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1.
AIDS ; 23(12): 1485-94, 2009 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-19528788

RESUMO

BACKGROUND: Preadministration of high-affinity humanized anti-HIV-1 mAb KD-247 by passive transfer provides sterile protection of monkeys from heterologous chimeric simian/human immunodeficiency virus infection. METHODS: Beginning 1 h, 1 day, or 1 week after simian/human immunodeficiency virus-C2/1 challenge (20 50% tissue culture infective dose), mature, male cynomolgus monkeys received multiple passive transfers of KD-247 (45 mg/kg) on a weekly basis for approximately 2 months. Concentrations and viral loads were measured in peripheral blood, and CD4 T-cell counts were examined in both peripheral blood and various lymphoid tissues. RESULTS: Pharmacokinetic examination revealed similar plasma maintenance levels ranging from 200 to 500 microg/ml of KD-247 in the three groups. One of the six monkeys given KD-247 could not maintain these concentrations, and elicitation of anti-KD-247 idiotype antibody was suggested. All monkeys given KD-247 exhibited striking postinfection protection against both CD4 T-cell loss in various lymphoid tissues and atrophic changes in organs compared with control group animals treated with normal human immunoglobulin G. The KD-247-treated groups were also partially protected against plasma viral load elevation in peripheral blood samples, although the complete protection previously reported with preadministration of this mAb was not achieved. CONCLUSION: Postinfection passive transfer of humanized mAb KD-247 with strong neutralizing capacity against challenged virus simian/human immunodeficiency virus-C2/1 protected CD4 T cells in lymphoid organs.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Tecido Linfoide/imunologia , Fragmentos de Peptídeos/imunologia , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Atrofia/prevenção & controle , Contagem de Linfócito CD4 , Imunização Passiva , Macaca fascicularis , RNA Viral/sangue , Vacinas contra a SAIDS/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/isolamento & purificação , Timo/patologia , Carga Viral
2.
J Virol ; 83(13): 6508-21, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19403685

RESUMO

All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction; P < 0.03) and at the set point (2.6-log reduction; P < 0.006) than those in control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated.


Assuntos
Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/imunologia , Replicação Viral , Animais , Epitopos de Linfócito T/imunologia , Produtos do Gene env/genética , Produtos do Gene env/imunologia , Macaca mulatta , Filogenia , RNA Viral/genética , Alinhamento de Sequência , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T/virologia , Vacinas de DNA/imunologia , Carga Viral
3.
J Exp Med ; 205(11): 2537-50, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18838548

RESUMO

An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Macaca , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral/fisiologia , Animais , Sequência de Bases , Primers do DNA/genética , Variação Genética , Dados de Sequência Molecular , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vacinas contra a SAIDS/genética , Análise de Sequência de RNA , Vírus da Imunodeficiência Símia/genética , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia
4.
J Virol ; 82(8): 4154-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18272571

RESUMO

Here we report the results of studies in the simian immunodeficiency virus (SIV)-rhesus macaque model of intravaginal transmission of human immunodeficiency virus type 1 in the setting of genital ulcerative diseases. We document preferential association of vRNA with induced ulcers during the first days of infection and show that allogeneic cells of the inoculum traffic from the vaginal lumen to lymphatic tissues. This surprisingly rapid systemic dissemination in this cell-associated SIV challenge model thus reveals the challenges of preventing transmission in the setting of genital ulcerative diseases and illustrates the utility of this animal model in tests of strategies aimed at reducing transmission under these conditions.


