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At least 19 recordsLinked to original sources
PubMed1994

Liposome targeting to human immunodeficiency virus type 1-infected cells via recombinant soluble CD4 and CD4 immunoadhesin (CD4-IgG).

HIV-infected cells producing virions express the viral envelope glycoprotein gp120/gp41 on their surface. We examined whether liposomes coupled to recombinant soluble CD4 (sCD4, the ectodomain of CD4 which binds gp120 with high affinity) could specifically bind to HIV-infected cells. sCD4 was chemically coupled by 2 different methods to liposomes containing rhodamine-phosphatidylethanolamine in their membrane as a fluorescent marker. In one method, sCD4 was thiolated with N-succinimidyl acetylthioacetate (SATA) and coupled to liposomes via a maleimide-derivatised phospholipid. In the other method, the oligosaccharides on sCD4 were coupled to a sulfhydryl-derivatised phospholipid, utilizing the bifunctional reagent, 4-(4-N-maleimidophenyl)butyric acid hydrazide (MPBH). The association of the liposomes with HIV-1-infected or uninfected cells was examined by flow cytometry. CD4-coupled liposomes associated specifically to chronically infected H9/HTLV-IIIB cells, but not to uninfected H9 cells. CD4-coupled liposomes also associated specifically with monocytic THP-1 cells chronically infected with HIV-1 (THP-1/HIV-1IIIB). Control liposomes without coupled CD4 did not associate significantly with any of the cells, while free sCD4 could competitively inhibit the association of the CD4-coupled liposomes with the infected cells. The chimeric molecule CD4-immunoadhesin (CD4-IgG) could also be used as a ligand to target liposomes with covalently coupled Protein A (which binds the Fc region of the CD4-IgG) to H9/HTLV-IIIB cells. The CD4-liposomes inhibited the infectivity of HIV-1 in A3.01 cells, and also bound rgp120. Our results suggest that liposomes containing antiviral or cytotoxic agents may be targeted specifically to HIV-infected cells.

CD4 Antigens↗
PubMed1990

Biological properties of a CD4 immunoadhesin.

Molecular fusions of CD4, the receptor for human immunodeficiency virus (HIV), with immunoglobulin (termed CD4 immunoadhesins) possess both the gp120-binding and HIV-blocking properties of recombinant soluble CD4, and certain properties of IgG, notably long plasma half-life and Fc receptor binding. Here we show that a CD4 immunoadhesin can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells, although, unlike natural anti-gp120 antibodies, it does not allow ADCC towards uninfected CD4-expressing cells that have bound soluble gp120 to the CD4 on their surface. In addition, CD4 immunoadhesin, like natural IgG molecules, is efficiently transferred across the placenta of a primate. These observations have implications for the therapeutic application of CD4 immunoadhesins, particularly in the area of perinatal transmission of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1990

CD4 immunoadhesin, but not recombinant soluble CD4, blocks syncytium formation by human immunodeficiency virus type 2-infected lymphoid cells.

Recombinant soluble CD4 (rCD4) has been shown to be an effective inhibitor of human immunodeficiency virus type 1 (HIV-1) and HIV-2 infection of lymphoid cells in vitro. In this report, we characterized the effects of rCD4, the V1V2 fragment of CD4, and the immunoadhesin CD4-immunoglobulin G on syncytium formation between lymphoid cells infected by HIV-1 or HIV-2 and uninfected cells. All three molecules blocked HIV-1-mediated syncytium formation, but only CD4-immunoglobulin G blocked HIV-2-mediated syncytium formation. rCD4 and the V1V2 fragment of CD4 enhanced HIV-2-mediated syncytium formation. These results suggest that the process of cell fusion is significantly different between HIV-1- and HIV-2-infected cells.

CD4 Antigens↗
PubMedDate not supplied

Modification of CD4 immunoadhesin with monomethoxypoly(ethylene glycol) aldehyde via reductive alkylation.

CD4 immunoadhesin (CD4-IgG) is a chimeric glycoprotein molecule comprised of the gp120-binding portion of human CD4 fused to the hinge and Fc portions of human IgG. As a candidate for human therapeutic use, CD4-IgG represents an important advance over soluble CD4, insofar as the systemic clearance in humans of CD4-IgG is significantly slower. In an effort to prolong its in vivo residence time even further, we have modified CD4-IgG chemically by attaching monomethoxypoly(ethylene glycol) (MePEG) moieties to lysine residues via reductive alkylation. We synthesized MePEG aldehyde and investigated reaction conditions for adding a range of MePEG moieties per protein molecule. At neutral pH in the presence of sodium cyanoborohydride, the reaction was sufficiently slow to allow for significant control over the extent of MePEGylation. Addition of 7.7 or 14.4 MePEG moieties to CD4-IgG resulted in an approximately 4- or 5-fold increase, respectively, in the persistence of the protein in rats, as compared with unmodified CD4-IgG. These results suggest that the therapeutic utility of a human receptor IgG chimera can be improved by MePEGylation technology, provided that the modified immunoadhesin retains its biological activity in vivo. Such modification can lead to a significant additional increase in the in vivo residence time of the protein.

