Functions of HIV-1 Tat and its association with diseases / 中国生物制品学杂志

@#Acquired immune deficiency syndrome,or AIDS,has been a major infectious disease that troubles the public health in a global scale. Human immunodeficiency virus type 1(HIV-1)is the causative reagent responsible for AIDS development. Even though the highly active anti-retroviral therapy(HAART,or the cocktail therapy)that has been widely applied could effectively suppress the infection and replication of HIV-1,the infected people suffer from other related diseases,such as the HIV-associated neurocognitive disorder(HAND). This paper mainly focused on the function of an important regulatory protein of HIV-1,trans-activator of transcription(Tat),and its correlation with HIV-1 replication and HAND development,so as to clarify the importance of developing anti-AIDS drugs targeting Tat protein

A Role of TREX1 in Immune Regulation and Human Diseases / 中国生物化学与分子生物学报

Three prime repair exonuclease 1 (TREX1), also known as DNase IE, is a major 3'-5' restriction exonuclease in most of tissues and cell types of the mammals. The exonuclease activity of TREX1 plays an essential role in maintaining the immune tolerance of the innate immune system, which avoids the excessive activation of the innate immune system and massive production of auto-antibodies induced by the abnormal accumulation of cytosolic DNA. cGAS-STING signaling was identified as an important innate immune response to pathogens and maintained cellular environmental homeostasis. TREX1 prevents occasional leakage of nuclear DNA into the cytosol, which activates cGAS and triggers the downstream type I interferons cascade. Mutations of human TREX1 cause a series of autoimmune diseases, such as Aicardi-Goutieres syndrome (AGS), Familial chilblain lupus (FCL), Systemic lupus erythematosus (SLE) and Leukodystrophy-related retinopathy (RVCL). Besides, TREX1 inhibits the innate immune response to human immunodeficiency virus type 1 (HIV-1) and plays an important role in mediating the viral immune evasion. Moreover, TREX1 acts as an upstream regulator of the DNA sensing pathway, which maintains tumor immune tolerance and prevents cell senescence. Here, we focus on the immune regulation of TREX1 and demonstrate the role of TREX1 in autoimmune diseases, HIV-1 infection, cancer and cell senescence to provide the basic theoretical guidance for human disease therapy.

In vitro anti-HIV-1 activity of the enzymatic extract enriched with laccase produced by the fungi Ganoderma sp. and Lentinus sp / Actividad anti-VIH-1 in vitro del extracto enzimático enriquecido con lacasa producido por los hongos Ganoderma sp. y Lentinus sp

Background: Natural compounds are a good source for the development of antiretroviral drugs with low cytotoxicity. The laccase enzyme, produced by fungi of the genera Ganoderma sp. and Lentinus sp., inhibits the reverse transcriptase (RT) of the human immunodeficiency virus 1 (HIV-1), in cell-free models in vitro. Objetives: In this study we evaluated the anti-HIV-1 activity of the enzymatic extracts (EE) enriched with laccase, produced by two native species of fungi of the same genera in an in vitro cell culture model. Methods: The inhibition of viral replication was performed using the U373-MAGI cell line infected with recombinant viruses in the presence/absence of the EE and 48 hpi, the percentage of infected cells was evaluated by flow cytometry for green fluorescent protein ­GFP­ and ELISA for p24. The inhibition of the RT was determined by quantification of early and late products of reverse transcription using quantitative PCR. Results: The EEs from Ganoderma sp. and Lentinus sp. inhibited the replication of HIV-1 between 80 and 90% and decreased the production of early and late transcripts between 55,5%-91,3% and 82,1%-93,6% respectively. The EE from Lentinus sp. had the best selectivity index (SI: 8.3). Conclusions: These results suggest the potential anti-HIV-1 activity of the EE for the exploration of an alternative therapy against HIV-1 infection.

