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Results for “HIV Core Protein p24”

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PubMed1994

Defective infection of rabbit peripheral blood monocyte cultures with human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) produces abortive infections of primary cultures of rabbit peripheral blood mononuclear cells (PMBCs). Mitogen activation of rabbit PBMCs or the addition of exogenous cytokines to the cultures does not change the level of release of the early HIV core protein, p24, into the culture medium. The amount of p24 increases steadily and reaches peak levels about 7 days after infection. HIV-1-specific DNA env sequences are also detected in infected PBMCs. However, reverse transcription of RNA of samples from activated infected cultures to cDNA, followed by amplification by the polymerase chain reaction, revealed transcription of gag, but not env, regions, suggesting that HIV-1 infection of rabbit PBMC does not lead to the replication and maturation of complete HIV-1 virions. In addition, neither CPE nor lytic infection was observed in HIV-1-infected rabbit cells and infectivity could not be transferred from rabbit cells infected with HIV for up to 2 weeks to MT-2 or H9 indicator cell lines. In addition, no CPE was seen in long-term cultures of the HTLV-I-transformed rabbit cell line PLT-1441, after inoculation with HIV. It is concluded that primary rabbit PBMCs may be infectable by HIV-1 but are not permissive for production of infectious virus. This conclusion is consistent with the apparent long-term latent infection seen after inoculation of rabbits with HIV-1 or HIV-1-infected cells.

Animals↗

PubMed1992

Rectal mucosal pathology varies with human immunodeficiency virus antigen content and disease stage.

Rectal mucosal biopsy specimens from 75 human immunodeficiency virus (HIV)-seropositive and 16 HIV-seronegative subjects were examined. The histopathologic changes were correlated with immunoperoxidase staining for UCHL-1 and HIV core protein p24, quantitative p24 enzyme-linked immunosorbent assay (ELISA) assay in homogenized rectal tissue and serum, and a modified Walter Reed clinical stage. Four phases were seen in the HIV-infected subjects: (1) early phase, in Walter Reed stage 1-2 subjects, with nearly normal histology and low p24; (2) inflammatory phase, typically in Walter Reed stage 3-4 subjects, with a superficial lamina propria infiltrate of lymphocytes, plasma cells, and eosinophils with degranulation, abundant UCHL-1 staining, and maximal p24 by both immunoperoxidase staining and ELISA; (3) transitional phase, in many Walter Reed 5 and some Walter Reed 6 subjects, with normal lymphocyte population density but with subtle inflammatory changes; and (4) lymphoid depletion phase, mainly in Walter Reed stage 6 subjects, with decreased lymphocytes but often with endothelial cell activation and apoptosis. These phases presumably result from effective HIV suppression by a relatively intact immune system, followed by maximal HIV infection and lymphocyte activation, then progressive lymphocyte depletion. The inflammation correlated with the presence and amount of HIV in rectal tissue determined by immunohistochemistry and ELISA and was maximal before overt immunodeficiency developed. Intestinal mucosa could be a preferred site of HIV proliferation and T-cell destruction.

Antibodies, Monoclonal↗

PubMed1998

HIV-1 p24 but not proviral load is increased in the intestinal mucosa compared with the peripheral blood in HIV-infected patients.

