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1.
PLoS One ; 10(3): e0120282, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25785629

RESUMEN

Attenuated live infectious laryngotracheitis virus (ILTV) vaccines are widely used in the poultry industry to control outbreaks of disease. Natural recombination between commercial ILTV vaccines has resulted in virulent recombinant viruses that cause severe disease, and that have now emerged as the dominant field strains in important poultry producing regions in Australia. Genotype analysis using PCR-restriction fragment length polymorphism has shown one recombinant virus (class 9) has largely replaced the previously dominant class 2 field strain. To examine potential reasons for this displacement we compared the growth kinetics and transmission potential of class 2 and class 9 viruses. The class 9 ILTV grew to higher titres in cell culture and embryonated eggs, but no differences were observed in entry kinetics or egress into the allantoic fluid from the chorioallantoic membrane. In vivo studies showed that birds inoculated with class 9 ILTV had more severe tracheal pathology and greater weight loss than those inoculated with the class 2 virus. Consistent with the predominance of class 9 field strains, birds inoculated with 10(2) or 10(3) plaque forming units of class 9 ILTV consistently transmitted virus to in-contact birds, whereas this could only be seen in birds inoculated with 10(4) PFU of the class 2 virus. Taken together, the improved growth kinetics and transmission potential of the class 9 virus is consistent with improved fitness of the recombinant virus over the previously dominant field strain.


Asunto(s)
Herpesvirus Gallináceo 1/clasificación , Herpesvirus Gallináceo 1/fisiología , Animales , Línea Celular Tumoral , Pollos/virología , Femenino , Genotipo , Herpesvirus Gallináceo 1/genética , Herpesvirus Gallináceo 1/crecimiento & desarrollo , Cinética , Masculino , Especificidad de la Especie , Replicación Viral
2.
J Gen Virol ; 92(Pt 1): 128-40, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21169215

RESUMEN

As sexual transmission of human immunodeficiency virus-1 (HIV-1) occurs via the mucosa, an ideal HIV-1 vaccine should induce both mucosal and systemic immunity. We therefore sought to evaluate the induction of mucosal responses using a DNA env prime-gp120 protein boost approach in which sequential nasal and parenteral protein administration was performed with two novel carbohydrate-based adjuvants. These adjuvants, Advax-M and Advax-P, were specifically designed for mucosal and systemic immune enhancement, respectively. Murine intranasal immunization with gp120/Advax-M adjuvant elicited gp120-specific IgA in serum and mucosal secretions that was markedly enhanced by DNA priming. Boosting of DNA-primed mice with gp120/Advax-M and gp120/Advax-P by sequential intranasal and intramuscular immunization, or vice versa, elicited persistent mucosal gp120-specific IgA, systemic IgG and memory T- and B-cell responses. Induction of homologous, but not heterologous, neutralizing activity was noted in the sera of all immunized groups. While confirmation of efficacy is required in challenge studies using non-human primates, these results suggest that the combination of DNA priming with sequential nasal and parenteral protein boosting, with appropriate mucosal and systemic adjuvants, could generate strong mucosal and systemic immunity and may block HIV-1 mucosal transmission and infection.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/sangre , Inmunidad Mucosa , Inmunización Secundaria/métodos , Linfocitos T/inmunología , Vacunación/métodos , Adyuvantes Inmunológicos/administración & dosificación , Administración Intranasal , Animales , Femenino , Anticuerpos Anti-VIH/análisis , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Inmunoglobulina A/análisis , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inyecciones Intramusculares , Ratones , Ratones Endogámicos BALB C , Pruebas de Neutralización , Vacunas de ADN/inmunología , Vacunas de Subunidad/inmunología
3.
J Virol Methods ; 163(2): 287-94, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19878696

