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Distinction of Human Immunodeficiency Virus Type 1 Neutralization and Infection Enhancement by Human Monoclonal Antibodies to Glycoprotein 120 Akira Takeda,* James E

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Distinction of Human Immunodeficiency Virus Type 1 Neutralization and Infection Enhancement by Human Monoclonal Antibodies to Glycoprotein 120 Akira Takeda,* James E Distinction of Human Immunodeficiency Virus Type 1 Neutralization and Infection Enhancement by Human Monoclonal Antibodies to Glycoprotein 120 Akira Takeda,* James E. Robinson, David D. Ho, Chrisfine Debouck, Nancy L. Haigwood, and Francis A. Ennis* *Division ofInfectious Diseases, Department ofMedicine, University ofMassachusetts Medical School, Worcester, Massachusetts 01655; Department ofPediatrics and Microbiology, Immunology and Parasitology, Louisiana State University School ofMedicine, New Orleans, Louisiana 70112; Division ofInfectious Diseases, The Aaron Diamond AIDS Research Center, New York University School of Medicine, New York 10016; Department ofMolecular Genetics, Smith Kline Beecham Pharmaceuticals, King ofPrussia, Pennsylvania 19479; and Chiron Corporation, Emeryville, California 94608 Abstract reference to HIV vaccine development, since very low concen- trations of anti-HIV- 1 antibodies can enhance HIV-1 infec- There is increasing evidence that sera from HIV-1-infected tion. Robinson et al. first reported complement-mediated en- individuals contain antibodies that enhance infection by HIV-1 hancement of HIV- 1 infection in a T cell line bearing comple- in vitro. Previous work has demonstrated that complement re- ment receptors (1). We have previously demonstrated ceptors on T lymphoid cells and Fc receptors for IgG (Fc'yR) on antibody-dependent enhancement of HIV-l infection via Fc monocytic cells are required for enhanced infection by anti- receptor (FcR)'-mediated entry using a human monocytic cell body-complexed HIV-1. Characterization of such infection-en- line U937 that possesses FcRs for IgG (3). Heat-inactivated hancing antibodies is essential because immunogenic epitopes sera from HIV- 1 antibody-positive individuals enhanced infec- which induce enhancing antibodies should be excluded from tion ofU937 cells. This enhancement was blocked by the pres- HIV-1 vaccines. This study was conducted to identify enhanc- ence of heat-aggregated -globulin, a potent ligand for FcRs. ing antibodies involved in Fc R-mediated enhancement ofHIV- The IgG fraction from an HIV- 1 antibody-positive serum-en- 1 infection employing IgG human monoclonal antibodies hanced HIV-1 infection at the same serum dilution equiva- (HMAbs) reactive against gpl20 of HIV-1, which were pro- lents. IgG-F(ab')2 failed to enhance HIV-1 infection, but still duced by B cell lines derived from an HIV-1-infected individ- possessed neutralizing activity for HIV-1. We thus concluded ual. A potent neutralizing HMAb N70-1.5e did not enhance that the enhancement of HIV- 1 infection requires the Fc por- infection by HIV-1 (IIIB and MN strains), whereas HMAb tion of IgG and is mediated by Fc Rs. We examined several N70-2.3a mediated enhancement of HIV-1 infection, but had HIV-1 antibody positive sera, and enhancement of infection little neutralizing activity. A competition radio immunoassay was generally detected at higher dilutions of the sera. The en- demonstrated that the two antibodies bind to distinct epitopes. hancement at subneutralizing concentrations raised a ques- These results indicated that enhancing and neutralizingantibod- tion: are enhancing antibodies and neutralizing antibodies dif- ies can be induced by different epitopes on gpl20, suggesting ferent categories ofantibodies, or are these activities concentra- the potential for development ofsafe vaccines against HIV-1 by tion-dependent phenomena due to the same antibodies? To exclusion of immunogenic epitopes for enhancing antibodies. address this question, we examined the reactivity ofthe sera on We made attempts to identify the epitope on gpl20 that is Western blots to antigens of HIV-I (human T cell lymphotro- recognized by the enhancing antibody N70-23a by using recom- phic virus-IIIB strain [HTLV-IIIB]) to determine whether en- binant HIV-1 proteins and found that the antibody binds to a hancing sera react with specific viral antigens; however, there conformational site of nonvariable sequences in the carboxyl were no specific differences in terms of major viral proteins half (aa 272-509) of gpl20. (J. Clin. Invest. 1992. 