Assuntos
Doenças Urogenitais Femininas/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Úlcera/virologia , Internalização do Vírus , Animais , Feminino , Linfonodos/virologia , Macaca mulatta , Vagina/patologia , Vagina/virologia
5.
Immunogenetics ; 59(9): 693-703, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17641886

RESUMO

The utility of the rhesus macaque as an animal model in both HIV vaccine development and pathogenesis studies necessitates the development of accurate and efficient major histocompatibility complex (MHC) genotyping technologies. In this paper, we describe the development and application of allele-specific polymerase chain reaction (PCR) amplification for the simultaneous detection of eight MHC class I alleles from the rhesus macaque (Macaca mulatta) of Indian descent. These alleles were selected, as they have been implicated in the restriction of CD8(+) T cell epitopes of simian immunodeficiency virus (SIV). Molecular typing of Mamu-A 01, Mamu-A 02, Mamu-A 08, Mamu-A 11, Mamu-B 01, Mamu-B 03, Mamu-B 04, and Mamu-B 17 was conducted in a high throughput fashion using genomic DNA. Our amplification strategy included a conserved internal control target to minimize false negative results and can be completed in less than 5 h. We have genotyped over 4,000 animals to establish allele frequencies from colonies all over the western hemisphere. The ability to identify MHC-defined rhesus macaques will greatly enhance investigation of the immune responses, which are responsible for the control of viral replication. Furthermore, application of this technically simple and accurate typing method should facilitate selection, utilization, and breeding of rhesus macaques for AIDS virus pathogenesis and vaccine studies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Vírus da Imunodeficiência Símia/imunologia , Alelos , Animais , Epitopos de Linfócito T/genética , Antígenos de Histocompatibilidade Classe I/genética , Macaca mulatta , Reação em Cadeia da Polimerase
6.
J Infect Dis ; 194(7): 912-6, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16960778

RESUMO

The goal of the present study was to develop a nonhuman primate model of intravaginal human immunodeficiency virus (HIV) transmission with cell-associated virus. Reproductively mature, cycling cynomolgus macaques with or without chemically induced, transient ulcers of the lower female reproductive tract repeatedly received challenge with a variable amount of in vitro simian immunodeficiency virus mac239-infected peripheral blood mononuclear cells. Persistent viremia was established with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus. This model will be indispensable for the testing of vaccines and topical agents that are aimed toward the prevention of heterosexual transmission of HIV.


Assuntos
Modelos Animais de Doenças , Infecções por HIV/transmissão , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/virologia , Vagina/virologia , Administração Intravaginal , Animais , Complexo CD3/metabolismo , Feminino , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Macaca fascicularis , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Viremia/fisiopatologia , Viremia/transmissão , Viremia/virologia
7.
J Virol ; 80(11): 5563-70, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16699037

RESUMO

In an accompanying report (Y. Eda, M. Takizawa, T. Murakami, H. Maeda, K. Kimachi, H. Yonemura, S. Koyanagi, K. Shiosaki, H. Higuchi, K. Makizumi, T. Nakashima, K. Osatomi, S. Tokiyoshi, S. Matsushita, N. Yamamoto, and M. Honda, J. Virol. 80:5552-5562, 2006), we discuss our production of a high-affinity humanized monoclonal antibody, KD-247, by sequential immunization with V3 peptides derived from human immunodeficiency virus type 1 (HIV-1) clade B primary isolates. Epitope mapping revealed that KD-247 recognized the Pro-Gly-Arg V3 tip sequence conserved in HIV-1 clade B isolates. In this study, we further demonstrate that in vitro, KD-247 efficiently neutralizes CXCR4- and CCR5-tropic primary HIV-1 clade B and clade B' with matching neutralization sequence motifs but does not neutralize sequence-mismatched clade B and clade E isolates. Monkeys were provided sterile protection against heterologous simian/human immunodeficiency virus challenge by the passive transfer of a single high dose (45 mg per kg of body weight) of KD-247 and afforded partial protection by lower antibody doses (30 and 15 mg per kg). Protective neutralization endpoint titers in plasma at the time of virus challenge were 1:160 in animals passively transferred with a high dose of the antibody. The antiviral efficacy of the antibody was further confirmed by its suppression of the ex vivo generation of primary HIV-1 quasispecies in peripheral blood mononuclear cell cultures from HIV-infected individuals. Therefore, KD-247 promises to be a valuable tool not only as a passive immunization antibody for the prevention of HIV infection but also as an immunotherapy for the suppression of HIV in phenotype-matched HIV-infected individuals.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/virologia , Fragmentos de Peptídeos/imunologia , Motivos de Aminoácidos/imunologia , Animais , Reações Cruzadas , Proteína gp120 do Envelope de HIV/química , HIV-1/classificação , HIV-1/imunologia , Haplorrinos , Humanos , Imunização Passiva , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Especificidade da Espécie
8.
J Virol ; 79(3): 1452-62, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15650171