RESUMEN

Nonhuman primates represent a robust model to evaluate preclinical efficacy of HIV-1 vaccine and therapeutic strategies. Plasma and tissue viral RNA as well as tissue proviral DNA load are key parameters in assessing efficacy of vaccines and therapeutics against simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) challenge. To quantitate SIV RNA in plasma and tissues, an isothermal nucleic acid sequence-based amplification (NASBA) method using real-time detection of amplified RNA with molecular beacons was developed. This assay has accuracy and reproducibility over seven orders of magnitude and has advantages over the electrochemiluminescence-based NASBA assay described previously, both in terms of higher throughput and sensitivity. Reproducibility and accuracy were also demonstrated for a TaqMan real-time PCR assay for quantitating proviral DNA load in PBMCs and lymphoid tissues. In infected macaques, the level of plasma viremia correlated with the tissue viral RNA but not always with proviral DNA loads. Further, animals with undetectable levels of viral RNA in plasma and proviral DNA in tissues, showed no sign of seroconversion and activation of Gag-specific CD8+ or CD4+ T cells in peripheral blood. These results suggest that simultaneous application of real-time NASBA and PCR assays provides quantitative evaluation of challenge outcome in macaques.


Asunto(s)
ADN Viral/análisis , VIH-1/aislamiento & purificación , Macaca mulatta/virología , ARN Viral/análisis , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral/métodos , Animales , ADN Viral/genética , VIH-1/genética , Leucocitos Mononucleares/virología , Tejido Linfoide/virología , Plasma/química , Provirus/genética , Provirus/aislamiento & purificación , ARN Viral/genética , Reproducibilidad de los Resultados , Replicación de Secuencia Autosostenida/métodos , Sensibilidad y Especificidad , Virus de la Inmunodeficiencia de los Simios/genética , Temperatura
4.
Retrovirology ; 6: 61, 2009 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-19573243

RESUMEN

BACKGROUND: Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity. Evidence suggests that a virulence factor for HIV-1 is resistance to CCR5-binding chemokines, most notably RANTES, which are believed to play a role in HIV-1 control in vivo. HIV-1 can achieve RANTES resistance either by phenotypic switching from an exclusive CCR5 usage to an expanded coreceptor specificity, or by the acquisition of alternative modalities of CCR5 usage. An infectious agent that might promote the evolution of HIV-1 toward RANTES resistance is human herpesvirus 6A (HHV-6A), which is frequently reactivated in HIV-1-infected patients and is a potent RANTES inducer in lymphoid tissue. RESULTS: SIV isolates obtained from pig-tailed macaques (M. nemestrina) after approximately one year of single infection with SIV(smE660) or dual infection with SIV(smE660) and HHV-6A(GS) were characterized for their growth capacity and sensitivity to HHV-6A- and RANTES-mediated inhibition in human or macaque lymphoid tissues ex vivo. Four out of 4 HHV-6A-coinfected macaques, all of which progressed to full-blown AIDS within 2 years of infection, were found to harbor SIV variants with a reduced sensitivity to both HHV-6A and RANTES, despite maintaining an exclusive CCR5 coreceptor specificity; viruses derived from two of these animals replicated even more vigorously in the presence of exogenous HHV-6A or RANTES. The SIV variants that emerged in HHV-6A-coinfected macaques showed an overall reduced ex vivo replication capacity that was partially reversed upon addition of exogenous RANTES, associated with suppressed IL-2 and enhanced IFN-gamma production. In contrast, SIV isolates obtained from two singly-infected macaques, none of which progressed to AIDS, maintained HHV-6A/RANTES sensitivity, whereas the only AIDS progressor among singly-infected macaques developed an SIV variant with partial HHV-6A/RANTES resistance and increased replication capacity, associated with expanded coreceptor usage. CONCLUSION: These results provide in vivo evidence of SIV evolution toward RANTES resistance in macaques rapidly progressing to AIDS. RANTES resistance may represent a common virulence factor allowing primate immunodeficiency retroviruses to evade a critical mechanism of host antiviral defense.


Asunto(s)
Quimiocina CCL5/inmunología , Herpesvirus Humano 6/inmunología , Infecciones por Roseolovirus/complicaciones , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Células Cultivadas , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/virología , Macaca , Técnicas de Cultivo de Órganos , Tonsila Palatina/inmunología , Tonsila Palatina/virología , Infecciones por Roseolovirus/inmunología , Infecciones por Roseolovirus/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación
5.
Vaccine ; 26(31): 3947-57, 2008 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-18724414

RESUMEN

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of human immunodeficiency virus type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial. Robust cross-subtype HIV-1 specific T cell responses were detected in IFN-gamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/sangre , VIH-1/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Reacciones Cruzadas , Femenino , Experimentación Humana , Humanos , Inmunización Secundaria , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Vacunas de ADN/inmunología , Vacunas de Subunidad/inmunología
6.
J Virol Methods ; 152(1-2): 91-7, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18597861

