Polimorfismo genético del correceptor CCR5 en pacientes cubanos VIH/sida de la tercera edad / Genetic polymorphism of the CCR5 coreceptor in Cuban elderly HIV/AIDS patients

Introducción: El polimorfismo en algunos genes de quimiocinas se asocia con resistencia a la infección por VIH-1, en este sentido la presencia de la mutación Δ32 del correceptor CCR5 en homocigosis, se relaciona con resistencia a la infección y la mutación heterocigótica con un retraso en la progresión de la enfermedad. Objetivos: Identificar la frecuencia del polimorfismo genético del correceptor CCR5 en los pacientes bajo estudio, así como su relación con los niveles de linfocitos T CD4+, la carga viral y las enfermedades oportunistas. Métodos: Se realizó un estudio de corte transversal en 45 pacientes VIH/sida de la tercera edad, cubanos atendidos en el Centro Hospitalario Universitario del IPK durante los meses de enero a mayo de 2019 en el servicio de Medicina del Centro Hospitalario Universitario del IPK, a los que se les realizó la reacción en cadena de la polimerasa (PCR) para determinar el polimorfismo genético del correceptor CCR5. Resultados: El polimorfismo genético del correceptor CCR5 que predominó fue el homocigótico salvaje con 87 por ciento seguido del heterocigótico Δ32 con 13 por ciento. El 80 por ciento de los pacientes presentaron carga viral no detectable y el 56 por ciento niveles de linfocitos T CD4+ por encima de 350 cél/µL. La enfermedad oportunista que predominó fue la neumonía por Pneumocystis jirovecii en 32 por ciento de los sujetos estudiados. No se observaron diferencias estadísticamente significativas entre el polimorfismo genético del correceptor CCR5 y los niveles de linfocitos T CD4+, la carga viral y las enfermedades oportunistas presentes en los pacientes estudiados. Conclusiones: Los polimorfismos genéticos del correceptor CCR5 hallados fueron el homocigótico salvaje y el heterocigótico-∆32. Fue limitado el polimorfismo del gen en los pacientes estudiados(AU)

Introduction: Polymorphism in some chemokine genes is associated to resistance to HIV-1 infection. Homozygous Δ32 mutation of the CCR5 coreceptor is related to resistance to infection, whereas heterozygous mutation is related to a delay in the progress of the disease. Objectives: Identify the frequency of genetic polymorphism of the CCR5 coreceptor in the patients studied, as well as its relationship to CD4+ T lymphocyte levels, viral load and opportunistic diseases. Methods: A cross-sectional study was conducted of 45 Cuban elderly HIV/AIDS patients attending the Medicine Service of the University Hospital Center at IPK from January to May 2019. These patients underwent polymerase chain reaction testing (PCR) to determine genetic polymorphism of the CCR5 coreceptor. Results: A predominance was found of wild homozygotous genetic polymorphism of the CCR5 coreceptor with 87 percent, followed by heterozygotous Δ32 genetic polymorphism with 13 percent. In 80 percent of the patients studied the viral load was undetectable, whereas in 56 percent CD4+ T lymphocyte levels were above 350 cel/µl. The prevailing opportunistic disease was Pneumocystis jirovecii pneumonia in 32 percent of the subjects. Statistically significant differences were not found between genetic polymorphism of the CCR5 coreceptor and CD4+ T lymphocyte levels, viral load and the opportunistic diseases present in the patients studied. Conclusions: The genetic polymorphisms of the CCR5 coreceptor found in the study were of the wild homozygotous and heterozygotous Δ32 types. Gene polymorphism was limited in the patients studied(AU)