Antecedentes: Los compuestos naturales son una buena fuente para el desarrollo de fármacos antirretrovirales con baja citotoxicidad. La enzima lacasa, producida por hongos del género Ganoderma sp. y Lentinus sp., inhibe la transcriptasa reversa (TR) del virus de la inmunodeficiencia humana tipo 1 (VIH-1), en modelos in vitro, libres de células. Objetivos: En este estudio se evaluó la actividad anti-VIH-1 del extracto enzimático (EE) enriquecido con lacasa, producida por dos especies nativas de hongos de los mismos géneros en un modelo in vitro de cultivo celular. Métodos: La inhibición de la replicación viral se realizó usando la línea celular U373-MAGI infectada con virus recombinantes en la presencia/ ausencia del EE y 48 hpi, el porcentaje de células infectadas se evaluó mediante citometría de flujo para GFP y ELISA para p24. La inhibición de la TR se determinó mediante la cuantificación de los productos tempranos y tardíos de la transcripción reversa utilizando una PCR cuantitativa. Resultados: El EE de Ganoderma sp. y Lentinus sp. inhibió la replicación del VIH-1 entre el 80 y 90% y disminuyó la producción de transcriptos tempranos y tardíos entre el 55,5% -91,3% y 82,1% -93,6%, respectivamente. El EE de Lentinus sp. mostró el mejor índice de selectividad (IS: 8.3). Conclusiones: Estos resultados sugieren el potencial anti-VIH-1 del EE para la exploración de una terapia alternativa contra la infección por el VIH-1.

Study of HIV-1 Drug Resistance in Patients Receiving Free Antiretroviral Therapy in China / 中国病毒学

To investigate the prevalence of drug-resistance mutations, resistance to antiretroviral drugs, and the subsequent virological response to therapy in treatment-naive and antiretroviral-treated patients infected with HIV/AIDS in Henan, China, a total of 431 plasma samples were collected in Queshan county between 2003 and 2004, from patients undergoing the antiretroviral regimen Zidovudine + Didanosine + Nevirapine (Azt+Ddi+Nvp). Personal information was collected by face to face interview. Viral load and genotypic drug resistance were tested. Drug resistance mutation data were obtained by analyzing patient-derived sequences through the HIVdb Program (http://hivdb.stanford.edu). Overall, 38.5% of treatment-naive patients had undetectable plasma viral load (VL), the rate significantly increased to 61.9% in 0 to 6 months treatment patients (mean 3 months) (P＜0.005) but again significantly decrease to 38.6% in 6 to 12 months treatment patients (mean 9 months) (P＜0.001) and 40.0% in patients receiving more than 12 months treatment (mean 16 months) (P＜0.005). The prevalence of drug resistance in patients who had a detectable VL and available sequences were 7.0%, 48.6%, 70.8%, 72.3% in treatment-na(1)ve, 0 to 6 months treatment, 6 to 12 months treatment, and treatment for greater than 12 months patients, respectively. No mutation associated with resistance to Protease inhibitor (PI) was detected in this study. Nucleoside RT inhibitor (NRTI) mutations always emerged after non-nucleoside RT inhibitor (NNRTI) mutations, and were only found in patients treated for more than 6 months, with a frequency less than 5%, with the exception of mutation T215Y (12.8%, 6/47) which occurred in patients treated for more than 12 months. NNRTI mutations emerged quickly after therapy begun, and increased significantly in patients treated for more than 6 months (P＜0.005), and the most frequent mutations were K103N, V106A, Y181C, G190A. There had been optimal viral suppression in patients undergoing treatment for less than 6 months in Queshan,Henan. The drug resistance strains were highly prevalent in antiretroviral-treated patients, and increased with the continuation of therapy, with many patients encountering virological failure after 6 months therapy.

Rhizosecretion of HIV-1 Recombinant Capsid Protein from Transgenic Lycium barbarum L.Hairy Roots / 中国生物工程杂志

HIV p24 core protein can induce both cellular and neutralizing antibody responses.HIV-1 CA-virus-like particles(VLPs)vaccines provide a promising approach for the development of an effective vaccination strategy against HIV infection.Rhizosecreion of the recombinant proteins provides a new manufacturing platform that can simplify the extraction and purification procedure.Lycium barbarum L.was transformed by Agrobacterium tumefaciens EHA105 harboring the plant expression vector pCAMBIA1305.2-MA4-CA with a GRP signal peptide and MA4-CA fusion gene.Transgenic hairy roots were induced and cultivated in hydroponic culture.Western blotting indicated that the recombinant CA proteins were present in two forms,a glycosylated monomer(37 kDa)and a dimer(50 kDa)in the roots and hydroponic medium.It appeared from the present immunohistochemical data that the recombinant CA proteins fused with GRP signal peptide were confined to the cytoplasm,cell wall and intercellular space,indicating targeting into the secretory pathway.It demonstrated for the first time the rhizosecretion of HIV-1 recombinant capsid protein in Lycium barbarum L.hairy roots,and may offer a novel method for expressing HIV-1 CA-VLPs vaccines in plants.