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Microbicides are an important strategy for preventing the sexual transmission of HIV but, so far, the most advanced tenofovir-based microbicides have had modest efficacy. This has been related to adherence problems and high prevalence of tenofovir-resistant HIV-1 strains. P3 is a new peptide with potent activity against HIV that may be a good microbicide candidate. In this work P3 was formulated in a gel of hydroxyethyl cellulose and its activity, stability and safety profile in Balb/c mice were evaluated. HIV infection was fully blocked by a 1.5% gel containing P3 at the IC90 (366.4 nM) concentration. The antiviral activity did not change at 4°C during 4 months and at 25, 37 and 65°C for 1 week. P3 was stable and fully functional at acidic pH up to 24h, under different concentrations of hydrogen peroxide and in the presence of genital fluids up to 48h. P3 had no antibacterial activity and did not affect sperm motility and vitality. Finally, P3 didn't cause significant alterations in the vaginal epithelium of Balb/c mice at 0.06 (456.8 μM) and 0.2 mg/day (1522.7 μM) doses. These findings indicate that P3 is an excellent candidate for further development as a microbicide gel for the prevention of HIV transmission in women.

Background Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients. Methods We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. Results The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups ( p  = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups ( p  = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p  = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p  = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values. Conclusions European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH-gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.

Background: Eradication of hepatitis C virus (HCV) promotes an improvement in liver disease and the deactivation of the immune system. Here, we aimed to evaluate the changes in liver disease scores and plasma biomarkers following HCV clearance with direct-acting antivirals (DAAs) in HIV-infected patients with advanced HCV-related cirrhosis. Methods: We performed an observational study of 50 patients with advanced cirrhosis who received DAAs therapy. Variables were assessed at baseline and 48 weeks after HCV treatment completion. Epidemiological and clinical data were collected through an online form. Liver stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and Child-Pugh-Turcotte (CTP) were evaluated by physicians. Plasma biomarkers were measured by multiplex immunoassay. Results: We found significant decreases in severity scores of liver disease [LSM ( q -value < 0.001), HVPG ( q -value = 0.011), and CTP ( q -value = 0.045)] and plasma biomarkers [LBP ( q -value < 0.001), IP-10 ( q -value < 0.001), IL-8 ( q -value < 0.001), IL-18 ( q -value < 0.001), IL-1RA ( q -value = 0.013), OPG ( q -value < 0.001), sVCAM-1 ( q -value < 0.001), sICAM-1 ( q -value < 0.001), PAI-1 ( q -value = 0.001), and VEGF-A ( q -value = 0.006)]. We also found a significant direct association between the change in LSM values and the change in values of LBP ( q -value < 0.001), IP-10 ( q -value < 0.001), MCP-1 ( q -value = 0.008), IL-8 ( q -value < 0.001), IL-18 ( q -value < 0.001), OPG ( q -value = 0.004), sVCAM-1 ( q -value < 0.001), sICAM-1 ( q -value < 0.001), and PAI-1 ( q -value = 0.002). For CTP values, we found significant positive associations with IP-10 ( q -value = 0.010), IL-6 ( q -value = 0.010), IL-1RA ( q -value = 0.033), and sICAM-1 ( q -value = 0.010). Conclusion: The HCV eradication with all-oral DAAs in HIV/HCV-coinfected patients with advanced cirrhosis promoted an improvement in the severity of advanced cirrhosis and plasma biomarkers (inflammation, coagulopathy, and angiogenesis). The decrease in plasma biomarkers was mainly related to the reduction in LSM values.

The development of a safe and effective microbicide to prevent the sexual transmission of human immunodeficiency virus (HIV)-1 is urgently needed. Unfortunately, the majority of microbicides, such as poly(L-lysine)-dendrimers, anionic polymers, or antiretrovirals, have proved inactive or even increased the risk of HIV infection in clinical trials, most probably due to the fact that these compounds failed to prevent semen-exposed HIV infection. We showed that G2-S16 dendrimer exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4/CCR5 interaction and providing a barrier to infection for long periods, confirming its multifactorial and nonspecific ability. Previously, we demonstrated that topical administration of G2-S16 prevents HIV transmission in humanized BLT mice without irritation or vaginal lesions. Here, we demonstrated that G2-S16 is active against mock- and semen-exposed HIV-1 and could be a promising microbicide against HIV infection.

[This corrects the article DOI: 10.1371/journal.pone.0195744.].

Interferon alpha (IFN-α) can potently reduce human immunodeficiency virus type 1 (HIV-1) replication in tissue culture and animal models, but may also modulate residual viral reservoirs that persist despite suppressive antiretroviral combination therapy. However, mechanisms leading to viral reservoir reduction during IFN-α treatment are unclear. We analyzed HIV-1 gag DNA levels in CD4 T cells by digital droplet polymerase chain reaction and CD8 T-cell and natural killer (NK) cell phenotypes by flow cytometry in a cohort of antiretroviral therapy-treated HIV-1/hepatitis C virus-coinfected patients (n = 67) undergoing treatment for hepatitis C infection with pegylated IFN-α and ribavirin for an average of 11 months. We observed that IFN-α treatment induced a significant decrease in CD4 T-cell counts (P < .0001), in CD4 T-cell-associated HIV-1 DNA copies (P = .002) and in HIV-1 DNA copies per microliter of blood (P < .0001) in our study patients. Notably, HIV-1 DNA levels were unrelated to HIV-1-specific CD8 T-cell responses. In contrast, proportions of total NK cells, CD56brightCD16- NK cells, and CD56brightCD16+ NK cells were significantly correlated with reduced levels of CD4 T-cell-associated HIV-1 DNA during IFN-α treatment, especially when coexpressing the activation markers NKG2D and NKp30. These data suggest that the reduction of viral reservoir cells during treatment with IFN-α is primarily attributable to antiviral activities of NK cells.

