RESUMO
TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:C), TLR4 (LPS), TLR7 (imiquimod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly I:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1beta, IL-6, TNF-alpha, and CCL3; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1.
Assuntos
Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Imunidade Adaptativa/imunologia , Aminoquinolinas/imunologia , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Citocinas/genética , Citocinas/metabolismo , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Imiquimode , Imunidade Inata/imunologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Poli I-C/imunologia , RNA Mensageiro/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia , Receptor 8 Toll-Like/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Susceptibility to HIV infection is widely different among individuals, and it is known that individuals can be identified who are repeatedly exposed to HIV but in whom neither infection nor disease are seen. The possibility that sheer luck is not the only determinant of this phenomenon begun to be considered in 1989 when it was reported that T cell responses to HIV proteins could be detected in antibody-negative sexual partners of known HIV-positive men. In this review, we will summarize the body of knowledge that stemmed from that first observation.
Assuntos
Infecções por HIV/imunologia , Infecções por HIV/transmissão , Soronegatividade para HIV , HIV-1/imunologia , Desaminase APOBEC-3G , Formação de Anticorpos , Quimiocinas CC/imunologia , Citidina Desaminase/imunologia , Feminino , Humanos , Imunidade Celular , Imunidade Inata , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologiaRESUMO
Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), a human cytidine deaminase, is a potent inhibitor of HIV replication. To explore a possible role of this protein in modulating in vivo susceptibility to HIV infection, we analyzed APOBEC3G expression in HIV-exposed seronegative individuals, HIV-seropositive patients, and healthy control subjects. The results showed that the expression of APOBEC3G is significantly increased in peripheral blood mononuclear cells (PBMCs)--mainly CD14(+) cells--and in cervical tissues of HIV-exposed seronegative individuals. Higher APOBEC3G expression correlated with a reduced susceptibility of PBMCs to in vitro infection with the HIV-1(Ba-L) R5 strain. APOBEC3G could be important in modulating in vivo susceptibility to sexually transmitted HIV infection.
Assuntos
Citidina Desaminase/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Desaminase APOBEC-1 , Estudos de Casos e Controles , Citidina Desaminase/genética , Feminino , Infecções por HIV/sangue , Soropositividade para HIV , HIV-1/patogenicidade , Humanos , Leucócitos Mononucleares/metabolismo , Edição de RNA , RNA Mensageiro/análise , Replicação Viral/fisiologiaRESUMO
Immunological analyses performed in healthy adolescents born of HIV-infected (seroreverters) or healthy mothers (healthy controls; HC) showed that immune activation and a skewing of postthymic differentiation are present in adolescent seroreverters. In-utero HIV exposure results in long-lasting imprinting on the immune system. Alternatively, an immune response naturally more prone to activation could prevent vertical infection. Endogenous antivirals (APOBEC, TRIM5alpha) were comparable in seroreverters and HC, and might not play a role in resistance to vertical HIV infection.