Alkylation↗
PubMed1992

CD4 immunoadhesins in anti-HIV therapy: new developments.

CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Prevention of HIV-1 IIIB infection in chimpanzees by CD4 immunoadhesin.

The first step in infection by the human immunodeficiency virus (HIV) is the specific binding of gp120, the envelope glycoprotein of HIV, to its cellular receptor, CD4. To inhibit this interaction, soluble CD4 analogues that compete for gp120 binding and block HIV infection in vitro have been developed. To determine whether these analogues can protect an uninfected individual from challenge with HIV, we used the chimpanzee model system of cell-free HIV infection. Chimpanzees are readily infected with the IIIB strain of HIV-1, becoming viraemic within about 4-6 weeks of challenge, although they do not develop the profound CD4+ T-cell depletion and immunodeficiency characteristic of HIV infection in humans. CD4 immunoadhesin (CD4-IgG), a chimaeric molecule consisting of the N-terminal two immunoglobulin-like regions of CD4 joined to the Fc region of human IgG1, was selected as the CD4 analogue for testing because it has a longer half-life than CD4, contributed by the IgG Fc portion of the molecule. In humans, this difference results in a 25-fold increased concentration of CD4-IgG in the blood compared with recombinant CD4. Here we report that pretreatment with CD4-IgG can prevent the infection of chimpanzees with HIV-1. The need for a preventative agent is particularly acute in perinatal HIV transmission. As recombinant CD4-IgG, like the parent IgG molecule, efficiently crosses the primate placenta, it may be possible to set up an immune state in a fetus before HIV transfer occurs, thus preventing infection.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Enzymatic cleavage of a CD4 immunoadhesin generates crystallizable, biologically active Fd-like fragments.

CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains four extracellular sequences homologous to Ig VL domains. The first of these (V1) is sufficient for binding to HIV; however, the structural basis for this binding has yet to be elucidated. While several models for the structure of Ig-like domains in CD4 have been proposed on the basis of crystal structures of Ig VL domains, direct evidence that CD4 and VL domains fold similarly has not been obtained. To produce individual domains of CD4 for structural studies, we used molecular fusions of such domains with Ig heavy chain (CD4 immunoadhesins), which are very efficiently expressed and secreted in mammalian cells and can be easily isolated in single-step purification with protein A. Since these fusion molecules are antibody-like homodimeric proteins, we investigated the possibility that they might be cleaved enzymatically to produce Fd-like and Fc fragments. We found that cleavage with papain releases an Fd-like fragment containing the V1 and V2 CD4 domains; this fragment fully retains the ability to bind to the HIV-1 envelope glycoprotein gp120 and to block HIV infection in vitro. Moreover, folding of the CD4 domains in the Fd-like fragment and in the parent immunoadhesin is indistinguishable, as indicated by circular dichroism. Spectral analysis of the Fd-like fragment suggests that secondary structure content is identical with that predicted from the known structure of Ig VL domains; this directly supports the hypothesis that the V1 and V2 domains of CD4 fold similarly to Ig VL domains.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Nevirapine synergistically inhibits HIV-1 replication in combination with zidovudine, interferon or CD4 immunoadhesin.

OBJECTIVE: To determine whether synergistic inhibition of HIV-1 replication would result from the in vitro use of nevirapine in combination with zidovudine, interferon (IFN)-alpha 2C, and CD4 immunoadhesin. DESIGN AND METHODS: The non-nucleoside reverse transcriptase inhibitor nevirapine (formerly BI-RG-587) was tested in combination with the other antiretrovial agents. Assays were performed on stimulated peripheral blood lymphocytes infected with HIV-1. Virus replication was assessed by the release of viral p24 antigen into culture supernatants. The median-effect principle was used to assess for synergistic interactions of the combined agents. RESULTS: Zidovudine, IFN-alpha 2C and CD4 immunoadhesin, when used in combination with nevirapine, synergistically inhibited HIV-1 replication in human peripheral blood lymphocytes compared with each agent used alone. Some analyses were also consistent with additive effects, but antagonism was not noted. CONCLUSION: These in vitro findings provide a scientific basis for future trials with similar drug combinations.

Antiviral Agents↗
PubMed2000

Gene transfer of anti-gp41 antibody and CD4 immunoadhesin strongly reduces the HIV-1 load in humanized severe combined immunodeficient mice.

