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W M Bogers

Publications and source records attributed to W M Bogers.

At least 19 recordsLinked to original sources
PubMed2001

Protection from secondary human immunodeficiency virus type 1 infection in chimpanzees suggests the importance of antigenic boosting and a possible role for cytotoxic T cells.

Recent evidence suggests a much higher prevalence of human immunodeficiency virus type 1 (HIV-1) recombinants than previously anticipated. These recombinants arise from secondary HIV infections in individuals already infected with the virus. It remains unclear why some individuals acquire secondary HIV-1 infections and others do not. To address this question, a study was undertaken of a small cohort of chimpanzees with well-defined HIV-1 infection. After exposure to an infectious dose of heterologous primary isolate, 4 of 8 HIV-1 seropositive chimpanzees resisted secondary infection, whereas 2 naive controls became readily infected. Only animals who were immunologically boosted were protected. Protection from heterologous secondary exposure appeared to be related to the repertoire of the cytolytic CD8(+) T cell responses to HIV-1. Data suggested that immunologic boosting by HIV-1 antigens or exposure to subinfectious doses of virus may be important events in sustaining sufficient immunity to prevent secondary infections from occurring.

AIDS Vaccines↗
PubMed2000

Antiretroviral therapy during primary immunodeficiency virus infection can induce persistent suppression of virus load and protection from heterologous challenge in rhesus macaques.

A limited period of chemotherapy during primary immunodeficiency virus infection might provide a long-term clinical benefit even if treatment is initiated at a time point when virus is already detectable in plasma. To evaluate this strategy, we infected rhesus macaques with the pathogenic simian/human immunodeficiency virus RT-SHIV and treated them with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for 8 weeks starting 7 or 14 days postinfection. PMPA treatment suppressed viral replication efficiently in all of the monkeys. After chemotherapy ended, virus replication rebounded and viral RNA in plasma reached levels comparable to that of the controls in four of the six monkeys. However, in the other two animals, virus loads peaked only moderately after withdrawal of the drug and then declined to low or even undetectable levels. These low levels of viremia remained stable for at least 31 weeks after cessation of therapy. At this time point, these two monkeys were challenged with SIV(8980) to evaluate whether the host responses which were able to keep RT-SHIV replication under control were also sufficient to protect against infection with a highly pathogenic heterologous virus. Both monkeys proved to be protected against the heterologous virus. In one of the two animals, low levels of SIV(8980) replication were detected. Thus, by chemotherapy during the acute phase of pathogenic virus replication, we could achieve not only persistent virus load suppression in two out of six monkeys but also protection from subsequent heterologous challenge. By this chemotherapeutic attenuation, the replication kinetics of attenuated viruses could be mimicked and a vaccination effect similar to that induced by live attenuated simian immunodeficiency virus vaccines was achieved.

Adenine↗
PubMed2000

Evidence for viral virulence as a predominant factor limiting human immunodeficiency virus vaccine efficacy.

Current strategies in human immunodeficiency virus type 1 (HIV-1) vaccine development are often based on the production of different vaccine antigens according to particular genetic clades of HIV-1 variants. To determine if virus virulence or genetic distance had a greater impact on HIV-1 vaccine efficacy, we designed a series of heterologous chimeric simian/human immunodeficiency virus (SHIV) challenge experiments in HIV-1 subunit-vaccinated rhesus macaques. Of a total of 22 animals, 10 nonimmunized animals served as controls; the remainder were vaccinated with the CCR5 binding envelope of HIV-1(W6.1D). In the first study, heterologous challenge included two nonpathogenic SHIV chimeras encoding the envelopes of the divergent clade B HIV-1(han2) and HIV-1(sf13) strains. In the second study, all immunized animals were rechallenged with SHIV(89. 6p), a virus closely related to the vaccine strain but highly virulent. Protection from either of the divergent SHIV(sf13) or SHIV(han2) challenges was demonstrated in the majority of the vaccinated animals. In contrast, upon challenge with the more related but virulent SHIV(89.6p), protection was achieved in only one of the previously protected vaccinees. A secondary but beneficial effect of immunization on virus load and CD4(+) T-cell counts was observed despite failure to protect from infection. In addition to revealing different levels of protective immunity, these results suggest the importance of developing vaccine strategies capable of protecting from particularly virulent variants of HIV-1.