OBJECTIVE: To investigate differences in viral and proviral load between the peripheral blood and the intestinal mucosal immune system in HIV-infected patients. DESIGN: HIV-1 p24 and HIV DNA content were compared in blood samples and intestinal biopsies from HIV-infected patients. METHODS: Intestinal biopsies and peripheral blood were simultaneously obtained from 27 HIV-infected patients undergoing diagnostic endoscopy. The p24 concentrations were measured in serum and homogenized intestinal biopsies by enzyme-linked immunosorbent assay after acid-dissociation of immune complexes. Proviral load was determined in blood and intestinal biopsies by a quantitative competitive polymerase chain reaction amplifying the HIV-1 nef gene from genomic DNA. RESULTS: No significant differences were found in proviral load comparing HIV copies per 1.5 x 10(5) cell equivalents in blood [2650 (600-44000)] and intestinal biopsies [4200 (1325-19 625)]. Paired analysis revealed a strong positive correlation between serum and mucosal proviral load. In contrast, HIV core protein p24 was detected in intestinal biopsies from 18 patients in much higher concentrations than in serum [858 (262-4111) pg/g versus 34 (9-242) pg/g; P < 0.005]. The p24 concentrations in serum and intestinal biopsies did not correlate and no significant correlation was observed in serum or intestinal biopsies between proviral load and p24 concentrations. No clear correlations were observed between clinical parameters and HIV DNA or HIV p24 levels in blood or biopsies. CONCLUSIONS: Our findings demonstrate a homogenous distribution of HIV proviral load in the peripheral blood and the intestinal mucosal immune system. The high viral antigen load in the intestine therefore indicates that mucosal HIV production is upregulated at the transcriptional and/or translational level. The intestinal mucosa is a major reservoir for HIV in HIV-infected patients.

Adult↗

PubMed1995

Monoclonal antibodies to p24-core protein of HIV-1 mediate ADCC and inhibit virus spread in vitro.

BACKGROUND: Certain antigens of the HIV-1, e.g., gp120-envelop proteins, can be expressed on the membrane of HIV-infected cells. Little is known about the membrane expression of other HIV-antigens and their interaction with specific antibodies. OBJECTIVE: To develop murine monoclonal antibodies (mAbs) to the p24-core protein of HIV-1 and to characterise their binding sites and biological activities on HIV-infected T cells. METHODS: Monoclonal antibodies were developed from mice hyperimmunised with a recombinant p24-core protein from HIV-1. Two mAbs were epitope-mapped on overlapping peptides and characterised for their reactivity with non-fixed HIV-infected T cells by immunofluorescence staining and flow cytometric analysis. Their biological activities were studied for antibody-dependent cellular cytotoxicity (ADCC) and suppression of viral spread in vitro. RESULTS: The epitopes of two selected mAbs were located on the amino terminal region of p24 in the regions 147-152 aa and 178-187 aa, respectively. The antibodies were able to react with living HIV-1 infected cells. The expression of the antigens was time-dependent after the infection of certain cell lines by HIV-1. The mAbs mediated a strong HIV-1-specific ADCC and were able to delay the spread of HIV-1 for about 6 days in cell cultures. CONCLUSIONS: Certain epitopes of the p24-core protein of HIV-1 can be expressed on living, HIV-infected T cells and are recognised by specific antibodies. Such antibodies can destroy infected cells by ADCC or delay the virus spread, and therefore, should be considered in immunisation strategies against HIV.

Journal Article↗

PubMed1990

Expression and purification of p24, the core protein of HIV, using a baculovirus-insect cell expression system.

The baculovirus Autographa californica nuclear polyhedrosis virus (AcNPV) has been genetically manipulated to yield a recombinant virus capable of expressing p24, the major core protein of HIV-1, in insect cell culture. The expressed product is a p24 protein flanked by short regions of p17 at the amino terminus and p12 at the carboxy terminus. It has been identified and characterized using monoclonal antibodies on Western blots and by amino-terminal sequence analysis. The presence of p24 in the soluble fraction of infected cells following lysis by detergent or sonication, combined with a high level of expression (in excess of 50 mg/l of culture) facilitates the enrichment of large quantities of recombinant HIV antigen in a simple two-step procedure involving ammonium sulphate fractionation and gel filtration. p24 antigen purified in this way is shown to be an efficient diagnostic reagent.

Amino Acid Sequence↗

PubMed1989

Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) antigens and genome in lymph nodes of HIV-positive patients affected by persistent generalized lymphadenopathy (PGL).

