233, 1986, 1084–1086.
Chirmule N. & Pahwa S.. Envelope glycoproteins of human immunodeficiency virus type 1profound influences on immune functions, Microbiol. Rev., 60, 1996, 386–406.
Muller S. & Kohler H.. B cell superantigens in HIV-1 infection, Int. Rev. Immunol., 14, 1997, 339–349.[Medline]
Gras G., Richard Y., Roques P., Olivier R. & Dormont D.. Complement and virus-specific antibody-dependent infection of normal B lymphocytes by human immunodeficiency virus type 1, Blood., 81, 1993, 1808–1818.
Poulin L., Paquette N., Moir S., Lapointe R. & Darveau A.. Productive infection of normal CD40-activated human B lymphocytes by HIV-1, AIDS., 8, 1994, 1539–1544.[Medline]
Embretson J., Zupancic M., Ribas J.L., Burke A., Racz P., Tenner-Racz K. & Haase A.T.. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS, Nature., 362, 1993, 359–362.[Medline]
Pantaleo G., Graziosi C., Demarest J.F., Butini L., Montroni M., Fox C.H., Orenstein J.M., Kotler D.P. & Fauci A.S.. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease, Nature., 362, 1993, 355–358.[Medline]
Garside P., Ingulli E., Merica R.R., Johnson J.G., Noelle R.J. & Jenkins M.K.. Visualization of specific B and T lymphocyte interactions in the lymph node, Science., 281, 1998, 96–99.
Jakubik J.J., Saifuddin M., Takefman D.M. & Spear G.T.. Immune complexes containing human immunodeficiency virus type 1 primary isolates bind to lymphoid tissue B lymphocytes and are infectious for T lymphocytes, J. Virol., 74, 2000, 552–555.
Davey R.T. Jr., Bhat N., Yoder C., Chun T.W., Metcalf J.A., Dewar R., Natarajan V., Lempicki R.A., Adelsberger J.W. & Miller K.D.. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression, Proc. Natl. Acad. Sci. USA., 96, 1999, 15109–15114.
van Gemen B., van Beuningen R., Nabbe A., van Strijp D., Jurriaans S., Lens P. & Kievits T.. A one-tube quantitative HIV-1 RNA NASBA nucleic acid amplification assay using electrochemiluminescent (ECL) labelled probes, J. Virol. Methods., 49, 1994, 157–167.[Medline]
Marechal V., Arenzana-Seisdedos F., Heard J.M. & Schwartz O.. Opposite effects of SDF-1 on human immunodeficiency virus type 1 replication, J. Virol., 73, 1999, 3608–3615.
Moir S., Lapointe R., Malaspina A., Ostrowski M., Cole C.E., Chun T.W., Adelsberger J., Baseler M., Hwu P. & Fauci A.S.. CD40-mediated induction of CD4 and CXCR4 on B lymphocytes correlates with restricted susceptibility to human immunodeficiency virus type 1 infectionpotential role of B lymphocytes as a viral reservoir, J. Virol., 73, 1999, 7972–7980.
Cutrona G., Leanza N., Ulivi M., Majolini M.B., Taborelli G., Zupo S., Baldari C.T., Roncella S. & Ferrarini M.. Apoptosis induced by crosslinking of CD4 on activated human B cells, Cell. Immunol., 193, 1999, 80–89.[Medline]
Wu L., Paxton W.A., Kassam N., Ruffing N., Rottman J.B., Sullivan N., Choe H., Sodroski J., Newman W., Koup R.A. & Mackay C.R.. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro, J. Exp. Med., 185, 1997, 1681–1691.
Berberian L., Goodglick L., Kipps T.J. & Braun J.. Immunoglobulin VH3 gene productsnatural ligands for HIV gp120, Science., 261, 1993, 1588–1591.
Golding H., Dimitrov D.S., Blackburn R., Manischewitz J., Blumenthal R. & Golding B.. Fusion of human B cell lines with HIV-1 envelope-expressing T cells is enhanced by antigen-specific Ig receptors. Possible mechanism for elimination of gp120-specific B cells in vivo, J. Immunol., 150, 1993, 2506–2516.[Abstract]
Prodinger W.M., Schwendinger M.G., Schoch J., Kochle M., Larcher C. & Dierich M.P.. Characterization of C3dg binding to a recess formed between short consensus repeats 1 and 2 of complement receptor type 2 (CR2; CD21), J. Immunol., 161, 1998, 4604–4610.
Cohen J.H., Fischer E., Kazatchkine M.D., Brochier J. & Revillard J.P.. Characterization of monoclonal antihuman-B-cell antibody BL13 as an anti-C3d-receptor (CR2) antibody, Scand. J. Immunol., 23, 1986, 279–285.[Medline]
Melchers F., Erdei A., Schulz T. & Dierich M.P.. Growth control of activated, synchronized murine B cells by the C3d fragment of human complement, Nature., 317, 1985, 264–267.[Medline]
Morris L., Binley J.M., Clas B.A., Bonhoeffer S., Astill T.P., Kost R., Hurley A., Cao Y., Markowitz M., Ho D.D. & Moore J.P.. HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy, J. Exp. Med., 188, 1998, 233–245.
Benedetto A., Di Caro A., Camporiondo M.P., Gallone D., Zaniratti S., Tozzi V. & Elia G.. Identification of a CD21 receptor-deficient, non-Ig-secreting peripheral B lymphocyte subset in HIV-seropositive drug abusers, Clin. Immunol. Immunopathol., 62, 1992, 139–147.[Medline]
Scott M.E., Landay A.L., Lint T.F. & Spear G.T.. In vivo decrease in the expression of complement receptor 2 on B-cells in HIV infection, AIDS., 7, 1993, 37–41.[Medline]
Nishanian P., Huskins K.R., Stehn S., Detels R. & Fahey J.L.. A simple method for improved assay demonstrates that HIV p24 antigen is present as immune complexes in most sera from HIV-infected individuals, J. Infect. Dis., 162, 1990, 21–28.[Medline]
Senaldi G., Peakman M., McManus T., Davies E.T., Tee D.E. & Vergani D.. Activation of the complement system in human immunodeficiency virus infectionrelevance of the classical pathway to pathogenesis and disease severity, J. Infect. Dis., 162, 1990, 1227–1232.[Medline]
Szabo J., Prohaszka Z., Toth F.D., Gyuris A., Segesdi J., Banhegyi D., Ujhelyi E., Minarovits J. & Fust G.. Strong correlation between the complement-mediated antibody-dependent enhancement of HIV-1 infection and plasma viral load, AIDS., 13, 1999, 1841–1849.[Medline]
Montefiori D.C., Lefkowitz L.B. Jr., Keller R.E., Holmberg V., Sandstrom E. & Phair J.P.. Absence of a clinical correlation for complement-mediated, infection-enhancing antibodies in plasma or sera from HIV-1-infected individuals. Multicenter AIDS Cohort Study Group, AIDS., 5, 1991, 513–517.[Medline]
Robinson W.E. Jr., Montefiori D.C. & Mitchell W.M.. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection, Lancet., 1, 1988, 790–794.[Medline]
Sullivan B.L., Knopoff E.J., Saifuddin M., Takefman D.M., Saarloos M.N., Sha B.E. & Spear G.T.. Susceptibility of HIV-1 plasma virus to complement-mediated lysis. Evidence for a role in clearance of virus in vivo, J. Immunol., 157, 1996, 1791–1798.[Abstract]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TABLE OF CONTENTS |
|
