RESUMO
Vaccination strategies for protection against a number of respiratory pathogens must induce T-cell populations in both the pulmonary airways and peripheral lymphoid organs. In this study, we show that pulmonary immunization using plasmid DNA formulated with the polymer polyethyleneimine (PEI-DNA) induced antigen-specific CD8(+) T cells in the airways that persisted long after antigen local clearance. The persistence of the cells was not mediated by local lymphocyte proliferation or persistent antigen presentation within the lung or airways. These vaccine-induced CD8(+) T cells effectively mediated protective immunity against respiratory challenges with vaccinia virus and influenza virus. Moreover, this protection was not dependent upon the recruitment of T cells from peripheral sites. These findings demonstrate that pulmonary immunization with PEI-DNA is an efficient approach for inducing robust pulmonary CD8(+) T-cell populations that are effective at protecting against respiratory pathogens.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Pulmão/imunologia , Vacinas de DNA/imunologia , Viroses/imunologia , Vírus/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos/genética , Antígenos/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Humanos , Imunização , Ativação Linfocitária/imunologia , Camundongos , Orthomyxoviridae/imunologia , Plasmídeos/genética , Plasmídeos/imunologia , Mucosa Respiratória/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Vaccinia virus/genética , Vaccinia virus/imunologiaRESUMO
An HIV-1 vaccine must elicit a clonally diverse virus-specific CD8+ T-cell response to contain mutant virus forms, and these responses must be present in mucosal tissues, which are the site of early HIV-1 replication. We show that systemic delivery of prototype vaccine vectors in rhesus monkeys induced SIV (simian immunodeficiency virus)-specific CD8+ T-cell responses in systemic and mucosal compartments with comparable clonal compositions. Although clonal sharing was maintained between the peripheral blood and lungs, the clonal constituents of the vaccine-induced CD8+ T-cell populations in the gastrointestinal mucosal tissues evolved away from the peripheral blood population. A phenotypic characterization indicated that the divergence was a consequence of differential trafficking and retention of the vaccine-induced cells in mucosal compartments. These findings highlight the circulation of vaccine-induced CD8+ T-cell populations between systemic and mucosal compartments and the importance of the expression of specific homing molecules for localization in mucosal tissues.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Mucosa/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Sequência de Aminoácidos , Animais , Epitopos de Linfócito T/química , Mucosa Gástrica/imunologia , Produtos do Gene gag/imunologia , Imunização , Memória Imunológica , Mucosa Intestinal/imunologia , Macaca mulatta , Dados de Sequência Molecular , Mucosa/virologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/genéticaAssuntos
Vacinas contra a AIDS , Terapia Genética/métodos , Anticorpos Anti-HIV/genética , Infecções por HIV/prevenção & controle , Vacinas contra a AIDS/imunologia , Animais , Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/imunologia , Haplorrinos , HumanosRESUMO
Multifocal submucosal stromal tumors were diagnosed in a 5.5-year-old rhesus macaque (Macaca mulatta) experimentally infected with simian immunodeficiency virus, strain SIVsmE660, and CD4+ T cell depleted. The animal was negative for simian retroviruses, SRV-1, -2, and -5. Polymerase chain reaction analysis of DNA from tumor and spleen tissue revealed abundant, preferential presence of retroperitoneal fibromatosis herpesvirus, the macaque homologue of the Kaposi sarcoma-associated herpesvirus (human herpesvirus-8), in the tumors. This was corroborated by demonstration of viral latent nuclear antigen-1 in the nuclei of a majority of the spindeloid tumor cells. Low levels of an additional macaque herpesvirus, rhesus rhadinovirus, were also detected in the spleen and tumor tissues. The spindeloid cells labeled positively for vimentin and CD117 but were negative for CD31, CD68, desmin, and smooth muscle cell actin. Collectively, these findings suggest a relation to but not absolute identity with simian mesenchymoproliferative disorders (MPD) or typical gastrointestinal stromal tumors (GISTs).