OBJECTIVE: To study the anti-HIV-1 effects of the delivery of anti-gp41 monoclonal antibody (mAb) and soluble CD4 (sCD4) immunoadhesin by genetically modified cells in HIV-1-infected, humanized severe combined immunodeficient (SCID) mice. DESIGN: The complementary DNA of mAb 2F5, an anti-HIV-1 gp41 antibody, and of sCD4-IgG chimeric immunoadhesin were transferred into 3T3 cells using Moloney murine leukaemia virus vectors. The cells were then incorporated into a collagen structure called the neo-organ, which allowed the continuous production of the therapeutic molecules. METHODS: The antiviral effects in vivo of 2F5 or sCD4-IgG or both compounds were evaluated in neo-organ-implanted SCID mice that were grafted with human CD4 CEM T cells and challenged with HIV-1 Lai or MN. RESULTS: In SCID mice implanted with 2F5 neo-organs, antibody plasma levels reached 500-2000 ng/ml. Viral loads after HIV-1 challenge were significantly reduced in neo-organ-implanted HIV-infected mice. Although 29 x 10(7) and 13 x 10(8) HIV-1-RNA copies/ml were detected at 12 days in the controls (mice injected with Lai and MN, respectively) less than 16.5 x 10(3) HIV-1-RNA copies/ml were observed in all implanted mice injected with either Lai or MN. The intracellular viral load was also reduced in CD4 cells recovered from the implanted mice. Comparable antiviral effects were obtained with CD4-IgG neo-organs. CONCLUSION: Our results confirm the anti-HIV properties of 2F5 and sCD4-IgG continuously produced in vivo after ex-vivo gene therapy in SCID mice.

3T3 Cells↗
PubMed1989

Designing CD4 immunoadhesins for AIDS therapy.

A newly-constructed antibody-like molecule containing the gp120-binding domain of the receptor for human immunodeficiency virus blocks HIV-1 infection of T cells and monocytes. Its long plasma half-life, other antibody-like properties, and potential to block all HIV isolates, make it a good candidate for therapeutic use.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera.

Seven diverse primary isolates of human immunodeficiency virus type 1 (HIV-1) were examined and found to be refractory to neutralization by antisera to recombinant gp120 (rgp120) protein from HIV-1 MN. This stands in marked contrast to the sensitivity exhibited by certain laboratory-adapted viruses. To understand the difference between primary and laboratory-adapted viruses, we adapted the primary virus ACH 168.10 to growth in the FDA/H9 cell line. ACH 168.10 was chosen because the V3 region of gp120 closely matches that of MN. After 4 weeks, infection became evident. The virus (168A) replicated in FDA/H9 cells with extensive cytopathic effect but was unchanged in sensitivity to antibody-mediated neutralization. Thus, growth in cell lines is not sufficient to render primary virus sensitive to neutralization. The 168A virus was, however, partially sensitive to CD4 immunoadhesin (CD4-Ig). Adaptation was continued to produce a persistently infected FDA/H9 culture that displayed minimal cytopathic effect. The virus (168C) was now sensitive to neutralization by MN rgp120 vaccine sera and by MN-specific monoclonal antibodies and showed increased sensitivity to HIVIG and CD4-Ig. 168C encoded three amino acid changes in gp120, including one within the V3 loop (I-166-->R, I-282-->N, G-318-->R). MN-specific monoclonal antibodies bound equally to the surface of cells infected with either neutralization-resistant or -sensitive virus. The coincidence of changes in neutralization sensitivity with changes in cell tropism and cytopathic effect suggests a common underlying mechanism(s) acting through the whole of the envelope protein complex.

AIDS Vaccines↗
PubMed1994

Evaluation of monoclonal antibodies to HIV-1 envelope by neutralization and binding assays: an international collaboration.

OBJECTIVE: To characterize a purified panel of monoclonal antibodies (MAb) to epitopes in HIV-1 envelope V3, CD4-binding region, C4 and gp41. DESIGN: Neutralization and/or binding activity data were obtained from 21 laboratories on a coded panel consisting of seven human MAb, seven mouse MAb, recombinant human CD4 immunoadhesin [CD4-immunoglobulin G (IgG)], normal human and normal murine Ig. METHODS: Laboratories performed a variety of neutralization assays and antigen binding assays with HIVIIIB, HIVMN and other laboratory strains of HIV-1. RESULTS: For a single MAb, there was up to a 10(3) range of neutralizing antibody titers between laboratories. The range in titers appeared to depend on the sensitivity of the neutralization assay. Two methods were used to consolidate the data from all laboratories, the geometric mean titer (GMT) and the median neutralizing titer (MNT). The panel of MAb were also analyzed by a variety of assays that measure binding activity to native or denatured epitopes. The relative binding activity of the MAb did not appear to correlate with neutralizing activity. CONCLUSION: Neutralization results from any single laboratory did not correlate with the collective data. The relative potency (rank order) of the MAb in the panel were equivalent when determined by GMT or MNT. These values may be useful to individual laboratories for estimating the sensitivity of their neutralization assays. The study also identified potential reference reagents with which neutralizing activity could be compared.