89:1952- between enhancing sera and nonenhancing sera (data not 1957.) Key words: HIV-1 * infection enhancement * neutraliza- shown). tion * monoclonal antibodies * epitope Therefore, we have attempted to approach this issue by using rabbit antisera raised against the amino- and the car- Introduction boxyl-terminal halves of HIV-l gpl20, and human monoclo- nal antibodies (HMAbs) directed against gpl2O, which were Enhancement of HIV-1 infection by specific antibodies has derived from HIV- 1-infected donor peripheral blood lympho- been described in vitro (1-6). This raises a major concern in cytes. Address correspondence and reprint requests to Dr. Francis A. Ennis, Methods Division ofInfectious Diseases and Immunology, Department ofMedi- cine, University of Massachusetts Medical School, Worcester, MA Viruses. HTLV-IIIB, a prototype HIV-1 strain (7) and HTLV-IIIMN 01655. (7) were obtained from the AIDS Research and Reference Reagent Receivedforpublication 9 July 1990 and in revisedform 9 January Program. These strains were grown in H9 cells as acutely infected cul- 1992. tures. A local strain, HIV-I J62 (8), that was isolated from the periph- eral blood mononuclear cells of an HIV-l-infected patient by coculti- 1. Abbreviations used in this paper: FBS, fetal bovine serum; FcR, Fc vation with mitogen-stimulated T cells from seronegative blood, was receptor; HMAb, human monoclonal antibodies; HTLV, human T used to prepare native gp 120 antigen for binding assays. cell lymphotrophic virus. Rabbit antisera raised against recombinant HIV-1 envelope con- structs. Recombinant protein Kp1 2ONN corresponding to the amino- J. Clin. Invest. terminal moiety ofgpl20 (aa 12-257) was obtained by expression of a © The American Society for Clinical Investigation, Inc. 738-bp Asp718I-PvuII filled-in restriction gpl2O gene fiagment in- 0021-9738/92/06/1952/06 $2.00 serted in the pOTSKF33 bacterial vector (9). Recombinant protein Volume 89, June 1992, 1952-1957 Kpl20C corresponding to the carboxyl-terminal halfofgpl20 (aa 258- 1952 A. Takeda, J. E. Robinson, D. D. Ho, C. Debouck, N. L. Haigwood, and F. A. Ennis 437) was obtained by expression of a 539-bp PvuII-HindIII filled-in - 115,000 cpm/Mg. Immobilized antigen or control nitrocellulose restriction fragment, in which an oligonucleotide containing transla- strips were incubated with 50 ug/ml of purified HMAb, N70-l.5e, tion stop codons in all three frames was inserted at the BglII site at the N70-2.3a, or buffer for 1 h, and then washed. Labeled HMAb N70-2.3a end ofgpl20. The gene fragments were isolated from the BHI 0 clone of was added for 1 h and then the nitrocellulose strips were washed and HIV-l (10). Polyclonal antibodies were obtained from rabbits that were counted for radioactivity. hyperimmunized with those constructs. The reactivity of those rabbit Recombinant HIV-I gpJ20proteins. Nonglycosylated HIV-SF2 re- sera with each construct was tested by ELISA. combinant envelope polypeptides, designated as env-2-3 (full length Human monoclonal antibodies to HIV-J gpJ20. IgG HMAbs with protein, AA2b-5 10), env 1 (NH2-terminal half, AA2b-376), env 4 specificity for HIV-l gpl20 were produced by EBV-transformed B cells (COOH-terminal half, AA272-509), and variants deleted in one to five established from peripheral blood of asymptomatic HIV-l-infected hypervariable regions, were obtained by expression ofgp 120 gene frag- subjects, as described previously (11). We used two HMAbs, designated ments inserted into the pHL15 yeast vector, as described previously N70-l .5e and N70-2.3a, that are derived from the same donor and bind (16). The gene fragments were derived from HIV-SF2 strains (17). to HTLV-IIIB. N70-l.5e identifies a relatively conserved conforma- ELISA with envelope polypeptides. Recombinant gp120 proteins tional epitope on gpl20 that is glycosylation dependent, and is in- were absorbed to microtiter plates at 2 ug/ml in borate buffer. After volved in binding ofgpl20 to CD4. This antibody has potent neutraliz- plates were washed, biotinylated HMAb N70-2.3a that was diluted seri- ing activity against a variety oflaboratory and primary strains ofHIV- 1 ally was added for 1 h and detected using streptavidin, streptavidin (12). N70-2.3a reacts with a well-conserved epitope on gpl2O, and its conjugated to horseradish peroxidase (HRP-streptavidin; Zymed Labs, poor reactivity with reduced gp120 suggested it recognized a conforma- Inc., San Francisco, CA). Wells were developed with 2,2'-amino-bis tion-dependent epitope (11). Both are of the IgGl subclass and are (3-ethyl-benzenethiozyline 6-sulfonic acid) (ABTS) (Sigma Chemical directed against relatively conserved epitopes of gpl20. N70-2.3a has Co., St. Louis, MO). reacted with all 12 strains tested, including HTLV-IIIB and HTLV- Comparison ofHMab binding affinities. To compare the relative IIIRF, and N70-l.5e reacts with a majority ofstrains but not with RF. affinities of 1.5e and 2.3a, we used an assay based in principle on the Another HMAb, N70-1.9b, which recognizes a linear epitope within method of Friguet et al. (18), in which antibody is first incubated in the V3 region of MN and J62, and does not bind to virus strains that solution with antigen and then the relative amount of unbound anti- lack the V3 region of MN (13), was also 13 used for binding assays to body is determined by indirect ELISA. For these experiments, both determine relative affinities of N70-l.5e and N70-2.3a. HMAbs were biotinylated as previously described (12), and used at an HIV-I infection enhancement assay in U937 cells. The assay for the estimated final concentration of 8 ng/ml. In the solution phase reac- detection of enhancement of HIV-l infection was performed with tion, biotinylated antibodies were mixed with equal volumes ofbaculo- HTLV-IIIB, using a slightly modified method from that which we virus expressed recombinant gpl20 at final concentrations ranging described previously (3).
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