Assuntos
Tumores do Estroma Gastrointestinal/veterinária , Macaca mulatta , Doenças dos Macacos/patologia , Doenças dos Macacos/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Vírus da Imunodeficiência Símia , Animais , Antígenos Nucleares/metabolismo , Primers do DNA , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/patologia , Herpesvirus Humano 8/metabolismo , Imuno-Histoquímica/veterinária , Reação em Cadeia da Polimerase/veterinária , Retrovirus dos Símios/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Vimentina/metabolismoRESUMO
To provide a basis for beginning to explore the CD94/NKG2 family of molecules in rhesus monkeys, we sought to characterize the expression of these inhibitory and activating cell signalling molecules in peripheral blood mononuclear cells (PBMCs) from healthy rhesus monkeys. We developed and employed a semiquantitative polymerase chain reaction (PCR)-based assay to evaluate mRNA expression levels of nine NKG2 molecules in PBMCs from the monkeys. In addition to quantitating NKG2A, NKG2B, NKG2C2, NKG2C and NKG2D expression, mRNA expression of transmembrane-deleted forms of these molecules was also evaluated. Significant variability in NKG2 mRNA expression in the PBMCs was detected, with 15 unique NKG2 expression level profiles detected in a study of 15 monkeys. We also found that the ratio of the expressed levels of mRNA of the four NKG2 splice variants, NKG2A, NKG2B, NKG2ADeltatm, and NKG2BDeltatm, was variable between the monkeys as well as in an individual monkey over a period of 1.5 years. These findings indicate the dynamic nature of NKG2 mRNA expression in the rhesus monkey.
Assuntos
Linfócitos/imunologia , Receptores Imunológicos/sangue , Animais , Expressão Gênica , Subpopulações de Linfócitos/imunologia , Macaca mulatta , Reação em Cadeia da Polimerase/métodos , Splicing de RNA/genética , RNA Mensageiro , Receptores Imunológicos/genética , Receptores de Células Matadoras Naturais , Reprodutibilidade dos TestesRESUMO
The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VPp1100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.
Assuntos
Vírus JC/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Citomegalovirus/imunologia , Proteínas de Ligação a DNA/imunologia , Antígenos HLA-A/metabolismo , Antígeno HLA-A2 , Humanos , Imunocompetência , Epitopos Imunodominantes , Vírus JC/patogenicidade , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/prevenção & controle , Leucoencefalopatia Multifocal Progressiva/virologia , Proteínas de Plantas , Transativadores , Fatores de Transcrição/imunologia , Replicação Viral/imunologiaRESUMO
Immune responses of lymphocyte populations during early phases of mycobacterial infection and reinfection have not been well characterized in humans. A non-human primate model of Mycobacterium bovis bacille Calmette-Guerin (BCG) infection was employed to characterize optimally the immune responses of mycobacteria-specific T cells. Primary BCG infection induced biphasic immune responses, characterized by initial lymphocytopenia and subsequent expansion of CD4+, CD8+ and gammadelta T cell populations in the blood, lymph nodes and the pulmonary compartment. The potency of detectable T cell immune responses appears to be influenced by the timing and route of infection as well as challenge doses of BCG organisms. Systemic BCG infection introduced by intravenous challenge induced a dose-dependent expansion of circulating CD4+, CD8+ and gammadelta T cells whereas, in the pulmonary compartment, the systemic infection resulted in a predominant increase in numbers of gammadelta T cells. In contrast, pulmonary exposure to BCG through the bronchial route induced detectable expansions of CD4+, CD8+ and gammadelta T cell populations in only the lung but not in the blood. A rapid recall expansion of these T cell populations was seen in the macaques reinfected intravenously and bronchially with BCG. The expanded alphabeta and gammadelta T cell populations exhibited their antigen specificity for mycobacterial peptides and non-peptide phospholigands, respectively. Finally, the major expansion of T cells was associated with a resolution of active BCG infection and reinfection. The patterns and kinetics of CD4+, CD8+ and gammadelta T cell immune responses during BCG infection might contribute to characterizing immune protection against tuberculosis and testing new tuberculosis vaccines in primates.
Assuntos
Infecções por Mycobacterium/imunologia , Mycobacterium bovis , Subpopulações de Linfócitos T/imunologia , Animais , Divisão Celular/imunologia , Células Cultivadas , Relação Dose-Resposta Imunológica , Memória Imunológica , Pulmão/imunologia , Linfonodos/imunologia , Linfopenia/imunologia , Linfopenia/microbiologia , Macaca mulatta , Macaca nemestrina , RecidivaRESUMO
T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIV(mac251 (561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIV(mac251 (561)) or SIV(SME660). However, a significant delay in CD4+ T-cell loss was observed in Mamu-A*01-positive macaques in each group. Of interest, in the case of intravenous or intrarectal challenge with the chimeric SIV/HIV strains SHIV(89.6P) or SHIV(KU2), respectively, MHC-I Mamu-A*01-positive macaques did not significantly restrict primary viremia. The finding of the protective effect of the Mamu-A*01 molecule parallels the protective effect of the B*5701 HLA allele in HIV-1-infected humans and needs to be accounted for in the evaluation of vaccine efficacy against SIV challenge models.