Amino Acid Sequence↗
PubMed1993

[HIV].

In Japan, recently, an increasing number of heterosexual contacts have resulted in HIV infection and warns of an explosive outbreak in a few years. Both the United States and Thailand experienced such explosive outbreaks in the past, through contacts with a large number of intravenous drug users. As the results of a survey in Japan showed a low HIV positive rate among intravenous drug users, an explosive outbreak might be avoided in the future. Since recognition of AIDS in 1981, many valuable new observations have been made. HIV can infect a variety of human cells lacking the CD4 molecule, such as liver cells and some nerve cells. Some human T cells show differential susceptibility despite high expression of the CD4 molecule. Biological properties such as high replication and syncytium inducing isolates are associated with a decrease in CD4 cells. The precursor frequency of HIV-1 expressing cells was about 1/1000 and that of HIV-1 DNA was at least 1/100 CD4 cells in AIDS patients. Soluble CD4 analog binds up gp120 with an affinity and specificity comparable to intact CD4 and is capable of neutralizing the infectiousness of HIV-1. The resistance of HIV-1 to soluble CD4 neutralization is largely determined by the sequence of the V3 loop in gp120. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant gp120 and prevention of HIV infection by CD4 immunoadhesin were confirmed. Unexplained CD4 T-lymphocyte depletion without evidence of HIV infection has been noted since 1989 and epidemiologic and laboratory investigations are in progress.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Location of CD4 dimerization site explains critical role of CDR3-like region in HIV-1 infection and T-cell activation and implies a model for complex of coreceptor-MHC.

CD4 cross-linking by antibodies or its natural ligands triggers a tyrosine kinase activity that is one of the necessary steps in the mechanism of human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and full Th-cell activation. In this study we mapped a part of the dimerization site of human CD4 to amino acids 87-98 using a bivalent CD4 immunoadhesin and a series of overlapping 12-mer peptides of the D1 domain. The dimerization site we found is part of the complementary determining region (CDR) 3-like region of CD4. Using the three-dimensional structure of other immunoglobulin dimers as a basis, a molecular modeling study was performed to dimerize the D1 domains of CD4. Both the peptide binding studies and molecular modeling studies independently led to the conclusion that the CDR3-like region is part of the CD4 dimerization site. The suggested dimerization of CD4 through its CDR3-like region explains the important role that has been ascribed to this region in Th-cell activation and HIV-1-mediated fusion. Based on this model of the CD4 dimer and published results of different mutational analysis studies, a model was proposed for the complex of the CD4 dimer with two MHC-II molecules. The CD4 dimer allows tight binding to a large surface of MHC-II and the complex of CD4 and MHC-II reconciles mutational analysis studies that were previously incompatible. Moreover, the complex suggests how CD4 can dimerize through ligand binding.

Amino Acid Sequence↗
PubMed1995

Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex.

To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

AIDS-Related Complex↗
PubMed2000

Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL.

OBJECTIVE: We sought to describe rates of and risk factors for complications by delivery mode among human immunodeficiency virus-infected women with CD4 counts of < or = 500/microL. STUDY DESIGN: Complication rates were calculated by delivery mode, as follows: planned cesarean delivery performed without labor or rupture of membranes, other cesarean delivery performed after labor or rupture of membranes, or vaginal delivery. Risk factors were evaluated. RESULTS: Major complications in the planned cesarean delivery (n = 37), other cesarean delivery (n = 95), and vaginal delivery (n = 365) groups were amnionitis or endometritis (16%, 27%, and 7%, respectively), wound infection (5%, 8%, and <1%, respectively), and transfusion (8%, 6%, and 3%, respectively). Any peripartum infection occurred among 16 (18%) of those with a CD4 count of <200/microL and 43 (13%) with a CD4 count of > or =200/microL (P =.17). On multivariate analyses, factors associated with amnionitis-endometritis were cesarean delivery and African American race, and a factor associated with transfusion was third-trimester anemia. CONCLUSION: Endometritis and wound infection occurred more frequently among human immunodeficiency virus-infected women after cesarean than among women undergoing vaginal delivery; however, complication rates overall were within the range reported in human immunodeficiency virus-negative women. Measures to decrease complications in human immunodeficiency virus-infected women, such as greater use of prophylactic antibiotics, should be assessed.

Adult↗