AIDS Vaccines↗
PubMed1999

Induction of inhibitory antibodies to the CCR5 chemokine receptor and their complementary role in preventing SIV infection in macaques.

The seven-transmembrane G-protein-linked CCR5 molecule functions as a major coreceptor for HIV or simian immunodeficiency virus (SIV) infection. Antibodies to CCR5 were studied in rhesus macaques immunized with SIV grown in human CD4(+) T cells. These macaques were completely protected against i.v. challenge with live SIV. Sera from the protected macaques showed significantly greater inhibition of SIV replication (p < 0.001) and macrophage inflammatory protein-1beta-generated CCR5-dependent chemotaxis (p < 0.01) than sera from unprotected macaques, in the absence of significant neutralizing antibodies to SIV. These two functional assays demonstrate serum antibodies to the CCR5 receptors which were specifically inhibited by CCR5-transfected HEK-293 cells. We postulate that anti-CCR5 antibodies may be complementary to beta-chemokines in blocking CCR5 coreceptors to HIV or SIV binding and fusion of CD4(+) cells.

Animals↗
PubMed1998

beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques.

One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian/HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inflammatory proteins 1alpha and 1beta produced by circulating CD8(+) T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with beta-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.

AIDS Vaccines↗
PubMed1998

Generation of CD8 suppressor factor and beta chemokines, induced by xenogeneic immunization, in the prevention of simian immunodeficiency virus infection in macaques.

Previous xenogeneic immunization experiments in rhesus macaques with simian immunodeficiency virus (SIV) grown in human CD4(+) T cells consistently elicited protection from challenge with live SIV. However, the mechanism of protection has not been established. We present evidence that xenogeneic immunization induced significant CD8 suppressor factor, RANTES (regulated upon activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP) 1alpha, and MIP-1beta (P < 0.001 - P < 0.02). The concentrations of these increased significantly in protected as compared with infected macaques (P < 0.001). Xenogeneic stimulation in vitro also up-regulated CD8 suppressor factors (SF; P < 0.001) and the beta chemokines which were neutralized by antibodies to the 3 beta chemokines. Recombinant human RANTES, MIP-1alpha and MIP-1beta which bind to simian CCR5, suppressed SIV replication in a dose-dependent manner, with RANTES being more effective than the other two chemokines. The results suggest that immunization with SIV grown in human CD4(+) T cells induces CD8-suppressor factor, RANTES, MIP-1alpha and MIP-1beta which may block CCR5 receptors and prevent the virus from binding and fusion to CD4(+) cells.

Animals↗
PubMed1998

A clinically relevant HIV-1 subunit vaccine protects rhesus macaques from in vivo passaged simian-human immunodeficiency virus infection.

OBJECTIVES: To investigate whether immunization with recombinant HIV-1 envelope protein derived from a clinical isolate could protect macaques from infection with an in vivo passaged chimeric simian-human immunodeficiency virus (SHIV). DESIGN AND METHODS: A total of 16 animals were studied from which three groups of four animals were immunized with vaccine formulations of the CC-chemokine receptor-5-binding recombinant gp120 of HIV-1W6.1D. Four weeks after the last immunization, all 16 animals were intravenously challenged with in vivo passaged SHIV derived from the same HIV-1 group B clinical isolate (W6.1D) as the vaccines. RESULTS: Vaccine protection from infection was demonstrated in 10 out of 12 macaques immunized with recombinant gp120. Complete protection from infection was achieved with all of the animals that received the SBAS2-W6.1D formulation, a potent inducer of both T-cell and humoral immune responses. Partial protection was achieved with SBAS1-W6.1D, a formulation based on immunomodulators known to induce T-cell responses in humans. In vaccinated animals that were infected, virus load was reduced and infection was delayed. CONCLUSIONS: In a relatively large number of primates, vaccine efficacy was demonstrated with a clinically relevant HIV-1 vaccine. These results reveal that it is possible to induce sterilizing immunity sufficient to protect from infection with SHIV which was passaged multiple times in vivo. Our findings have implications for current HIV-1 clinical vaccine trials and ongoing efforts to develop safe prophylactic AIDS vaccines.

AIDS Vaccines↗
PubMed1998

Characteristics of primary infection of a European human immunodeficiency virus type 1 clade B isolate in chimpanzees.