The presence of human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) antigens and genome has been investigated in 50 lymph nodes involved by persistent generalized lymphadenopathy (PGL). All the patients were HIV infected and most of them (42 of 50) also had anti-EBV serum antibodies. At lymph node level, HIV and EBV antigens were studied by immunohistochemistry using monoclonal antibodies directed against viral core proteins. The HIV p24 protein was detected in 43 of 50 lymph nodes within the B-cell germinal centers with a reticular pattern. Few cells with positive results for EBV antigens were found in only 2 of 50 lymph nodes. These rare EBV-positive centrocyte-like cells were mainly located in the germinal centers. The presence of HIV and EBV genome was also studied in lymph nodes involved by PGL, with the use of in situ and Southern blot hybridization. A positive reaction for HIV genome was detected in only 1 of 14 lymph nodes with the Southern blot hybridization, and the presence of EBV genome was never demonstrated in these lymph nodes with the use of both in situ and Southern blot hybridization. The expression of EBV antigens and genome was also investigated in the peripheral blood of 15 patients with PGL in which cells with positive results for EBV antigens were detected in a single case with a frequency of 1 X 10(-4). No evidence of EBV genome was found with the use of the in situ hybridization. These results suggest that EBV is not present in lymph nodes during the PGL phase and that its possible implication in the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated lymphoma might be a late event.

Adolescent↗

PubMed1989

IgG subclass responses to a transmembrane protein (gp41) peptide in HIV infection.

The IgG subclass distribution to the E34/E32 peptides, derived from the HIV-1 glycoprotein 41 transmembrane protein, was analyzed in ELISA. Sera from individuals at different stages of the disease were assayed. A restricted subclass response of mainly IgG1 and IgG2 was found. The subclass response was of a different type than the one observed to HIV whole Ag and to a synthetic peptide from the C'-terminal part of the HIV-1 p24 core protein. An increased subclass restriction was observed in progressed stages of the disease.

Amino Acid Sequence↗

PubMed1993

Generation, characterization and cross-reactivities of monoclonal antibodies against the p24 core protein and the gp130 envelope glycoprotein of HIV-2ben.

The purpose of this study was to characterize antigenic determinants on structural polypeptides of human immunodeficiency virus type 2 (HIV-2ben). Therefore, three HIV-2-specific monoclonal antibodies (mAbs) against the p24 core protein (gag) and one mAb against the gp130 envelope glycoprotein (env) were produced. In addition to p24 the anti-core mAbs recognized the primary translation product of the viral gag gene p55 and an intermediate cleavage product p41. Core mAbs cross-reacted with another HIV-2 isolate (HIV-2rod), and several simian immunodeficiency viruses (SIVagm TYO7 and SIVmac), but not with SIVmnd and the HIV-1 isolates investigated (HIV-1han and HIV-1lai). The env mAb cross-reacted with HIV-2rod and SIVmac but not with SIVagm, SIVmnd or HIV-1. In competition assays and with epitope mapping possible binding sites for the mAbs were identified. The processing of HIV-2 core proteins is compared in retrovirus-infected T cell lines and during the expression by recombinant vaccinia virus. Finally, the mAb XIV DC10 which recognized a highly conserved epitope could be useful for an assay to detect HIV-1 and HIV-2 simultaneously. II D8 is the first mAb raised against HIV-2 env glycoprotein.

Amino Acid Sequence↗

PubMed1992

Immunoblotting analysis of IgA and IgM antibody to human immunodeficiency virus type 1 (HIV-1) polypeptides in seropositive infants.

Seventy infants born to human immunodeficiency virus type 1 (HIV-1) seropositive mothers were studied for specific antibody (IgA, IgM and IgG) production and the presence of active infection (detectable level of virus in peripheral blood lymphocytes). Among these children, followed for up to 15-40 months after birth, 11 presented unequivocal signs of HIV-1 infection (persistent p24 antigenemia and/or positive virus isolation). Analysis of sera by immunoblotting showed that IgA antibody to HIV-1 p24 core protein, alone or associated with envelope glycoproteins (gp120, gp41), was present in the majority of infected babies (7 of 11), while IgM was found in a lower percentage of cases (4 of 11). No IgA and or IgM antibody to HIV-1 was ever found in babies, born to seropositive mothers, who seroreverted after birth or in the control group enrolled in this study. Our results indicate that immunoblotting analysis of IgA antibody to HIV-1 polypeptides may represent a useful complementary prognostic marker in children born to HIV-1 seropositive mothers.

