Assuntos
Antígenos CD/metabolismo , Interferons/farmacologia , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Biomarcadores/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Células de Langerhans/efeitos dos fármacos , Monócitos/citologiaRESUMO
Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-ß signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells' infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells' susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4(+) T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission.
Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Células de Langerhans/virologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular , Humanos , Monócitos/metabolismo , Proteínas de Resistência a Myxovirus/metabolismo , Proteína 1 com Domínio SAM e Domínio HD , Fator de Crescimento Transformador alfa/metabolismo , Replicação Viral/fisiologiaRESUMO
Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T-cell responses, as well as B-cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , HIV-1/imunologia , Imunidade Celular/efeitos dos fármacos , Vacinas/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Humanos , Nanopartículas/administração & dosagem , Polipropilenos/farmacologia , Sulfetos/farmacologiaRESUMO
Early events during dengue virus (DENV) infection remain poorly understood. In this issue, Schaeffer and colleagues employ ex vivo human skin cells to investigate viral infection. They show that skin-resident immune cells are infected by DENV and that their infectability is increased in the inflammatory skin conditions (especially those in which IL-4 is released) that accompany the mosquito bites transmitting the virus.