CD72 is a Negative Regulator of B Cell Responses to Nuclear Lupus Self-antigens and Development of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by production of autoantibodies to various nuclear antigens and overexpression of genes regulated by IFN-I called IFN signature. Genetic studies on SLE patients and mutational analyses of mouse models demonstrate crucial roles of nucleic acid (NA) sensors in development of SLE. Although NA sensors are involved in induction of anti-microbial immune responses by recognizing microbial NAs, recognition of self NAs by NA sensors induces production of autoantibodies to NAs in B cells and production of IFN-I in plasmacytoid dendritic cells. Among various NA sensors, the endosomal RNA sensor TLR7 plays an essential role in development of SLE at least in mouse models. CD72 is an inhibitory B cell co-receptor containing an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region and a C-type lectin like-domain (CTLD) in the extracellular region. CD72 is known to regulate development of SLE because CD72 polymorphisms associate with SLE in both human and mice and CD72−/− mice develop relatively severe lupus-like disease. CD72 specifically recognizes the RNA-containing endogenous TLR7 ligand Sm/RNP by its extracellular CTLD, and inhibits B cell responses to Sm/RNP by ITIM-mediated signal inhibition. These findings indicate that CD72 inhibits development of SLE by suppressing TLR7-dependent B cell response to self NAs. CD72 is thus involved in discrimination of self-NAs from microbial NAs by specifically suppressing autoimmune responses to self-NAs.

HIV small-molecule entry inhibitors targeting gp120, CD4 and CXCR4: Research advances / 国际药学研究杂志

AIDS is an infectious disease caused by human immunodeficiency virus (HIV) and has done great harm to human beings. The envelope glycoprotein surface subunit gp120 and its receptor CD4 and coreceptor CXCR4 play important roles in HIV-1 entry. The Phe43 pocket and Arg59 of gp120 are two important regions that interact with CD4. Recently, HIV small-molecule entry inhibitors have become a hot topic in anti-HIV drug research, which are able to inhibit the virus before the cells are infected. The Phe43 pocket is an attractive target and the study of Phe43 pocket-targeting small-molecule entry inhibitors is underway, including BMS-378806, BHS-488043 and its analogs, and NBD-556 and its analogs. Besides, CXCR4 antagonist is another important approach.

HIV small-molecule entry inhibitors targeting gp120, CD4 and CXCR4:research advances / 国际药学研究杂志

AIDS is an infectious disease caused by human immunodeficiency virus(HIV)and has done great harm to human beings. The envelope glycoprotein surface subunit gp120 and its receptor CD4 and coreceptor CXCR4 play important roles in HIV-1 en?try. The Phe43 pocket and Arg59 of gp120 are two important regions that interact with CD4. Recently,HIV small-molecule entry inhib?itors have become a hot topic in anti-HIV drug research,which are able to inhibit the virus before the cells are infected. The Phe43 pocket is an attractive target and the study of Phe43 pocket-targeting small-molecule entry inhibitors is underway,including BMS-378806,BHS-488043 and its analogs,and NBD-556 and its analogs. Besides,CXCR4 antagonist is another important approach.

Distribution of SDF1-3'A polymorphisms in three different ethnic groups from Brazil

A mutation described as a G-to-A transition has been reported in SDF-1 gene (SDF1-3'A), being prevalent in all ethnic groups, except in Africans. This mutation is associated with the onset of AIDS progression. Our aim was to identify the frequency of this allele in different groups from Brazil: Tiriyó and Waiampi Amerindian tribes (Asian ancestry); selected blood donors from Joinville (German descendents); and from Salvador (predominance of African and Portuguese mixture). SDF1-3'A was screened by PCR/RFLP with MspI enzyme. Our results showed a high allelic frequency in Tiriyó tribe (0.24) and Joinville population (0.21), and a frequency of 0.17 and 0.05 in the Salvador population and in the Waiampi tribe, respectively. There was no statistical difference among the allelic frequencies in the studied ethnic groups, except in the Waiampi. Due to the great genetic diversity among Brazilian population and the lack of studies on SDF1-3'A allele, our study of this allelic frequency in these different Brazilian ethnic groups could be important to identification of biomarker for therapeutic support in progression to AIDS and a molecular marker for analysis of evolutionary relationships among human populations.