RESUMO

Although the correlates of vaccine-induced protection against human immunodeficiency virus type 1 (HIV-1) are not fully known, it is presumed that neutralizing antibodies (NAb) play a role in controlling virus infection. In this study, we examined immune responses elicited in rhesus macaques following vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing an HIV-1 Env V3 antigen (rBCG Env V3). We also determined the effect of vaccination on protection against challenge with either a simian-human immunodeficiency virus (SHIV-MN) or a highly pathogenic SHIV strain (SHIV-89.6PD). Immunization with rBCG Env V3 elicited significant levels of NAb for the 24 weeks tested that were predominantly HIV-1 type specific. Sera from the immunized macaques neutralized primary HIV-1 isolates in vitro, including HIV-1BZ167/X4, HIV-1SF2/X4, HIV-1CI2/X4, and, to a lesser extent, HIV-1MNp/X4, all of which contain a V3 sequence homologous to that of rBCG Env V3. In contrast, neutralization was not observed against HIV-1SF33/X4, which has a heterologous V3 sequence, nor was it found against primary HIV-1 R5 isolates from either clade A or B. Furthermore, the viral load in the vaccinated macaques was significantly reduced following low-dose challenge with SHIV-MN, and early plasma viremia was markedly decreased after high-dose SHIV-MN challenge. In contrast, replication of pathogenic SHIV-89.6PD was not affected by vaccination in any of the macaques. Thus, we have shown that immunization with an rBCG Env V3 vaccine elicits a strong, type-specific V3 NAb response in rhesus macaques. While this response was not sufficient to provide protection against a pathogenic SHIV challenge, it was able to significantly reduce the viral load in macaques following challenge with a nonpathogenic SHIV. These observations suggest that rBCG vectors have the potential to deliver an appropriate virus immunogen for desirable immune elicitations.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , Mycobacterium bovis/genética , Fragmentos de Peptídeos/imunologia , Recombinação Genética , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/administração & dosagem , Proteína gp120 do Envelope de HIV/genética , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Macaca mulatta , Masculino , Testes de Neutralização , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/genética , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/imunologia , Vacinação
9.
Virology ; 313(1): 8-12, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12951016

RESUMO

We have monitored kinetics of peripheral blood Interleukin (IL)-18 level, viral RNA load, and CD4(+) T cell counts in cynomolgus and rhesus macaques following infections of various simian/human immunodeficiency viruses (SHIVs) causing differential pathogenicity. Infections of cynomolgus and rhesus macaques with pathogenic SHIVs-C2/1 and -89.6PD, respectively, induced high levels of plasma IL-18 (0.1-1 ng/ml) and enhanced apoptosis of peripheral blood T cells during primary viremia, along with a rapid decline of CD4(+) T cells and a high level of set point viral load after primary viremia (six of six cases). In contrast, infections of cynomolgus macaques with nonpathogenic SHIVs-TH09V3 and -MD14 did not cause such IL-18 elevation, showing no decline of CD4(+) T cells and no or low viral set point level following primary viremia (three of three cases). Thus, the elevation of circulating IL-18 level during primary viral infection can be a good indicator of an active pathogenic viral infection. However, the role of increased IL-18 remains to be elucidated and needs further investigation.


Assuntos
Interleucina-18/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia , Animais , Apoptose , Biomarcadores/sangue , Contagem de Linfócito CD4 , Modelos Animais de Doenças , HIV/patogenicidade , Macaca fascicularis , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/diagnóstico , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/fisiologia , Carga Viral
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