RESUMEN

Simian betaretroviruses (SRV), formerly known as simian type D retroviruses, are endemic in many populations of Asian monkeys of the genus Macaca. Asian monkeys have been used extensively as animal models for preclinical HIV vaccine development, therapeutics, and other biomedical studies. SRV infection can sometimes lead to immune deficiency disease, which complicates such studies; thus, it is important to screen for SRV infection and remove infected animals from test populations. Real-time PCR assays were developed to specifically quantify SRV-1/3, SRV-2, and SRV-5 proviral DNA. The SRV provirus copy numbers were standardized relative to real-time PCR measurements of the rhesus macaque albumin gene. The primers and TaqMan probe sequences for the rhesus macaque (Indian origin) albumin gene also detect cynomolgus macaque and rhesus macaque (Chinese origin) albumin genes. The SRV primers and probes were designed to amplify gag gene sequences of SRV-1/3 (GeneBank accession number M11841), SRV-2 (GeneBank accession number M16605), and SRV-5 (GeneBank accession number AF252389). The optimized reactions for detection of each SRV serotype and the macaque albumin gene had amplification efficiencies of greater than 90% with a linear range spanning 1 x 10(1) to 2.5 x 10(6) copies per reaction. The R(2) values of all standard curves were greater than 0.995. Of 40 animals housed in quarantine, four animals were positive for SRV-1/3 with 28, 5450, 9780, and 14,500 copies of provirus per 10(6) PBMCs, and one animal was positive for SRV-2 with provirus copy number of 7790 per 10(6) PBMCs. All of 40 animals appeared to be seronegative and had normal CD4(+) and CD8(+) T-cell counts. These quantitative real-time PCR assays enhance the detection and quantitation of SRV infection and will facilitate the elimination of this virus from macaque colonies.


Asunto(s)
Betaretrovirus/clasificación , Betaretrovirus/genética , ADN Viral/análisis , Macaca mulatta/virología , Enfermedades de los Monos/diagnóstico , Reacción en Cadena de la Polimerasa/métodos , Infecciones por Retroviridae/veterinaria , Animales , Betaretrovirus/aislamiento & purificación , Calibración , Cartilla de ADN/genética , ADN Viral/genética , Leucocitos Mononucleares/virología , Macaca mulatta/genética , Reproducibilidad de los Resultados , Infecciones por Retroviridae/diagnóstico , Sensibilidad y Especificidad , Serotipificación
7.
Vaccine ; 26(35): 4420-4, 2008 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-18588934

RESUMEN

This report describes the safety observations following administration of a polyvalent DNA prime-protein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactions were the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein+QS21 adjuvant. Questions remain regarding the cause of the vasculitis, but the unique DTH observation may have contributed to the high level of immune responses previously reported for this vaccine.


Asunto(s)
Vacunas contra el SIDA/efectos adversos , Inmunización Secundaria/efectos adversos , Vacunas de ADN/efectos adversos , Vacunas contra el SIDA/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Femenino , Experimentación Humana , Humanos , Hipersensibilidad Tardía/etiología , Masculino , Saponinas/administración & dosificación , Piel/patología , Vacunas de ADN/administración & dosificación , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversos , Vasculitis/etiología
8.
Vaccine ; 26(40): 5223-9, 2008 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-18468743

RESUMEN

We used optimized DNA expression vectors to compare two gene delivery methodologies in rhesus macaques, namely direct DNA injection and in vivo adaptive constant-current electroporation via the intramuscular route. The use of in vivo electroporation increased levels of gene expression and immune responses. We used an optimized HIV gag expression plasmid to show the development of new cellular immune responses in SIV-infected animals controlling viremia. Furthermore, after vaccination with SIV expression plasmids the recall responses to the SIV antigens were very high, indicating that DNA is a strong boost in the presence of antiretroviral treatment in SIV-infected animals. There was substantial animal-to-animal variability in DNA expression, revealed by plasma measurements of IL-15 produced by co-injected IL-15 DNA. IL-15 expression levels correlated with peak immune responses. Electroporation led to an expansion of antigen-specific CD4+ and CD8+ T cells of both central and effector memory phenotype. These results indicate that improved gene delivery and expression by electroporation dramatically increases immunogenicity of DNA vaccines. Electroporation is thus an important method to improve the effectiveness of DNA vaccination.