Assuntos
Produtos do Gene env/administração & dosagem , Produtos do Gene gag/administração & dosagem , Produtos do Gene pol/administração & dosagem , Antígenos de Histocompatibilidade Classe I/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Vacinação , Vacinas Virais/administração & dosagem , Animais , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene pol/imunologia , Macaca , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vaccinia virus , Vacinas Virais/imunologiaRESUMO
Although high frequencies of T lymphocytes specific for certain tumor-associated antigens have been detected in some cancer patients, increasing evidence suggests that these T cells may be functionally defective in vivo and fail to induce meaningful clinical responses. One strategy to overcome this limitation is to target novel antigens that are ignored during the natural antitumor immune response but are nevertheless capable of triggering effector T-cell responses against tumors after optimal presentation by antigen-presenting cells. Here, we show that the telomerase catalytic subunit (hTERT)-a nearly universal tumor antigen identified by epitope deduction rather than from patient immune responses-is immunologically ignored by patients despite progressive tumor burden. Nevertheless, HLA-A2-restricted CTLs against hTERT are equivalently induced ex vivo from patients and healthy individuals and efficiently kill human tumor cell lines and primary tumors. Thus, telomerase-specific T cells from cancer patients are spared functional inactivation because of immunological ignorance. These findings support clinical efforts to target the hTERT as a tumor antigen with broad therapeutic potential.
Assuntos
Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Telomerase/imunologia , Adulto , Idoso , Proteínas de Ligação a DNA , Epitopos de Linfócito T/imunologia , Feminino , Antígeno HLA-A2/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologiaRESUMO
Although systemic virus-specific cytotoxic T lymphocyte (CTL) responses are of critical importance in controlling virus replication in individuals infected with human immunodeficiency virus 1 (HIV-1), little is known about this immune response in the gastrointestinal (GI) tract. This study investigated the GI tract CTL response in a nonhuman primate model for HIV-1 infection, simian immunodeficiency virus (SIV)-infected rhesus monkeys. Lymphocytes from duodenal pinch biopsy specimens were obtained from 9 chronically SIVmac-infected rhesus monkeys and GI tract lymphocytes were harvested from the jejunum and ileum of 4 euthanized SIVmac-infected rhesus monkeys. Lymphocytes were also assessed in GI mucosal tissues by in situ staining in histologic specimens. SIVmac Gag-specific CTLs were assessed in the monkeys using the tetramer technology. These GI mucosal tissues of chronically SIVmac-infected rhesus monkeys contained levels of CTLs comparable to those found in the peripheral blood and lymph nodes. The present studies suggest that the CD8(+) CTL response in GI mucosal sites is comparable to that seen systemically in SIVmac-infected rhesus monkeys.
Assuntos
Sistema Digestório/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Biópsia , Antígenos CD8/análise , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Duodeno/imunologia , Duodeno/patologia , Produtos do Gene gag/análise , Produtos do Gene gag/imunologia , Produtos do Gene gag/metabolismo , Íleo/imunologia , Íleo/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Jejuno/imunologia , Jejuno/patologia , Ativação Linfocitária , Macaca mulatta , Microscopia ConfocalRESUMO
The ability to monitor vaccine-elicited CD8(+) cytotoxic T-lymphocyte (CTL) responses in simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys has been limited by our knowledge of viral epitopes predictably presented to those lymphocytes by common rhesus monkey MHC class I alleles. We now define an SIV and SHIV Nef CTL epitope (YTSGPGIRY) that is presented to CD8(+) T lymphocytes by the common rhesus monkey MHC class I molecule Mamu-A*02. All seven infected Mamu-A*02(+) monkeys evaluated demonstrated this response, and peptide-stimulated interferon gamma Elispot assays indicated that the response represents a large proportion of the entire CD8(+) T-lymphocyte SIV- or SHIV-specific immune response of these animals. Knowledge of this epitope and MHC class I allele substantially increases the number of available rhesus monkeys that can be used for testing prototype HIV vaccines in this important animal model.