Child, Preschool↗

PubMed1989

Interaction of HIV and EBV at lymphoid tissue level: immunohistochemistry and in situ hybridization.

The presence of Epstein-Barr virus antigens and genome was studied in lymph nodes from HIV + patients affected by PGL. Cryostat sections from 50 lymph nodes of HIV + patients were immunostained with EBV-VCA (viral capsid antigen), EBV-EA (early antigen) and p24 HIV major core protein monoclonal antibodies. In situ hybridization was performed using a biotin conjugated EBV DNA probe; the reaction product was demonstrated by immunohistochemical method. As positive controls, EBV producer B95-8 and HIV infected H9 cell lines were used. The majority of patients had circulating EBV antibodies mainly directed against the viral capsid antigen and only in few cases against early antigens. Positivity for HIV p24 protein was detected in 43 out of 50 lymph nodes within the germinal centers with a reticular pattern. Only 2 out of 50 lymph nodes presented very few positive cells for EBV antigens and none expressed detectable EBV genome. Our results suggest that EBV cellular expression does not correlate with serum positivity; furthermore the absence of EBV antigens and genome at tissue level might indicate that EBV is not directly involved in the pathogenesis of PGL.

AIDS-Related Complex↗

PubMed1993

Murine HIV-1 p24 specific T lymphocyte activation by different antigen presenting cells: B lymphocytes from immunized mice present core protein to T cells.

Mice were injected with three doses of baculovirus-produced recombinant HIV-1 p24 core protein in alum adjuvant. CD4 positive T lymphocytes from immunized animals proliferated in vitro in the presence of antigen and peritoneal macrophages (Mps) or splenic dendritic cells (DCs) from non-immunized mice as antigen presenting cells (APCs). DCs were approximately three times more efficient than Mps on a cell for cell basis. No synergy was observed between Mps and DCs in this system. B lymphocytes from immunized animals also presented p24 antigen to the specific T cells. Mps did synergize with B cells to enhance the level of T lymphocyte proliferation. This may have implications for the induction of specific immune responses to pathogens after administration of single protein vaccines.

AIDS Vaccines↗

PubMed1995

AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations.

To evaluate the presence and distribution of central nervous system infection by human immunodeficiency virus type 1 (HIV-1), we used immunohistochemical methods to map the HIV-1 p24 core protein in the brains of 55 autopsied patients with acquired immunodeficiency syndrome (AIDS). In a subset of 40 of these patients who had undergone antemortem neurological evaluation of the AIDS dementia complex (ADC), we analyzed the relation between the severities of the viral infection and clinical dysfunction. Viral antigen was detected in macrophages and cells with morphological and immunohistochemical characteristics of microglia as well as multinucleated cells. The distribution of antigen-positive cells preferentially involved certain deep brain structures, especially the globus pallidus, other basal ganglia nuclei, and the central white matter. Overall, the presence and frequency of infected cells were highly correlated with the histological findings of multinucleated-cell encephalitis and in general with the clinical ADC stage. However, infection was often more limited than might be "anticipated" from the severity of patients' clinical dysfunction: Only 61% of patients with at least ADC stage 1 had detectable antigen and of these only approximately 30% of the brain sections were antigen positive. These results suggest a pathogenetic model of ADC where virus- or cell-coded toxins amplify the effect of limited brain infection.

AIDS Dementia Complex↗

PubMed1991

Perturbation of host-cell membrane is a primary mechanism of HIV cytopathology.