Asunto(s)
Electroporación , Vacunas contra el SIDAS , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas de ADN , Viremia/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Memoria Inmunológica , Inyecciones Intramusculares , Macaca mulatta , Plásmidos/genética , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/genética , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Vacunación , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Vacunas de ADN/inmunología , Viremia/prevención & control , Viremia/virología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética
9.
Biochem Biophys Res Commun ; 370(1): 22-6, 2008 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-18329382

RESUMEN

Selection of potent yet low reactogenic adjuvants for protein immunization is important for HIV-1 vaccine development. Immunogenicity of electroporated DNA (HIV env) and recombinant gp120, administered with either QS-21 or the orally administered immunomodulator, Talabostat, was evaluated in BALB/c mice. Electroporation of low dose DNA elicited Th1 cytokines and anti-envelope antibodies. Immunization with gp120 protein alone with or without Talabostat elicited lower Th1 and Th2 cytokine levels but comparable anti-gp120 antibodies to QS-21-formulated protein. Boosting of DNA-primed mice with gp120/Talabostat induced similar anti-gp120 antibody titers and slightly higher levels of Th1 and Th2 cytokines relative to QS-21-formulated protein. Induction of CD8(+) and CD4(+) T cells and functional CTL activity was noted. These results highlight the potential use of orally administered Talabostat for efficient protein boosting of antibody and T-cell responses primed by DNA.


Asunto(s)
Vacunas contra el SIDA/inmunología , Ácidos Borónicos/administración & dosificación , Dipéptidos/administración & dosificación , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Vacunas de ADN/inmunología , Animales , Formación de Anticuerpos , Citocinas/metabolismo , ADN Viral/genética , Electroporación , Femenino , Proteína gp120 de Envoltorio del VIH/administración & dosificación , Proteína gp120 de Envoltorio del VIH/genética , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología
10.
Vaccine ; 26(8): 1098-110, 2008 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-18243434

RESUMEN

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNgamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/sangre , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Linfocitos T/inmunología , Vacunas de ADN/inmunología , Adolescente , Adulto , Experimentación Humana , Humanos , Inmunoglobulina G/sangre , Interferón gamma/biosíntesis , Persona de Mediana Edad , Pruebas de Neutralización
11.
Biochem Biophys Res Commun ; 366(1): 29-35, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18036339

RESUMEN

Intramuscular needle injection of HIV-1 DNA vaccines typically elicits weak immune responses in immunized individuals. To improve such responses, the immunogenicity of a vaccine consisting of electroporated DNA followed by intramuscular protein boost was evaluated in rabbits and macaques. In macaques, electroporation of low dose DNA encoding HIV-1 env followed by gp120 protein elicited Th1 cytokines and functional CTL that persisted for over 1 year. In both macaques and rabbits, robust anti-envelope antibodies, elicited by electroporated DNA, were augmented by gp120 protein and such responses neutralized sensitive SHIV isolates. These findings highlight efficient priming of immune responses by electroporated DNA that in conjunction with protein boost may give rise to long-term immunity in immunized hosts.


Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Electroporación/métodos , VIH-1/inmunología , Linfocitos T/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Animales , Anticuerpos/inmunología , VIH-1/genética , Macaca fascicularis , Conejos , Transfección/métodos
12.
Viral Immunol ; 21(4): 411-23, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19115930

RESUMEN

Insights into the host factors that contribute to an effective antiviral immune response may be obtained by examining global gene expression in simian human immunodeficiency virus (SHIV)-infected nonhuman primates that exhibit different virological outcomes. Immune responses and gene expression profiles in peripheral blood mononuclear cells (PBMCs) were compared between animals that controlled or did not control viremia after infection. Rectal inoculation of eight rhesus macaques with R5-tropic SHIV(SF162P3) resulted in a high level of plasma viremia during the acute phase of infection. The viremia was controlled to below levels of detection in six of these animals at the set point (controllers), whereas two animals had persistent viremia throughout the 140 wk that the animals were monitored (non-controllers). CD4(+) T-cell counts declined slightly in both controllers and non-controllers in the acute phase of infection, but CD4(+) T-cell counts continued to decline only in the non-controllers. Neutralizing antibodies to the challenge virus were variable and could not account for the control of viremia. However, analysis of the cellular gene expression profiles in the PBMCs from both groups of animals revealed distinctive gene expression patterns between controllers and non-controllers. Using the paired LPE test, 59 genes with p values <0.01 were identified and specific differences in the gene expression profiles in PBMCs from controllers versus non-controllers were detected.


