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1.
Biochem Biophys Res Commun ; 443(1): 301-7, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24309114

RESUMO

The presence of anti-CCR5 and anti-HIV-1 envelope glycoprotein (ENV) gp41 antibodies (Abs) at sites of HIV-1 exposure was effective in preventing its transmission to HIV-1-exposed seronegative (ESN) subjects. Here, we design an immunogen that can induce Abs against CCR5 and SIVmac239 ENV simultaneously and show that bovine alpha-2-HS-glycoprotein (bAHSG) functions as a booster antigen for efficiently stimulating humoral immune responses to CCR5 and ENV. Initially, we generated a rhesus CCR5-derived cyclopeptide (cDDR5) conjugated with a recombinant trimeric SIVmac239 Env. When inguinally administered to rhesus macaques, the immunogen simultaneously induced both anti-CCR5 and anti-ENV Abs in sera, and the purified serum IgG fraction exerted an inhibitory effect on SIVmac239 infection in vitro. When further boosted with bAHSG, the responses of both Abs were significantly enhanced. To examine the cross-reactivity of bAHSG, it was administered to naïve cynomolgus macaques. The results showed a statistically significant increase in IgG response against cynomolgus CCR5 and SIVmac239 ENV, and the induction of neutralizing activity against SIVmac239. These findings suggest that bAHSG is useful for immune strategies aimed at generating Abs against CCR5 and ENV simultaneously to confer HIV-protective immunity.


Assuntos
Vacinas contra a AIDS/imunologia , Produtos do Gene env/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Imunização Secundária/métodos , Receptores CCR5/imunologia , Vírus da Imunodeficiência Símia/imunologia , alfa-2-Glicoproteína-HS/imunologia , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Antígenos/imunologia , Bovinos , Proteína gp120 do Envelope de HIV , Proteína gp41 do Envelope de HIV/imunologia , Imunidade Humoral , Macaca fascicularis , Proteínas Recombinantes/imunologia , Vacinas Sintéticas/imunologia
2.
J Immunol ; 182(10): 6061-70, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19414757

RESUMO

Effective uptake of Ags by specialized M cells of gut-associated lymphoid tissues is an important step in inducing efficient immune responses after oral vaccination. Although stable nontoxic small molecule mimetics of lectins, such as synthetic multivalent polygalloyl derivatives, may have potential in murine M cell targeting, it remains unclear whether synthetic multivalent polygalloyl derivatives effectively target nonhuman and human M cells. In this study, we evaluated the ability of a tetragalloyl derivative, the tetragalloyl-D-lysine dendrimer (TGDK), to target M cells in both in vivo nonhuman primate and in vitro human M-like cell culture models. TGDK was efficiently transported from the lumen of the intestinal tract into rhesus Peyer's patches by M cells and then accumulated in germinal centers. Oral administration of rhesus CCR5-derived cyclopeptide conjugated with TGDK in rhesus macaque resulted in a statistically significant increase in stool IgA response against rhesus CCR5-derived cyclopeptide and induced a neutralizing activity against SIV infection. Furthermore, TGDK was specifically bound to human M-like cells and efficiently transcytosed from the apical side to the basolateral side in the M-like cell model. Thus, the TGDK-mediated vaccine delivery system represents a potential approach for enabling M cell-targeted mucosal vaccines in primates.


Assuntos
Imunidade nas Mucosas , Lisina/administração & dosagem , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Vacinação/métodos , Vacinas/administração & dosagem , Animais , Antígenos/imunologia , Células CACO-2 , Dendrímeros , Feminino , Imunofluorescência , Humanos , Lisina/imunologia , Macaca mulatta , Microscopia Eletrônica de Transmissão , Nódulos Linfáticos Agregados/metabolismo , Receptores CCR5/imunologia , Vírus da Imunodeficiência Símia , Vacinas/imunologia
3.
Biochem Biophys Res Commun ; 368(3): 501-7, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18261987

RESUMO

Humans and some Old World monkeys, chimpanzees, and cynomolgus macaques, are susceptible to oral poliovirus (PV) infection. Interestingly, rhesus macaques, although sensitive to injected PV, are not susceptible to gut infection. Not much is known about the initial event of gut infection by PV in rhesus macaques so far. Here, we show that PV can efficiently enter the lamina propria (LP) by penetrating across intestinal villous M-like cells in rhesus macaques. We found by immunofluorescence analysis that PV effectively invades LP rather than germinal centers (GCs) in rhesus macaques despite expressing PV receptor CD155 on cells within GCs and LP. Furthermore, energy dispersive X-ray spectroscopy demonstrated that gold-labeled PV is spatiotemporally internalized into villous M-like cells and engulfed by macrophage-like cells in LP. These results suggest that rhesus macaques may be resistant to productive gut PV infection owing to a defective translocation of PV to GCs.


Assuntos
Íleo/patologia , Íleo/virologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Poliomielite/patologia , Poliomielite/virologia , Poliovirus/fisiologia , Internalização do Vírus , Animais , Feminino , Humanos , Macaca mulatta , Poliovirus/ultraestrutura
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