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Biomedical subjects

G Voss

Publications and source records attributed to G Voss.

At least 37 records · Page 2Linked to original sources
PubMed1999

Use of major histocompatibility complex class I/peptide/beta2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys.

To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8(+) CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8(+) CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/beta2m complexes. All SHIV-infected Mamu-A*01(+) rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8(+) CTL response is dominant and the p41A- and p68A-specific CD8(+) CTL responses are nondominant. These results indicate that CD8(+) CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8(+) CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach.

Amino Acid Sequence↗
PubMed1999

A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia.

RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.

Adolescent↗
PubMed1999

Virtual cutting of anatomical structures.

In the context of medicine cutting is one of the most important operations. Many surgical tasks start with an incision, allowing the surgeon to access the region of interest, using either conventional or minimal invasive surgery techniques. The work presented herein should be seen in the context of surgical training and preoperative planning using computer assisted medical simulation systems. The main result of this work is the proposed cutting algorithm based on predefined templates. To integrate this approach in the existing surgical training simulator and to handle additional tasks like soft tissue deformation, needed by the medical environment, a generic simulation framework was developed. This framework is able to utilize given multiprocessor- and network-environments to achieve the desired realtime interactivity.

Algorithms↗
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

Administration of recombinant human interleukin 12 to chronically SIVmac-infected rhesus monkeys.

With the demonstration that interleukin 12 can enhance natural killer (NK) cell activity and drive CD4+ lymphocytes toward T helper type 1 (Thl) responses, there is a strong rationale for exploring the use of this cytokine as an immunomodulatory therapy in HIV-1-infected individuals. To assess its potential safety and effects on both immune and virologic aspects of HIV-1 infection, recombinant human IL-12 (rhIL-12) was assessed in rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques (SIVmac). The activity of rhIL-12 on rhesus monkey lymphocytes was confirmed with the demonstration that peripheral blood lymphocyte lysis of the NK-sensitive cell line Colo was enhanced by this recombinant cytokine. Further, rhIL-12 was shown to induce interferon-gamma production by rhesus monkey lymphocytes in vitro. Then, in separate studies, two treatment regimens of rhIL-12 were assessed in SIVmac-infected monkeys: a low-dose regimen (0.1 microg/kg, daily for 4 weeks) and a high-dose regimen (2.5 microg/kg, every 3-4 days, for 3 weeks). Both rhIL-12 treatment regimens were well tolerated by these virus-infected animals. The high-dose regimen of rhIL-12 induced transient decreases in circulating lymphocytes in the SIVmac-infected monkeys. Furthermore, no changes in lymphocyte-associated SIVmac DNA or SIVmac plasma RNA levels were seen in the treated monkeys. These studies indicate that short-term treatment with rhIL-12 is well tolerated and causes no measurable changes in virus load in chronically SIVmac-infected rhesus monkeys.

Animals↗
PubMed1996

Simian immunodeficiency virus (SIV) gp130 oligomers protect rhesus macaques (Macaca mulatta) against the infection with SIVmac32H grown on T-cells or derived ex vivo.

The efficacy of three SIVmac32H gp130 vaccines was compared in rhesus monkeys. Three rhesus monkeys were each immunized over a period of 20 weeks with a total of 600 microgram virion-derived gp130 oligomers (O-gp130) mixed with keyhole limpet hemocyanin and emulsified with incomplete Freund's adjuvant. Three other monkeys were infected with 5 x 10(8) PFU of vaccinia virus wild type (VV-wt) while three additional animals received an equivalent dose of VV expressing the gp130 of SIVmac (VV-gp130). At Week 8, the two VV-wt animals received an additional immunization with 100 microgram O-gp130 each. All VV-infected animals then received booster immunizations at Weeks 12, 16, and 20 with a total of 300 microgram O-gp130 per animal. All animals along with two controls were challenged iv with 50 MID50 of T-cell-grown SIVmac32H at Week 22. Four weeks after the challenge and thereafter, both controls and one animal from either VV group were infected as demonstrated by polymerase chain reaction (PCR), virus isolation, and antibody response. In contrast, all O-gp130 animals and one animal each from the VV-wt and the VV-gp130 group were completely protected as shown by negative PCR and virus reisolation. One animal of the VV-gp130 group was partially protected, since it remained virus isolation negative but became PCR positive. All protected animals did not develop a secondary antibody response. Six months after the first challenge, the five completely protected animals were reimmunized twice 4 weeks apart with a total of 200 microgram O-gp130 per animal. Two weeks later, all animals were challenged with 5 MID50 of the SIVmac32H/spI prepared from the spleen of an immunized, but unprotected SIV-infected rhesus monkey. After the second challenge, all three control animals and one of the vaccinees become productively infected. In contrast, two animals were completely protected, one from the former O-gp130 and one from the former VV-gp130 group. One animal from the former VV-wt group was only DNA-PCR positive and thus partially protected. Therefore, immunization with virion-derived gp130 oligomers of SIVmac32H can confer protection against the infection with T-cell-grown SIVmac32H as well as the ex vivo isolate SIVmac32H/spI.

Animals↗
PubMed1996

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile.