Asunto(s)
Perfilación de la Expresión Génica , Infecciones por VIH/genética , VIH-1/inmunología , Animales , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Macaca mulatta , Análisis de Secuencia por Matrices de Oligonucleótidos , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia
13.
J Virol ; 81(16): 8563-70, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17553898

RESUMEN

As the diversity of potential immunogens increases within certain classes of vectors, the possibility has arisen of employing heterologous prime/boost immunizations using diverse members of the same family of vectors. The present study was initiated to explore the use of divergent pox vectors in a prime/boost regimen to elicit high-frequency cellular immune responses to human immunodeficiency virus type 1 envelope and simian immunodeficiency virus gag in rhesus monkeys. We demonstrated that monkeys vaccinated with a recombinant modified vaccinia virus Ankara (rMVA) prime/recombinant fowlpox virus (rFPV) boost regimen and monkeys vaccinated with a recombinant vaccinia virus prime/rFPV boost regimen developed comparable cellular immune responses that were greater in magnitude than those elicited by a homologous prime/boost with rMVA. Nevertheless, comparable magnitude recall cellular immune responses were observed in monkeys vaccinated with heterologous and homologous recombinant poxvirus following challenge with the CXCR4-tropic SHIV-89.6P. Consistent with this finding, comparable levels of containment of viral replication and CD4(+) T-lymphocyte preservation were seen in these groups of recombinant poxvirus-vaccinated monkeys. This study supports further exploration of combining recombinant vectors of the same family in prime/boost immunization strategies to optimize vaccine-elicited cellular immune responses.


Asunto(s)
Vectores Genéticos/inmunología , Inmunización Secundaria/métodos , Poxviridae/inmunología , Vacunación/métodos , Virus Vaccinia/inmunología , Animales , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Vectores Genéticos/genética , Inmunidad Celular , Macaca mulatta , Poxviridae/genética , ARN Viral/sangre , Virus Vaccinia/genética , Replicación Viral
14.
Virology ; 366(1): 197-211, 2007 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-17499328

RESUMEN

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.


Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/uso terapéutico , Animales , Codón , Citocinas/análisis , Citocinas/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Genes env , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/patogenicidad , Inmunización Secundaria , Macaca mulatta , Ratones , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T Citotóxicos/inmunología , Células TH1/inmunología , Células Th2/microbiología
15.
Proc Natl Acad Sci U S A ; 104(12): 5067-72, 2007 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-17360322

RESUMEN

Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4(+) T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development in dually infected animals was heralded by an early depletion of both CD4(+) and CD8(+) T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/patología , Síndrome de Inmunodeficiencia Adquirida/virología , Herpesvirus Humano 6/fisiología , Macaca/virología , Síndrome de Inmunodeficiencia Adquirida/inducido químicamente , Animales , Progresión de la Enfermedad , Regulación Viral de la Expresión Génica , Humanos , Ganglios Linfáticos/virología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , ARN Viral/metabolismo , Virus de la Inmunodeficiencia de los Simios/fisiología , Replicación Viral/fisiología
16.
J Virol ; 81(4): 1972-9, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17135321

RESUMEN

Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.