Cytopathic viruses injure cells by a number of different mechanisms. The mechanism by which HIV-1 injures T cells was studied by temporally examining host-cell macromolecular syntheses, stages of the cell cycle, and membrane permeability following acute infection. T cells cytopathically infected at an m.o.i. of 1-5 grew normally for 24-72 hr, depending on the cell line, followed by the first manifestation of cell injury, slowing of cell division. At that time significant amounts of unintegrated HIV DNA and p24 core protein became detectable, and acridine orange flow cytometric cell cycle studies demonstrated the presence of fewer cells in the G2/M stage of the cell cycle. There was no change in the frequency of cells in the S-stage, and metabolic pulsing with radioactive precursors demonstrated that host-cell DNA, RNA, and protein syntheses were normal at that time and normal up to the time cells started to die (approximately 24 hr later), when all three decreased. Cellular lipid synthesis, however, was perturbed when cell multiplication slowed, with phospholipid synthesis reduced and neutral lipid synthesis enhanced. Permeability of the host-cell membrane to small molecules, such as Ca2+ and sucrose, was slightly enhanced early postinfection, and by the time of slowing of cell division, host membrane permeability was greatly increased to both Ca2+ and sucrose (Stokes radius 5.2 A) but not to inulin (Stokes radium 20 A). These changes in host-cell membrane permeability and phospholipid synthesis were not observed in acutely infected H9 cells, which are not susceptible to HIV cytopathology. Thus, HIV-1 appeared to predominantly injure T cells by perturbing host-cell membrane permeability and lipid synthesis, which is similar to the cytopathic mechanisms of paramyxoviruses.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Anti-idiotypic antisera raised against monoclonal antibody specific for a p24 gag region epitope detects a common interspecies idiotype associated with anti-HIV responses.

One potential strategy for the control of human immunodeficiency virus (HIV) infection is immune network manipulation using anti-idiotypic antibodies: this study was undertaken to demonstrate experimentally the potential of such an approach which, in a more highly evolved form, could be used for the treatment of the acquired immune deficiency virus (AIDS) and related disorders. Anti-idiotypic antibodies were generated in rabbits against a murine monoclonal antibody identifying an epitope on the p24 gag core protein of HIV. After extensive absorption on affinity columns to remove isotype- and allotype-specific antibodies, the purified anti-idiotypic antibody preparation was shown to have specific complementarity with the immunizing mouse monoclonal antibody. This anti-idiotypic antibody was also shown to recognize a common idiotype associated with HIV-specific antibodies from both humans and chimpanzees infected with the AIDS virus. In addition a group of rats immunized with the anti-Id responded with significant antibody titers to recombinant derived p24 gag. These data indicate that at least a subpopulation of these polyclonal anti-Id antibodies structurally mimics an HIV gag region epitope and suggest that immunoregulation by anti-idiotypic antibodies may have therapeutic utility for the AIDS epidemic.

Animals↗

PubMed1991

Sensitivity and specificity of anti-HIV ELISA employing recombinant (p24, p66, gp120) and synthetic (gp41) viral antigenic peptides.

We have developed two immunoassay systems, one designated HIV (p24, p66, gp41) ELISA that uses as antigens the immunodominant epitopes mixed from each of three major groups of HIV-1 proteins: the core (p24), the pol (p66) and the env (gp41) gene. The other immunoassay system consists of four separate ELISAs for detection of single antibodies to HIV gag gene (p24), HIV pol gene (p66) and HIV env gene (gp41 and gp120). In the present study 200 specimens from patients with AIDS and 200 specimens from patients with ARC were repeatedly positive by HIV (p24, p66, gp41) ELISA. 1425 specimens from HIV drug addicts positive at W.B. were positive at HIV (p24, gp41, p66) ELISA. In addition, 60 samples that were indeterminate by W.B., were repeatedly positive at HIV (p24, p66, gp41) ELISA. The sensitivity and specificity of HIV (p24, p66, gp41) is estimated to be 100%. In this study 1507 specimens from HIV drug addicts, positive at W.B., were all positive (more than one test positive) at HIV p24 ELISA, HIV gp41 ELISA, HIV p66 ELISA and HIV gp120 ELISA used in combination. 135 samples from HIV positive drug addicts, positive at standard ELISA but indeterminate at W.B., were positive by HIV p24 ELISA, HIV gp41 ELISA, HIV p66 ELISA and HIV gp120 ELISA using the same criteria as in W.B. interpretation. The specificity (defined in terms of percentage of non-reacting persons in a low risk population) of HIV p24 ELISA, HIV gp41 ELISA, HIV p66 ELISA, HIV gp120 ELISA is 100%. In this work we demonstrated that: a) HIV (p24, p66, gp41) ELISA could be used as an adjunct or reliable alternative to standard ELISA for detection or confirmation of HIV antibodies in human sera; b) the specificity and sensitivity of antibodies to p24, p66, gp41, gp120 by ELISA used alone and/or in combination, is equal to or greater than W.B.