Assuntos
Alelos , Produtos do Gene nef/imunologia , Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I/genética , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Animais , Epitopos , Macaca mulatta , Dados de Sequência MolecularRESUMO
RNA viruses undergo rapid sequence variation as the result of error-prone RNA replication mechanisms. When viable mutations arise in RNA regions encoding B or T cell epitopes, mutant viruses that can evade immune detection may be selected. In the carefully studied CTL response to the Gag p11C(C-M) epitope in SIVmac-infected Mamu-A*01(+) rhesus monkeys, it has been shown that CTL recognition of that epitope can occur even in the face of accruing mutations. To explore the underlying mechanism for this breadth of recognition, we have constructed Mamu-A*01 tetramers which discriminate T cells specific for epitope variants. Using these reagents we have defined discrete subsets of p11C(C-M)-specific T cells that cross-react with cells presenting variant peptides. We have found that individual Mamu-A*01(+) monkeys differ functionally in their ability to recognize epitope variants despite consistently strong recognition of the p11C(C-M) epitope. This functional difference is accounted for by the relative number of variant-specific T cells and by differences in the functionally relevant TCR repertoire of the infected monkeys. We have also found that monkeys immunized with DNA vaccine constructs encoding only the wild-type epitope sequence develop p11C(C-M)-specific CTL cross-reactive with variant peptides. Thus, cross-reactive CTL do not merely arise secondary to the emergence and immune presentation of viral CTL escape mutants but rather arise de novo following priming with a dominant epitope peptide sequence. Taken together, our results support the concept that the CTL response to a dominant viral epitope, although highly focused, can be clonally diverse and recognize potential epitope variants.
Assuntos
Produtos do Gene gag/imunologia , Epitopos Imunodominantes , Fragmentos de Peptídeos/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Reações Cruzadas , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/fisiologia , Macaca mulatta , MutaçãoRESUMO
Cholera toxin (CT) is frequently used as an experimental adjuvant intranasally for the induction of systemic and mucosal immunity. However, CT is highly reactogenic and not approved for use in humans. To define the cytokine requirements for the nasal activation of the systemic and mucosal immune system, and to design new adjuvants with efficacy similar to CT, we defined the cytokines that were able to replace CT as a nasal adjuvant for the induction of CTL. BALB/c mice were nasally immunized with an HIV immunogen that contains an MHC class I-restricted CTL epitope +/- cytokines and tested for HIV-specific immune responses. We found that combinations of IL-1alpha plus IL-18, IL-1alpha plus IL-12, and IL-1alpha plus IL-12 plus GM-CSF each induced optimal splenocyte anti-HIV CTL responses in immunized mice (range 60-71% peptide-specific (51)Cr release). Peak H-2D(d)-peptide tetramer-binding T cell responses induced by cytokine combinations were up to 5.5% of CD8(+) PBMC. Nasal immunization with HIV immunogen and IL-1alpha, IL-12, and GM-CSF also induced Ag-specific IFN-gamma-secreting cells in the draining cervical lymph node and the lung. The use of IL-1alpha, IL-12, and GM-CSF as nasal adjuvants was associated with an increased expression of MHC class II and B7.1 on nonlymphocytes within the nasal-associated lymphoid tissue/nasal mucosa. Thus, IL-1alpha, IL-12, IL-18, and GM-CSF are critical cytokines for the induction of systemic and mucosal CTL after nasal immunization. Moreover, these cytokines may serve as effective adjuvants for nasal vaccine delivery.
Assuntos
Citocinas/farmacologia , Linfócitos T Citotóxicos/imunologia , Administração Intranasal , Animais , Antígeno B7-1/análise , Complexo CD3/análise , Toxina da Cólera/imunologia , Feminino , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe II/análise , Imunidade nas Mucosas/efeitos dos fármacos , Imunização , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Accumulating evidence has demonstrated the importance of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes in controlling HIV-1 replication. We have elicited immune responses in rhesus monkeys utilizing DNA vaccines augmented by the administration of IL-2/Ig, a fusion protein consisting of interleukin-2 and the Fc portion of IgG2. These vaccine-elicited immune responses did not prevent infection following a high-dose intravenous challenge with SHIV(89.6P) but did control viremia to nearly undetectable levels and prevented immunodeficiency and clinical disease. In contrast, control monkeys developed high levels of viremia and exhibited a rapid loss of CD4(+) T cells, significant clinical disease progression, and death in half of the animals by day 140 following challenge. Vaccine approaches that elicit immune responses capable of reducing plasma viral loads, but not capable of inducing sterilizing immunity, may still provide substantial clinical benefits.