Asunto(s)
Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunación , Animales , Antirretrovirales/uso terapéutico , Antígenos Virales/inmunología , Enfermedad Crónica , Evaluación Preclínica de Medicamentos , Inyecciones Intramusculares , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Carga Viral/veterinaria , Vacunas Virales
17.
AIDS Res Hum Retroviruses ; 22(6): 516-28, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16796527

RESUMEN

A cohort of 22 rhesus macaques of Indian origin infected as neonates, juveniles, or adults by Rev-independent strains of SIV was monitored over several years. After the initial acute phase, virus replication was controlled and plasma virus loads were persistently below the threshold of the assay. The animals were monitored for up to 7.6 years after infection for viral loads, cellular and humoral immune responses, hematological changes, and overall health and no signs of immune dysfunction or AIDS were observed. This study represents several years of additional observation compared to the previously published results, and indicates that the Rev-independent SIV clones tested do not cause AIDS-like progressive disease within 7.6 years from infection. All the animals showed persistent humoral and cellular SIV-specific immune responses, consistent with chronic infection. Different Rev-independent SIV strains showed similar properties and lack of pathogenicity. Multicolor flow cytometric analysis demonstrated preservation of the Central Memory subset of T cells in the attenuated SIV-infected animals. This study demonstrates a potent, long-lasting control of the Rev-independent attenuated SIV in macaques independent of the age at virus exposure.


Asunto(s)
Productos del Gen rev/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Animales , Anticuerpos Antivirales/sangre , Productos del Gen rev/genética , Macaca mulatta , ARN Viral/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/clasificación , Virus de la Inmunodeficiencia de los Simios/genética , Factores de Tiempo , Carga Viral
18.
Vaccine ; 24(23): 5064-72, 2006 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-16621178

RESUMEN

Although replication-competent adenovirus (Ad) vectors are promising in AIDS vaccine design, their safety in immune compromised hosts is unknown. To initially address this question, enteric-coated tablets containing a replicating Ad vector were orally administered to SHIV- and SIV-infected rhesus macaques with normal, intermediate or low CD4 T cell counts and stable disease. The vector was detected within a week after tablet administration in stools of all animals but not in nasal secretions, indicating no spread of virus to the upper respiratory tract. CD4 T cell counts and viral loads remained stable in all animals and no signs of fever, weight loss, or other clinical symptoms of Ad-induced disease were observed during 10 weeks of follow-up. Oral delivery of the replicating Ad vector was safe and well tolerated by SHIV- and SIV-infected hosts. Oral enteric-coated tablets may prove safe for administering replicating Ad-vectored vaccines in areas with high HIV prevalence.


Asunto(s)
Vacunas contra el SIDA/efectos adversos , Adenovirus Humanos/genética , Adenovirus Humanos/fisiología , Macaca mulatta/fisiología , Macaca mulatta/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Replicación Viral , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/metabolismo , Administración Oral , Animales , Anticuerpos Antivirales/sangre , Temperatura Corporal , Recuento de Linfocito CD4 , Vectores Genéticos/genética , Vectores Genéticos/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Viremia
19.
J Virol ; 80(8): 3732-42, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16571790

RESUMEN

Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV(KU2) (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.


Asunto(s)
Vacunas contra el SIDA/inmunología , Recuento de Linfocito CD4 , VIH-1/inmunología , ARN Viral/análisis , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Anti-VIH/sangre , VIH-1/aislamiento & purificación , Inmunización Secundaria , Macaca mulatta , Proyectos de Investigación , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral , Viremia/prevención & control
20.
Blood ; 107(8): 3258-64, 2006 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-16373659

RESUMEN

Natural HIV transmission occurs through mucosa, but it is debated whether mucosal cytotoxic T lymphocytes (CTLs) can prevent or reduce dissemination from the initial mucosal site to the systemic circulation. Also, the role of CTL avidity in mucosal AIDS viral transmission is unknown. To address these questions, we used delay in acute-phase peak viremia after intrarectal challenge as an indicator of systemic dissemination. We found that a peptide-prime/poxviral boost vaccine inducing high levels of high-avidity mucosal CTLs can have an impact on dissemination of intrarectally administered pathogenic SHIV-ku2 in macaques and that such protection correlates better with mucosal than with systemic CTLs and particularly with levels of high-avidity mucosal CTLs.


Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Linfocitos T CD8-positivos/inmunología , VIH-1/inmunología , Inmunidad Mucosa/inmunología , Vacunas de Subunidad/inmunología , Vacunas contra el SIDA/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/terapia , Síndrome de Inmunodeficiencia Adquirida/transmisión , Administración Rectal , Animales , VIH-1/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Macaca mulatta , Poxviridae/genética , Poxviridae/inmunología , Vacunación/métodos , Vacunas de Subunidad/administración & dosificación
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