AIDS-Related Complex↗

PubMed1990

HIV p24-specific helper T cell clones from immunized primates recognize highly conserved regions of HIV-1.

We have investigated Th cell recognition of the HIV core protein p24 by using CD4+ T cell clones derived from cynomolgus macaques immunized with hybrid HIV p24: Ty virus-like particles (VLP). T cell lines from two immunized animals responded to p24: Ty-VLP, control Ty-VLP, purified p24, and whole inactivated HIV, indicating the presence of T cells specific for p24 as well as the Ty carrier protein. The HIV determinants recognized by the T cell lines were identified by using a series of overlapping peptides synthesized according to the sequence of p24. Both T cell lines recognized peptide 11 (amino acids 235-249) and peptide 14 (amino acids 265-279). In addition, one T cell line also responded to peptide 9 (amino acids 215-229). Definitive identification of two T cell epitopes on p24 was confirmed at the clonal level: from a total of four T cell clones generated from one of the T cell lines, two respond specifically to peptide 11 and two to peptide 14. The T cell clones were CD4+ and MHC class II-restricted and secreted IL-2 in response to stimulation with purified p24, inactivated HIV or a single synthetic peptide. The specificity of the Th clones for variant peptides demonstrated cross-reactivity with two simian immunodeficiency virus isolates, but only limited responses to HIV-2 sequences. However, the Th cell epitopes identified on p24 are highly conserved between 12 HIV-1 isolates and were recognized by both of the immunized primates. These sequences may therefore be useful for priming a broadly reactive immune response to HIV-1.

Amino Acid Sequence↗

PubMed2003

HIV-1 infection in a small animal human vaginal xenograft model.

A limitation in advancing the study of HIV-1 is the lack of a suitable small animal model system that allows for HIV-1 infection to be monitored within human target epithelium. Studies have demonstrated that HIV-1 can infect vaginal mucosa after sexual exposure; however, the primary target cells for HIV-1 in the vagina and interactions between these target cells are not completely defined. A mouse human vaginal xenograft model that recapitulates, histologically and cytochemically, the features of the human vaginal epithelial barrier has been developed in our laboratory. Results of experiments utilizing this system to characterize HIV-1 BaL and IIIB infections within human vaginal xenografts are reported here. HIV-1 RNA, spliced transcripts, and HIV-1 p24 core antigen protein were detected in the xenografts 7 days after infection. This unique system offers a small animal model for studying HIV-1 transmission and replication within the context of natural host tissue and for examining initial events and cell populations involved in the establishment of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Increased PGE2 production mediates the in vitro inhibitory effect of the human immunodeficiency virus P24 immunosuppressive heptapeptide Ch7.

Previous work from our laboratory demonstrated that a synthetic heptapeptide (Ch7), corresponding to a conserved sequence of human immunodeficiency virus (HIV) core protein p24 (amino acids 232-238), was able to specifically abrogate antigen-induced responses in cultures of normal human peripheral blood lymphocytes (PBL). Addition of recombinant human interferon-gamma (IFN-gamma) to Ch7-suppressed cultures restored the capacity to mount an antigen-specific antibody response, suggesting that a cytokine imbalance may be at the basis of the Ch7 immunosuppressive activity. In the present paper we show that the Ch7-dependent in vitro immunosuppression was accompanied by a significant up-regulation of prostaglandin E2 (PGE2) production and induction of interleukin-10 (IL-10)-secreting cells. In the presence of the PGE2 inhibitor indomethacin, IL-10 up-regulation was prevented and the induction of a specific antibody response was partially restored. PGE2 is indeed an important regulator of immune responses with the ability to differentially affect cytokine production. Thus, our results demonstrate that the Ch7 immunosuppressive epitope may primarily act by up-regulating PGE2 production and, through this mediator, by causing a cytokine dysregulation, finally responsible for immune response suppression.

Antibody Formation↗