The aim of the study was to select, from a panel of candidate European human immunodeficiency virus type 1 (HIV-1) clade B primary virus isolates, one isolate based on replication properties in chimpanzee peripheral blood mononuclear cells (PBMC). Secondly, to evaluate the in vivo kinetics of primary infection of the selected isolate at two different doses in two mature, outbred chimpanzees (Pan troglodytes). Four different low passage, human PBMC-cultured 'primary' HIV-1 isolates with European clade B consensus sequence were compared for their ability to replicate in vitro in chimpanzee versus human PBMC. The isolate which yielded the highest titre and most vigorous cytopathic effect in chimpanzee PBMC was evaluated for coreceptor usage and chosen for evaluation in vivo. Only the HIV-1Han2 isolate replicated in chimpanzee PBMC in vitro at detectable levels. This isolate was demonstrated to utilize CCR4, CCR5 and CXCR4 coreceptors and could be inhibited by beta-chemokines. Infection of chimpanzees was demonstrated by viral RNA and DNA PCR analysis, both in plasma as well as in PBMC and lymph node cells as early as 3 weeks after inoculation. Antibodies developed within 6 weeks and continued to increase to a maximum titre of approximately 12800, thereafter remaining in this range over the follow-up period of 2 years. Compared to cell line-adapted HIV-1 isolates there were slight but no dramatic differences in the kinetics of infection of chimpanzees with this particular primary isolate.

Animals↗
PubMed1997

Comparison of in vitro and in vivo infectivity of different clade B HIV-1 envelope chimeric simian/human immunodeficiency viruses in Macaca mulatta.

The use of HIV-1 env/SIVmac chimeric viruses expressing divergent HIV-1 envelopes of clinical isolates, facilitates homologous and heterologous evaluation of various recombinant HIV-1 envelope vaccine candidates in lower primates. In this study we compare the in vitro and in vivo infectivity, via intravenous (IV) and intravaginal (IVAG) routes of infection, of stocks of chimeric viruses expressing env from four different clade B HIV-1 isolates. The TCID50/ml was 7.1 x 10(4), 1.0 x 10(4), 6.3 x 10(4), and 1.2 x 10(3) for SHIVsf13, SHIVHan2, SHIVNM-3rn, and SHIVW6.1D, respectively, with a MID50/ml upon IV inoculation of 3.2 x 10(3), 3.2 x 10(4), 3.2 x 10(4), and 3.2 x 10(3), respectively. The same SHIVsf13 stock was infectious after IVAG administration, requiring a 300-fold higher virus dose. Plasma antigenemia and cell-associated viremia were generally highest at weeks 2 or 4 after infection and decreased to subdetectable levels after 8-12 weeks. All infected animals tested developed anti-HIV-1 gp120 antibodies. Inoculated virus dose showed no (linear) quantitative correlation with cellular virus load, duration of viremia, plasma antigenemia, and anti-gp120 antibody titers. No significant changes in peripheral blood CD4 cell levels were observed and none of the animals has shown evidence of disease progression to date (i.e., 13 months postinfection). Four in vivo passages of cell-associated SHIVW6.1D did not result in increased virulence. Vaccine development studies in macaques monkeys have become feasible with the use of various clade B HIV-1 env SHIV chimeras.

Animals↗
PubMed1997

A recombinant prime, peptide boost vaccination strategy can focus the immune response on to more than one epitope even though these may not be immunodominant in the complex immunogen.

Rhesus monkeys were successfully vaccinated using a strategy of priming with a candidate envelope subunit vaccine and boosting with synthetic peptides. Priming was carried out with recombinant HIV-1 SF2 envelope glycoprotein incorporated into ISCOMs, following the attachment of a lipid tail. Peptides, covalently linked to ISCOMs, representing linear sequences with the V2 and V3 regions, were used to boost functional antibodies-to neutralizing epitopes in both of these regions. Injections with these peptide formulations substantially increased the titre of serum neutralizing antibodies from low or undetectable levels. In addition to completely neutralizing the homologous HIV-1 SF2 strain, these sera also neutralized the escape variant, HIV-1 SF13. However, no antibodies were boosted which could compete with human, neutralizing monoclonal antibodies recognising conformational epitopes. The peptides also boosted antibodies to a peptide whose sequence lies close to the V2 region neutralizing epitope but does not overlap with it. Importantly, the level of antibodies to an unrelated epitope associated with enhancement of HIV-1 SF13 continued to fall after the peptide boost. Successful protection against challenge with chimeric simian immunodeficiency virus expressing HIV-1 SF13 envelope glycoproteins (SHIV SF13) may be due to an increase in the ratio of neutralizing to enhancing antibodies by selectively boosting with peptides to critical neutralizing epitopes.