Assuntos
Vacinas contra a AIDS/farmacologia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Macaca mulatta/imunologia , Vacinas contra a SAIDS/farmacologia , Vacinas de DNA/farmacologia , Animais , Contagem de Linfócito CD4 , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/imunologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Interleucina-2/administração & dosagem , Testes de Neutralização , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Viremia/imunologia , Viremia/prevenção & controleRESUMO
Most immunosuppressed individuals who develop progressive multifocal leukoencephalopathy (PML) have a rapid fatal outcome, whereas some become long-term survivors. We explored the impact of the cellular immune response against JC virus (JCV) on the clinical outcome of 7 HIV+ and 3 HIV- individuals with PML. Of the 4 HIV+/PML survivors, all had detectable cytotoxic T lymphocytes (CTL) specific for JCV T or VP 1 proteins compared to none of the 3 HIV+/PML progressors tested. Of the 3 HIV-/PML patients, 1 was recently diagnosed with PML and showed evidence of neurologic improvement without any treatment. This patient had CTL specific for the VP1 protein of JCV. The other 2 HIV-/PML survivors were stable 3-8 years after the diagnosis of PML. They did not have any detectable CTL against JCV. These findings suggest that JCV-specific immune response is associated with favorable outcome in HIV+ individuals with PML. The lack of detectable JCV-specific CTL in 2 HIV-/PML survivors might indicate a burnt-out disease without sufficient antigenic stimulation to maintain the cellular immune response. The detection of JCV-specific CTL in an HIV- patient recently diagnosed with PML, who was showing evidence of neurological improvement without any treatment, indicates that this finding may be used as a favorable prognostic marker of disease evolution in the clinical management of patients with PML. As the quest for an effective treatment of PML continues, JCV-specific cellular immune response deserves further attention because it appears to play a crucial role in the prevention of disease progression.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Imunidade Celular/imunologia , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/virologia , Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/virologia , Humanos , Leucoencefalopatia Multifocal Progressiva/mortalidade , Leucoencefalopatia Multifocal Progressiva/virologia , Prognóstico , Taxa de Sobrevida , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologiaRESUMO
The contribution of immune reconstitution following antiretroviral treatment to the prevention or treatment of human immunodeficiency virus-related primary or reactivation tuberculosis remains unknown. Macaque models of simian immunodeficiency virus-Mycobacterium bovis BCG (SIV/BCG) coinfection were employed to determine the extent to which anti-Mycobacterium tuberculosis immunity can be restored by antiretroviral therapy. Both SIV-infected macaques with active BCG reinfection and naive animals with simultaneous SIV/BCG coinfection were evaluated. The suppression of SIV replication by antiretroviral treatment resulted in control of the active BCG infection and blocked development of the fatal SIV-related tuberculosis-like disease. The resolution of this disease coincided with the restoration of BCG purified protein derivative (PPD)-specific T-cell immune responses. In contrast, macaques similarly coinfected with SIV/BCG but not receiving antiretroviral therapy had depressed PPD-specific primary and memory T-cell immune responses and died from tuberculosis-like disease. These results provide in vivo evidence that the restoration of anti-mycobacterial immunity by antiretroviral agents can improve the clinical outcome of an AIDS virus-related tuberculosis-like disease.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Mycobacterium bovis/efeitos dos fármacos , Nelfinavir/uso terapêutico , Organofosfonatos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Tuberculose/fisiopatologia , Adenina/uso terapêutico , Animais , Células Cultivadas , Macaca mulatta , Macaca nemestrina , Compostos Organofosforados/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Linfócitos T/citologia , Linfócitos T/imunologia , Tenofovir , Tuberculose/imunologiaRESUMO
Immune containment of persistent viral infections has long been a focus of interest for investigators. However, the technologies needed to evaluate the role of CD8+ cytotoxic T lymphocytes (CTLs) in this process have only recently become available. Recent studies performed using tetramer, ELISPOT and cytokine-production assays have evaluated the role of CD8+ CTLs in controlling lentivirus and herpesvirus infections in humans and nonhuman primates. These studies demonstrate dramatic expansions of virus-specific CTLs in primary infection and the maintenance of unexpectedly high levels of virus-specific CTLs in chronic infection. These findings underscore the importance of CD8+ CTLs in the immune control of persistent viral infections.