One of the major questions in AIDS is the role that the host immune system and the virus play in the dynamics of infection and the development of AIDS in an infected individual. In order to test the role of antibody in controlling viral infection, high-dose SIV-immune globulin was passively transferred to infected macaques early in infection. Immune globulin purified from the plasma of an SIV-infected long-term non-progressor macaque (SIVIG) or a pool of normal immune globulin (normal Ig) was infused into SIVsmE660-infected macaques (170 mg/kg) at one and fourteen days post infection. Animals were monitored for SIV-specific antibodies, viremia, plasma antigenemia, and clinical course. All animals were infected by SIV. At 16 months post infection, five macaques in the combined control groups have been euthanized, one as a rapid progressor with debilitating disease at 20 weeks post infection. Four macaques from the comparison groups have signs of AIDS, accompanied by high and increasing levels of virus and p27 antigenemia. One of the ten control animals had a very low virus load in plasma and peripheral blood and lymph node mononuclear cells at all times tested and has remained disease-free. In the SIVIG treatment group, two macaques were euthanized at 18-20 weeks due to AIDS, rapid progressors to disease. Three macaques in the SIVIG group had an initial high level of virus in plasma, peripheral blood mononuclear cells (PBMC), and lymph node mononuclear cells (LNMC), which dropped to baseline at 6 weeks post infection and has remained very low or negative for 16 months, a disease profile which has not been observed in untreated animals in this model to date. These macaques have remained clinically healthy. The sixth treated animal is also healthy, with very low virus burden that is detectable only by nested set polymerase chain reaction (PCR). All SIVIG-treated macaques had no detectable p27 plasma antigenemia for the first 10 weeks of infection, demonstrating that the IgG effectively complexed with the virus. The immunological correlates in the treated animals include development of de novo virus-specific antibodies and/or cytotoxic T cell (CTL), both of which are hallmarks of long term non-progressors. The two SIVIG-treated macaques that progress to disease rapidly had no detectable de novo humoral immune responses, as is often seen in rapid HIV disease in humans. Envelope-specific and virus neutralizing antibodies alone were not sufficient to prevent disease progression, as the plasma of both non-progressors as well as progressors had high titers of envelope-specific and neutralizing antibodies against SIVsmE660. Poor clinical prognosis was associated with moderate to high and increasing virus loads in plasma, PBMC, and lymph nodes. Good clinical prognosis correlated with low or undetectable post acute viremia in the peripheral blood and lymph nodes. We hypothesize that SIVIG reduced the spread of virus by eliminating or reducing plasma virus through immune complexes during the first four to 8 weeks of infection and then maintaining this low level of viremia until the host immune response was capable of virus control. Reduction of virus burden early in infection by passive IgG can alter disease outcome in SIV infection of macaques. Modifications of this strategy may lead to effective early treatment of HIV-1 infection in humans.

Animals↗
PubMed1996

Simian immunodeficiency virus-specific cytotoxic T-lymphocyte induction through DNA vaccination of rhesus monkeys.

In view of the growing evidence that virus-specific cytotoxic T lymphocytes (CTL) play an important role in containing the early spread of human immunodeficiency virus type 1 (HIV-1) in infected individuals, novel vaccine strategies capable of eliciting HIV-1-specific CTL are being pursued in attempts to create an effective AIDS vaccine. We have used the simian immunodeficiency virus of macaques (SIVmac)/rhesus monkey model to explore the induction of AIDS virus-specific CTL responses by DNA vaccination. We found that the inoculation of rhesus monkeys with plasmid DNA encoding SIVmac Env and Gag elicited a persisting SIVmac-specific memory CTL response. These CTL were CD8+ and major histocompatibility complex class I restricted. These studies provide evidence for the potential utility of DNA inoculation as an approach to an HIV-1 vaccine.

Animals↗
PubMed1996

Definition of human immunodeficiency virus type 1 gp120 and gp41 cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I alleles in simian-human immunodeficiency virus-infected rhesus monkeys.

With the development of chimeric simian-human immunodeficiency virus (SHIV)-infected macaques as a model for assessing novel human immunodeficiency virus type I (HIV-1) envelope glycoprotein (Env)-based vaccine strategies for preventing HIV-1 infection in man, it will be important to determine HIV-1 Env-specific cytotoxic T-lymphocyte (CTL) responses in vaccinated and virus-infected monkeys. To facilitate performing such CTL studies, we have defined two HIV-1 Env CTL epitopes in SHIV-infected rhesus monkeys and characterized the major histocompatibility complex (MHC) class I alleles that bind these Env peptide fragments and present them to CTL. A 9-amino-acid (aa) fragment of HIV-1 gp4l (p6B, aa 553 to 561) is presented to CD8+ CTLs of SHIV-infected animals by the rhesus monkey HLA-B homolog molecule Mamu-B*12. An 8-aa HIV-1 gpl.20 peptide (p9CD, aa 117 to 124) represents a CTL epitope in rhesus monkeys restricted by the HLA-A homolog MHC allele Mamu-A*08. This gp120 CTL epitope is fully conserved in all simian immunodeficiency virus, HIV-1, and HIV-2 isolates that have been sequenced to date and exhibits functional cross-reactivity. Screening of 14 unselected rhesus monkeys for expression of the two novel MHC class I alleles revealed the presence of each of the alleles in more than 40% of the animals. The characterization of the two HIV-1 Env CTL epitopes and their restricting MHC class I alleles will provide a basis for studying vaccine- and virus-elicited cytotoxic effector cell responses in rhesus monkeys.