AIDS Vaccines↗
PubMed1997

CD8+ cell-mediated immune responses: relation to disease resistance and susceptibility in lentivirus-infected primates.

Immune responses mediated by CD8+ lymphocytes have been correlated with protection from HIV infection and disease progression in humans and nonhuman primates. The CD8+ cell population is heterogeneous in terms of biological function and phenotype. We have undertaken a review of the current state of knowledge of subtypes of CD8+ cells and their role in immune responses directed to HIV and related primate lentiviruses. Differences in the pathogenesis of lentivirus infections in various primate hosts were examined and the possible roles of the various subpopulations of CD8+ lymphocytes in the resistance and/or susceptibility to lentivirus-related disease were compared.

Animals↗
PubMed1995

The involvement of Kupffer cells and liver endothelial cells in the clearance of large sized soluble IgA aggregates in rats.

These findings suggests that AIgA is bound both by KC and EC in normal situations. Because of the great phagocytic capacity of KC, the contribution of EC in handling AIgA in normal rats is minimal. However, when KC are defect or absent (as after Cl2MDP treatment), the handling of AIgA by EC may become of mayor importance, i.e. it will take over the phagocytic function of KC. Studies concerning a possible receptor on EC involved in binding of AIgA are in progress.

Animals↗
PubMed1995

Protection from HIV-1 envelope-bearing chimeric simian immunodeficiency virus (SHIV) in rhesus macaques infected with attenuated SIV: consequences of challenge.

OBJECTIVES: To determine whether prior infection with simian immunodeficiency virus (SIV)BK28 protects macaques from subsequent exposure to an HIV-1 envelope chimeric SIV (SHIV). Also, to determine the consequences of viral challenge on CD4 numbers and virus load on the current SIV infection. DESIGN AND METHODS: A total of 12 mature outbred Macacca mulatta were studied. Four naive controls and four previously infected with attenuated SIVBK28 were challenged with SHIV; four naive controls were not infected with SHIV. Sampling occurred twice monthly, and monthly thereafter. Changes in virus load, CD4 and CD8 populations were monitored. Highly sensitive and specific discriminative polymerase chain reaction (PCR) assays were used to distinguish between virus populations. RESULTS: SHIV readily infected challenged control animals, which developed a peak in virus load and a decline in CD4+ cell numbers. In controls, viral load declined and CD4 cell numbers rose to near normal levels after seroconversion. In contrast, in SIV-infected animals there was only a minor increase in viral load in only two out of four animals, 100-1000-fold lower than in naive animals. Interestingly, a decline in CD4 cells occurred in all four SIV-infected animals after SHIV challenge, which appeared more pronounced than in animals infected by SHIV alone. One SIV-infected animal which had low CD4 cell numbers at the time of SHIV challenge, developed a further decline in CD4 cells with a rising viral load. Discriminative PCR did not reveal SHIV in the challenged SIV animals. Interestingly the increase in viral load was due to SIV and not SHIV. CONCLUSIONS: Broad protection of animals previously infected with live attenuated SIV was demonstrated with protection from subsequent infection with HIV-1 envelope-bearing chimeric SIV. Subsequent exposure in cases with low CD4 cell numbers reveal the possibility of activation of the vaccine strain with the possible risk of inducing disease progression.

Amino Acid Sequence↗
PubMed1994

Rat interleukin-2 immunoglobulin M fusion proteins are cytotoxic in vitro for cells expressing the IL-2 receptor and can abolish cell-mediated immunity in vivo.