Assuntos
Herpesviridae/imunologia , Lentivirus/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Citomegalovirus/imunologia , HIV-1/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Vírus da Imunodeficiência Símia/imunologia , Viroses/imunologiaRESUMO
The T cell-stimulatory cytokine interleukin 2 (IL-2) is being evaluated as a therapeutic in the clinical settings of HIV infection and cancer. However, the clinical utility of IL-2 may be mitigated by its short in vivo half-life, toxic effects, and high production costs. We show here that an IL-2/Ig fusion protein possesses IL-2 immunostimulatory activity in vitro and a long in vivo half-life. IL-2/Ig treatment of healthy rhesus monkeys induced significant increases in CD4(+) T lymphocyte counts and expression of CD25 by these cells. Short courses of IL-2/Ig treatment of simian immunodeficiency virus (SIV)-infected rhesus monkeys in conjunction with antiretroviral drugs resulted in increased CD25 expression on T lymphocytes, and transient increases in CD4(+) T lymphocyte counts. Plasma viremia did not increase in these treated animals. Treatment of healthy or SIV-infected rhesus monkeys with a plasmid encoding the IL-2/Ig protein did not affect CD4(+) T lymphocytes. These results demonstrate that IL-2/Ig has potential utility as an immunostimulatory therapeutic.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunoglobulina G/uso terapêutico , Interleucina-2/uso terapêutico , Proteínas Recombinantes de Fusão , Proteínas Recombinantes de Fusão/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Fármacos Anti-HIV/administração & dosagem , Citometria de Fluxo , Imunoglobulina G/genética , Interleucina-2/genética , Contagem de Linfócitos , Macaca mulatta , Plasmídeos/administração & dosagem , Plasmídeos/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética , Transfecção , Carga ViralRESUMO
Since cytotoxic T lymphocytes (CTLs) are critical for controlling human immunodeficiency virus type 1 (HIV-1) replication in infected individuals, candidate HIV-1 vaccines should elicit virus-specific CTL responses. In this report, we study the immune responses elicited in rhesus monkeys by a recombinant poxvirus vaccine and the degree of protection afforded against a pathogenic simian-human immunodeficiency virus SHIV-89.6P challenge. Immunization with recombinant modified vaccinia virus Ankara (MVA) vectors expressing SIVmac239 gag-pol and HIV-1 89.6 env elicited potent Gag-specific CTL responses but no detectable SHIV-specific neutralizing antibody (NAb) responses. Following intravenous SHIV-89.6P challenge, sham-vaccinated monkeys developed low-frequency CTL responses, low-titer NAb responses, rapid loss of CD4+ T lymphocytes, high-setpoint viral RNA levels, and significant clinical disease progression and death in half of the animals by day 168 postchallenge. In contrast, the recombinant MVA-vaccinated monkeys demonstrated high-frequency secondary CTL responses, high-titer secondary SHIV-89.6-specific NAb responses, rapid emergence of SHIV-89.6P-specific NAb responses, partial preservation of CD4+ T lymphocytes, reduced setpoint viral RNA levels, and no evidence of clinical disease or mortality by day 168 postchallenge. There was a statistically significant correlation between levels of vaccine-elicited CTL responses prior to challenge and the control of viremia following challenge. These results demonstrate that immune responses elicited by live recombinant vectors, although unable to provide sterilizing immunity, can control viremia and prevent disease progression following a highly pathogenic AIDS virus challenge.
Assuntos
HIV-1/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Vacinas Sintéticas/administração & dosagem , Vaccinia virus/genética , Animais , Anticorpos Antivirais/análise , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Progressão da Doença , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene pol/imunologia , HIV-1/genética , Humanos , Macaca mulatta , RNA Viral/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Linfócitos T Citotóxicos/imunologia , Fatores de Tempo , Vacinas Sintéticas/imunologia , Vaccinia virus/imunologiaRESUMO
The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.