Alleles↗
PubMed1996

An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.

To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity.

Animals↗
PubMed1995

Human immunodeficiency virus type 1 envelope glycoprotein-specific cytotoxic T lymphocytes in simian-human immunodeficiency virus-infected rhesus monkeys.

Because of the importance of the envelope glycoprotein (Env) in determining the pathogenicity of HIV-1 and the importance of the immune response to Env in controlling virus spread, attempts are being made to study HIV-1 Env-directed immunity in primate models. To date HIV-1 Env-specific effector T lymphocyte responses have not been demonstrated in virus-infected nonhuman primates. We have previously reported that cynomolgus monkeys can develop a persistent infection with a chimeric simian-human immunodeficiency virus (SHIV) composed of SIVmac239 carrying the HIV-1 env, tat, rev, and vpu genes. We now demonstrate that SHIV-infection of another macaque species, the rhesus monkey, generates persistent, HIV-1 Env-specific cytolytic T lymphocyte (CTL) responses. These CTL are CD8+ and major histocompatibility complex (MHC) class I-restricted. The induction of CTL was correlated neither to the virus load nor to the MHC class I haplotypes of the monkeys. The SHIV-infected rhesus monkey can, therefore, now be employed for studying effector T lymphocyte recognition of HIV-1 Env.

Animals↗
PubMed1994

Early helper T-cell dysfunction in simian immunodeficiency virus but not in human immunodeficiency virus type-2-infected macaques.

Both naive and vaccinated macaques acquired a virus-specific proliferative helper T-cell reactivity in response to infection with the nonpathogenic human immunodeficiency virus type 2 (HIV-2). In contrast, macaques infected with the pathogenic simian immunodeficiency virus of the macaque strain (SIVmac) did not develop a helper T-cell response. Furthermore, a vaccine-induced preexisting T-cell reactivity was abrogated after SIVmac infection in vaccine failures. These differences may reflect the different pathogenicity of the two closely related viruses.

AIDS Vaccines↗
PubMed1994

Comparison of humoral immunity and induction of proliferating T lymphocytes in vaccinia virus-infected rabbits and rhesus macaques.

Vaccina virus (VV) infection induces specific antibodies and cytotoxic T cells in various animal species. Therefore, helper T cells also should be induced that stimulate the humoral and cellular immune responses. We determined such helper T-cell activity in 2 species after VV infection. Rabbits and rhesus macaques were infected with the Copenhagen strain of VV or with recombinant VV expressing retroviral proteins. Animals of both species developed antibodies and specific proliferative T-cell response. This reactivity could be enhanced by booster infection with VV. The proliferating macaque cells were CD4+ and major histocompatibility complex class II-restricted. These data confirm the broad immunogenicity of VV. Expression of additional polypeptides expressed from a recombinant VV does not lead to altered immune response to VV antigens. However, strength of the helper T-cell response, as well as clinical reactions, differed between macaques and rabbits. Infection with recombinant VV as delivery vectors offers the opportunity for combined vaccination against recombinant proteins and does not diminish cellular and humoral immune responses to VV itself.

Animals↗
PubMed1994

Immunization with virion-derived glycoprotein 130 from HIV-2 or SIV protects macaques against challenge virus grown in human or simian cells or prepared ex vivo.

We have compared in the macaque model the efficacy of the virion-derived glycoprotein of HIV-2ben (HIV-2 gp130) with that of SIVmac251/32H (SIV gp130). The latter vaccination trial was in part combined with vaccinia virus (VV) priming. Both antigen preparations induced a strong humoral, but a weak cellular, immune response. The first challenge was performed with autologous virus grown on a human T cell line. More than 50% of the monkeys immunized with HIV-2 gp130 (five of nine) and 63% of the monkeys immunized with SIV gp130 (five of eight) were protected. All such protected animals received one or two booster immunizations before they were rechallenged either with heterologous HIV-2SBL6669 grown on monkey peripheral blood mononuclear cells or with an ex vivo stock of SIVmac251/32H prepared from the spleen of an SIV-infected macaque and not passaged in vitro. Immunization with HIV-2 gp130 did not protect against the second challenge, but one animal showed limited infection as indicated by positive PCR only. Challenge of the SIV gp130-immunized monkeys with the spleen-derived virus led to infection of three animals; remarkably, one of these was only PCR positive. Two animals were completely protected. Thereby we can exclude the influence of cellular proteins on protective immunity. Priming with VV was not superior to immunization with gp130 alone. Neither at the first nor at the second challenge were the virus-specific humoral and cellular immune responses of the vaccinees clearly correlated with protection. However, neutralizing antibodies may have been important in the SIV gp130-immunized animals at first challenge.

AIDS Vaccines↗