A hybrid cDNA coding for a fusion protein between rat interleukin 2 (IL-2) and a truncated heavy chain from rat immunoglobulin M (IgM) was constructed. The rat IL-2 and rat IgM CH2-3-4 hybrid gene was subcloned into a vector (PKCR6) for expression of the fusion molecule in Chinese hamster ovary (CHO) cells. Cells transfected with the hybrid cDNA secrete multimeric forms of the fusion protein (IL-2-Mu). Size analysis of the construct revealed that the majority (95%) of the secreted proteins have a high mw (> 500 kDa). The IL-2-Mu construct bind specifically to cells bearing the IL-2 receptors (IL-2R) with a binding affinity around 5 nM. The specific binding to IL-2R leads to T cell proliferation or, if rabbit complement is added, to T cell lysis. Multimeric forms (> 500 kDa) of the fusion protein mediate complement-dependent lysis but trigger only weak proliferation when compared with the low-mw forms (< 500 kDa). In contrast, the latter only efficiently mediate T cell proliferation without inducing complement-dependent lysis. After intravenous administration of CHO supernatant containing IL-2-Mu, or purified IL-2-Mu proteins into rats, the fusion proteins disappeared from the circulation with a t1/2 of 1 hr. The circulating IL-2-Mu constructs in the rat serum retained their capacity to induce complement-dependent lysis of IL-2R-bearing T cells in vitro. Furthermore, the IL-2-Mu construct was able to suppress the delayed-type hypersensitivity (DTH) reaction (an IL-2R, T helper cell-dependent event) in mice. A weak immune response (antirat IL-2-Mu antibodies) was observed when rats received multiple daily injections of the construct.

Animals↗
PubMed1993

Complement enhances the elimination of soluble aggregates of IgG by rat liver endothelial cells in vivo.

In the present study, we have investigated the role of complement (C) and possible C receptors present on rat liver endothelial cells (EC) in the clearance and tissue distribution of soluble aggregates of IgG (AIgG). To study the effect of elimination of AIgG by EC in vivo, Kupffer cell (KC)-depleted rats were used, with or without an intact C system (These rats will be referred to throughout this report as EC-rats.) In EC-rats with an intact C system, clearance of AIgG (2000-3000 kDa, 20-27 IgG molecules/aggregate) occurred in a biphasic manner with a first T 1/2 (T1) of 9.4 +/- 2.3 min and a second T 1/2 (T2) of 44.7 +/- 16.0 min. In EC-rats without an intact C system [cobra venom factor (COVF)-treated group], clearance of AIgG was significantly delayed with a T1 of 25.3 +/- 9.9 min (p < 0.005) and a T2 of 124.5 +/- 18.4 min (p < 0.001). There were less degradation products of AIgG in the circulation in EC-rats treated with COVF as compared to EC-rats with an intact C system. Eight minutes after injection, 27.5 +/- 11.6% of the injected AIgG was found in the livers of EC-rats while 15.1 +/- 3.2% was found in the livers of the COVF-treated group. Double immunofluorescence studies indicated that AIgG in the liver was associated with EC in the rats with an intact C system. Clear deposits of C3 and lesser amounts of C1q accompanied the deposition of AIgG. In COVF-treated EC-rats, AIgG together with C1q was also associated with EC but no detectable C3 was seen. These data suggest clearance of AIgG via Fc and C receptors present on EC in vivo.

Animals↗
PubMed1993

Role of liver endothelial and Kupffer cells in clearance of human C1q in rats.

In the present study the contribution of rat liver endothelial cells (EC) and Kupffer cells (KC) in the clearance of human (hu) C1q in rats was investigated. In untreated rats and rats depleted from KC the clearance kinetics and the tissue distribution of hu C1q were measured. In untreated rats, the clearance of hu C1q occurred in a monophasic manner with a half-life of 66 +/- 26.7 min. The clearance of hu C1q in KC-depleted rats was delayed significantly (p < 0.001) and occurred with a half-life of 217 +/- 78.8 min. Fifteen min after injection, 11 +/- 3.5% of hu C1q was found in the liver of untreated rats and 8 +/- 1.4% was found in the liver of KC-depleted rats. The percentage non-trichloroacetic acid precipitable activity in the circulation, as a measure for degradation of C1q, reached a level of 11.6 +/- 5.6% at 240 min in untreated rats compared with 4.6 +/- 5.8% in KC-depleted rats. Double immunofluorescence staining 5 min after administration of C1q in untreated rats, revealed that C1q was associated with KC and EC in the liver. Fifteen minutes after i.v. injection of hu C1q, there was an uptake of C1q in the hepatocytes. In KC-depleted rats, 5 min after administration of hu C1q, C1q was bound to the EC. Fifteen minutes after injection, C1q was also found in the hepatocytes. Electron microscopical studies revealed that C1q binds to EC, and that it is internalized in the hepatocytes and KC. The clearance of hu C1q in untreated rats was inhibited by preadministration of high concentrations of bovine C1q. These data show that rats depleted from KC are able to bind, internalize and degrade C1q, and that EC may play a role in the handling of C1q and C1q bound to immune complexes.

Animals↗