The inhibitory effect of CCR5Delta32 protein on cell surface expression of the HIV-1 coreceptor CCR5 and CXCR4 / 中国免疫学杂志

Objective: To demonstrate that expression of the CCRSDelta32 protein in PBMCs able to down-regulate surface expression of the HIV-1 coreceptor CCR5 and CXCR4.Methods:CCR5Delta32 gene was amplified from human peripheral blood mononuclear cells(PBMCs)genomic DNA by using PCR, and then cloned into lentiviral vector pLenti6/V5-D-TOPO.Recombinant lentiviral particles were produced by packaging using 293T cells.Human PBMCs were transfected with the constructed recombinant lentiviral particles and the expression of CCR5Delta32 was detected by Western blot.The level of CCR5 and CXCR4 expression on transfected PBMCs was detected by FACS analysis.Results: The recombinant lentiviral vector pLenti-CCR5Delta32 was constructed successfully, and the target protein was expressed in PBMCs.FACS analysis showed that CCR5Delta32 protein expressed in PBMCs was able to down-regulate cell surface expression of CCR5 and CXCR4.Conclusion: This study is expected to be used for the gene therapy on AIDS, which deserves further study.

Advancement in developing a new class of anti-AIDS drugs: HIV entry inhibitors / 中国药理学通报

Process of HIV fusion with target cells, mediated by the HIV envelope glycoprotein surface subunit gp120 and the transmembrane subunit gp41, is an important step for drug intervention. The membrane fusion events leading to HIV entry into the target cell are initiated by the binding of gp120 to CD4 and subsequently to a co-receptor, CXCR4 or CCR5. Consequently, gp41 undergoes conformational changes, resulting in the fusion between the viral and cellular membranes or between the infected and uninfected cells. Therefore, gp120 and gp41 on the virions and CD4 and coreceptors on the target cells may serve as targets for development of a new class of anti-HIV drugs, HIV entry inhibitors, with a mechanism of action different from those mediated by reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs), the two classes of antiretroviral drugs approved by FDA for clinical application. The successful development of a peptidic anti-HIV drug T-20, which is targeted to the HIV gp41, implies that HIV entry inhibitors are milestone in the current anti-HIV therapy. Application of the HIV entry inhibitors alone or in combination with the RTIs and PIs will increase the efficacy and reduce the toxicity of these anti-HIV drugs and will save lives of AIDS patients who fail to response to the current antiretroviral drugs. The advancement in the study and development of the HIV entry inhibitors was reviewed here in detail

DETECTION OF HIV CORECEPTOR CCR5 MUTATION IN UIGUR POPULATION FROM SINKIANG UIGUR AUTONOMOUS REGION / 解放军医学杂志

Whole blood samples were collected from 316 Uigur subjects inhabiting Kashi City, Sinkiang Uigur Autonomous Region, and their genomic DNA was extracted using QIAgen Blood Kit. DNA fragment spanning CCR5?32 and CCR5m303 mutation points were amplified by PCR and genotyped by directed electrophoresis and RFLP with HinCII respectively. In all 316 samples only 22 heterozygotes of CCR5?32 were found, in accordance with Hardy Weinberg equilirium. No CCR5m303 mutation was found. No difference existed between male and female individuals. The frequency of CCR5?32 in Uigur population is 3.48%, similar to Medi Asia ethnic groups (higher than that of Chinese Han people and lower than that of Caucasian people), i.e, in continuity regarding district distribution. Due to its slow down effect on clinical course of AIDS , high frequency of CCR5?32 is highly significant in prevention and treatment of AIDS in Uigur population.

CHARACTERISTICS AND CLINICAL IMPLICATION OF HIV-1 CORECEPTOR CX_3CR1 ALLELIC POLYMORPHISM IN UIGUR ETHNIC GROUP FROM SINKIANG UIGUR AUTONOMOUS REGION / 解放军医学杂志

It was reported that 249I 280M haplotype of HIV coreceptor CX 3 CR1 was associated with accelerated AIDS progression. In this study, genomic DNA of 119 Uigur subjects (98 normal, 21 HIV 1 infected) was purified from PBMC, and 249I and 280M allelic frequencies were identified by PCR RFLP. All data were tested by ? 2 analysis.It was found that allelic frequency of 249I and 280M was 15 8% and 13 8%, respectively, and there was no difference between normal and HIV infected groups. Both population and sex distribution were in accordance with Hardy Weinberg equilibrium. Frequency of 249I280M haplotype was 13 8%, close to that of Caucasian people. No linkage was found between CX 3 CR1 and CCR5?32, but strong linkage existed between 249I and 280M ( P