The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

Despite multiple sexual exposures to HIV-1 virus, some individuals remain HIV-1 seronegative. Although several genetic factors have been related to HIV-1 resistance, the homozygosity for a mutation in CCR5 gene (the 32-bp deletion, i.e., CCR5-Delta32 allele) is presently considered the most relevant one. The C-type lectins, DC-SIGN (present on dendritic cells and macrophages) and DC-SIGNR (present on endothelial cells in liver and lymph nodes) efficiently bind and transmit HIV-1 to susceptible cell in trans, thereby augmenting the infection. A potential association of the DC-SIGN and DC-SIGNR neck domain repeat polymorphism and risk of HIV-1 infection is currently under debate. To determine the influence of host genetic factors on HIV-1 resistance, we conducted genetic risk association study in HIV-1-exposed seronegative (n = 47) individuals, HIV-1 seronegative (n = 262) healthy control, and HIV-1-infected seropositive patients (n = 168) for polymorphism in neck domain of DC-SIGN and DC-SIGNR genes. The DC-SIGN and DC-SIGNR genotypes were identified by polymerase chain reaction method in DNA extracted from peripheral blood and confirmed by sequencing. Fisher exact or chi (2) test was used for static analysis. DC-SIGN genotype and allele distribution was fairly similar in HIV-1-exposed seronegative, HIV-1 seropositive, and HIV-1 seronegative control. There was no statistical significance in the differences in the distribution of DC-SIGN genotypes. A total of 13 genotypes were found in DC-SIGNR neck repeat region polymorphism. Among all the genotypes, only 5/5 homozygous showed significant reduced risk of HIV-1 infection in HIV-1-exposed seronegative individuals (p = 0.009). A unique genotype 8/5 heterozygous was also found in HIV-1 seropositive individual, which is not reported elsewhere.

The relationships between host immune factors and HIV-1 disease progression are still in dispute. The RANTES SNPs exhibit distinct ethnic distribution and are associated with different effects on the course of HIV infection. Therefore, impact of RANTES gene polymorphism on HIV-1 transmission and progression needs to be evaluated. The RANTES genotypes were identified by PCR-RFLP method and confirmed by sequencing in HIV-1 seronegative (HSN; n=315), HIV-1 exposed seronegative (HES; n=47) and HIV-1 seropositive (HSP; n=196) patients classified into different clinical stages (i.e. Stages I, II, III). Fisher exact test was used for statistical analysis and Arlequin software for haplotype analysis. RANTES allele -403G, -28C and In1.1 T were the predominant allele in the subject studied. HSP group have higher frequency of RANTES In1.1 T allele compared with HSN (91.32% vs. 86.19%; P=0.013) and HES (91.32% vs. 78.72%; P=0.001). Higher frequency of RANTES In1.1 C allele in Stage III was observed, compared with Stage I (14.28% vs. 6.39%) and was significantly associated with high risk (P=0.047, OR=2.439, C.I.=1.061-5.609). Haplotype II (ACT) was significantly higher in HSP compared with HSN (9.69% vs. 1.58%) and associated with high risk (P<0.001, OR=6.655, C.I.=2.443-18.132). There were no significant differences in RANTES -403 A/G and -28 C/G genotype and allele distribution in all the groups compared. Our results implicate that RANTES In1.1 T allele and haplotype II (ACT) may be a risk factor for HIV-1 transmission while RANTES In1.1 C allele may be risk factor for disease progression among North Indians.

A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

IGF-1R signaling controls various vital cellular functions and this signaling is deregulated in many cancers, including pancreatic cancer. Several efforts have mainly focused on inhibiting the IGF-1R signaling cascade. The outcomes of these focused preclinical studies have been positive, whereas clinical trials of IGF-1R inhibitors in pancreatic cancer have failed, raising the questions about this therapeutic approach. This necessitates a better understanding of the role of IGF-1R signaling in pancreatic cancer. We investigated the impact of IGF-1R signaling on crucial transcription factors and identified the FOXC1 as one of the crucial regulator of IGF-1R signaling. We employed genetic approaches to overexpress and silence FOXC1 in pancreatic cancer cells. Our results demonstrate that IGF-1R and FOXC1 seem to positively regulate each other. Further, FOXC1 increased the metastatic abilities of pancreatic cancer cells by enhancing cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, and angiogenesis. The data from xenograft experiments further established the importance of FOXC1 in pancreatic tumorigenesis. In conclusion, FOXC1 is a potent oncogenic transcription factor, which promotes pancreatic cancer growth and metastasis. Thus, targeting FOXC1 could be a potential therapeutic strategy against pancreatic cancer.