RESUMEN
SAMHD1 (sterile alpha motif and HD domain 1) is a protein that is found in myeloid cells, which restricts HIV1 replication. It depletes the de-oxy-nucleoside tri-phosphate (dNTPs) pool needed for a viral cDNA synthesis leading to inhibition of viral replication inside the cells. However, it does not restrict HIV2 replication in myeloid cells due to the presence of viral Vpx protein. Vpx is a virion-associated protein which augments viral infectivity and it only exists in HIV2 and it has been recently shown in Simian Immunodeficiency Virus (SIV) and which can induce degradation of SAMHD1 protein. This increases the amount of dNTPs for viral reverse transcription in cytoplasm and HIV infection. HIV2 reverse transcription is believed to be less active than HIV1 and this could be the reason for the absence of Vpx from HIV1. Protein expression and interaction between Vpx and SAMHD1 remains unclear. The interaction of SAMHD1 and HIV2-VPx patients' cells can be considered as a first step to help in the development for more effective anti-HIV drugs and possible novel intervention therapy in the future. Present review article provides comprehensive insights on the above issue. We performed a comprehensive literature search in the bibliographic database "Pubmed," looking at studies discussing the SAMHDI and Vpx interactions.
RESUMEN
SAMHD1, a human host factor found in myeloid cells which restricts HIV-1 replication. It depletes the dNTPs pool for viral cDNA syntheses, thus preventing the viral replication in the cells. The viral accessory protein, Vpx, exists only in SIVmac/HIV-2 particles. Vpx in SIVmac can induce proteosomal degradation of SAMHD1, which then leads to a decrease in the cytoplasmic dNTP pool. The protein-protein interaction between Vpx and SAMHD1 and its consequences are still unclear. Methods: In this study, we cloned, for the first time, Vpx gene from a HIV-2 infected patient and found up to 30% sequence variation compared to known HIV-2 strains. We then analyzed the role of SAMHD1 protein expression in transfected THP-1 and U937 cells by transfecting with the Vpx gene derived from SIVmac, HIV-2 from the NIH sample as well as HIV-2 from a Saudi patient. We found that Vpx gene expression led to reduced levels of intracellular SAMHD1. When the supernatants of the transfected cell lines were examined for secreted cytokines, chemokines and growth factors, Vpx expression seemed to be suppressive of pro-inflammatory response, and skewed the immune response towards an anti-inflammatory response. These results suggest that Vpx can act at two levels: clearance of intracellular restriction factor and suppression of cytokine storm: both aimed at long-term latency and host-pathogen stand-off, suggesting that Vpx is likely to be a potential therapeutic target.
Asunto(s)
Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-2/fisiología , Interacciones Huésped-Patógeno , Proteína 1 que Contiene Dominios SAM y HD/metabolismo , Proteínas Reguladoras y Accesorias Virales/metabolismo , Secuencia de Aminoácidos , Línea Celular , Clonación Molecular , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Regulación Viral de la Expresión Génica , Humanos , Inmunofenotipificación , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/virología , Unión Proteica , Análisis de Secuencia de ADN , Proteínas Reguladoras y Accesorias Virales/genética , Latencia del VirusRESUMEN
BACKGROUND/AIM: Hepatitis C virus (HCV) infection is a worldwide health issue with about 3% of the world's population having HCV. In Saudi Arabia, prevalence ranges from 1.0% to 5.87%. Cutaneous diseases can indicate the presence of HCV infection. OBJECTIVES: The research project aims to identify prospectively the prevalence of HCV infection in 200 patients with various types of skin disorders and 50 healthy blood donors, and to quantify this association through clinical and laboratory investigations. METHODS: Two hundred patients with cutaneous manifestations who presented at the Dermatology outpatient clinics of King Khalid University Hospital (KKUH) and King Abdulaziz University Hospital (KAUH), Riyadh, and 50 healthy blood donors were prospectively studied. Patients were examined by a team of dermatologists and clinical data were collected through a standard questionnaire. Ten milliliters of venous blood were collected from fully consented, 8-10 h fasting patients and serum was analyzed for AST, ALT, double infection with HBsAg, anti-HCV antibodies, and screened for HCV-RNA-PCR. RESULTS: Patients from the study (n = 200) consisted of 25 (12.5%) males and 175 (87.5%) females, with a mean age of 42.9 ± 15.06 years. Clinical examinations revealed that (35%) had urticaria, followed by pruritus (28%), lichen planus (25.5%), prurigo (10%), and palpable purpura (1.5%). The main serum levels of ALT and AST were within the normal reference ranges. Twenty-four patients (12%) tested positive for anti-HCV antibodies, with 15 (62.5%) being positive for the presence of HCV-RNA by PCR and 9 (37.5%) resulting negative for the viral RNA. Of the 24 anti-HCV positive patients, pruritus 12 (50%), urticaria 5 (20.8%), lichen planus 5(20.8%), and palpable purpura 2(8.3%). Five (2.5%) patients were positive for HBsAg, with 3 (60%) having pruritus and 2 (40%) presenting with urticaria. Of the 50 healthy blood donors, only one (2%) tested positive for the presence of anti-HCV antibodies, and all the donors tested negative for HBsAg. CONCLUSION: Results clearly indicate the prevalence of anti-HCV antibodies in 24 out of 200 patients (12%) with skin manifestations seen at the dermatology outpatient clinics and documented with HCV-RNA-PCR positivity of 15/24 (62.5%). A p-value of <0.05 was considered significant, therefore, it is suggested that patients presenting with urticaria, pruritus and LP be investigated to exclude the possibility of HCV infection.
RESUMEN
The main objective of this study was to estimate the prevalence of Hepatitis C virus (HCV) genotypes in 56 pruritus patients and 50 healthy blood donors on the basis of clinical and laboratory investigations. Both demographic and clinical data were collected from each subject after obtaining informed consent and approval from an ethics committee. Ten milliliters of venous blood was collected from fasting patients (8-10 h) and serum was used for aspartate transaminase and alanine transaminase tests, anti-HCV antibody testing, HCV-RNA polymerase chain reaction screening, and genotyping analysis. HCV was found to be significantly predominant over HBV infection among the pruritus patients (p<0.001). Twelve pruritus patients (21.42%) were positive for anti-HCV antibodies and nine of them were confirmed positive for HCV RNA presence. Of the two major genotypes revealed, genotype 4 was found to be significantly predominant over the mixed genotype, that is, 4a/c+3a (p<0.001). Subtyping results showed that a significant majority of the type 4 were of the HCV subtype 4a (five patients), followed by 4c (two patients) and 4b genotypes (one patient) and mixed genotype 4a/c+3a (one patient). Results of this prospective study indicated the significant association between pruritus and HCV infection. HCV genotype 4 is the most predominant genotype among the pruritus patients and warrants larger studies in different ethnicities to find the molecular association between HCV genetic variants and pruritus.