Background Interleukin-7 (IL-7) is a critical factor for T cell development and for maintaining and restoring homeostasis of mature T cells. Polymorphisms at α-chain of the IL-7 receptor (IL7R or CD127) gene are related to evolution of HIV-infection, but there are no data concerning the evolution of hepatitis C virus (HCV) infection. The aim of this study was to analyze the association between IL7R polymorphisms and severe liver disease in HCV/HIV coinfected patients. Methods We performed a cross-sectional study in 220 naïve patients who underwent a liver biopsy. IL7R polymorphisms (rs6897932, rs987106 and rs3194051) were genotyped using the GoldenGate ® assay. The outcome variables were: (a) liver biopsy: advanced fibrosis (F ≥ 3), severe activity grade (A3); (b) non-invasive indexes: advanced fibrosis (APRI ≥1.5 and FIB-4 ≥3.25). Logistic regression analysis was used to investigate the association between IL7R polymorphisms and outcome variables. This test gives the differences between groups and the odds ratio (OR) for liver disease. Results Patients with rs6897932 CC genotype had higher likelihood of having A3 than patients with rs6897932 CT/TT (adjusted odds ratio (aOR) = 4.16; p = 0.026). Patients with rs987106 TT genotype had higher odds of having F ≥ 3 (aOR = 3.09; p = 0.009) than rs987106 AA/AT carriers. Finally, patients with rs3194051 AA genotype had higher odds of having severe liver fibrosis (F ≥ 3; APRI ≥1.5, and FIB4 ≥3.25) than patients with rs3194051 AG/GG genotype [aOR = 2.73 (p = 0.010); aOR = 2.52 (p = 0.029); and aOR = 4.01 (p = 0.027); respectively]. The CTA haplotype (comprised of rs6897932, rs987106, and rs3194051) carriers had higher odds of having F ≥ 3 (aOR = 1.85; p = 0.012), APRI ≥1.5 (aOR = 1.94; p = 0.023), and FIB4 ≥3.25 (aOR = 2.47; p = 0.024). Conversely, the CAG haplotype carriers had lower odds of having F ≥ 3 (aOR = 0.48; p = 0.011), APRI ≥1.5 (aOR = 0.48; p = 0.029), and FIB4 ≥3.25 (aOR = 0.29; p = 0.010). Conclusions The presence of IL7R polymorphisms seems to be related to severe liver disease in HIV/HCV coinfected patients, because patients with unfavorable IL7R genotypes (rs6897932 CC, rs987106 TT, and rs3194051AA) had a worse prognosis of CHC.

The Fat Mass and Obesity-Associated Protein (FTO) gene rs9939609 single nucleotide polymorphism (SNP) has been associated with obesity, metabolic syndrome, insulin resistance (IR), and type 2 diabetes mellitus in the general population. The aim of our study was to examine for the first time the association of the rs9939609 polymorphism with metabolic disturbances, liver disease and virologic response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) in human immunodeficiency virus (HIV)/HCV coinfected patients. We carried out a cross-sectional study in 261 patients, of whom 178 were subsequently treated with pegIFNα/RBV therapy. FTO rs9939609 and IFNL3 rs12980275 polymorphisms were genotyped by GoldenGate®. The main outcomes were: 1) metabolic disturbances: insulin resistance (homeostatic model assessment (HOMA-IR)) and overweight (body mass index (BMI)); 2) liver disease (Metavir score): significant fibrosis (F ≥2) and steatosis (>10% fatty hepatocytes); and 3) virologic response to HCV treatment: sustained virologic response (SVR). The rs9939609 AA genotype was associated with higher values of BMI (adjusted arithmetic mean ratio (aAMR) = 1.08; 95% confidence interval (95%CI) = 1.03 to 1.14; P = 0.002) and HOMA-IR (aAMR = 1.32; 95%CI = 1.03 to 1.69; P = 0.027). Patients with an rs9939609 AA genotype had higher likelihoods of achieving values of BMI ≥27.5 kg/m2 (adjusted odds ratio (aOR) = 3.46; 95%CI =1.17 to 10.21; P = 0.024), HOMA-IR ≥2.5 (aOR = 2.09; 95%CI = 1.02 to 4.32; P = 0.045), significant fibrosis (aOR = 2.34; 95%CI =1.02 to 5.36; P = 0.045) and steatosis (aOR = 3.65; 95%CI = 1.29 to 10.36; P = 0.015). The rs9939609 AT/AA genotype decreased the likelihood of achieving SVR (aOR = 0.58; 95%CI = 0.34 to 0.99; P = 0.044). A decision tree was performed with the genotypes of HCV, IFNL3 and FTO. The incorporation of rs9939609 significantly improves the prediction of SVR (P <0.05). The overall accuracy was 68.2%. Patients carrying the unfavourable AT/AA genotype of rs9939609 polymorphism had higher odds of metabolic disturbances and a lower likelihood of achieving successful virologic response to HCV therapy.

Background Peroxisome proliferator-activated receptor gamma-2 gene ( PPARγ2 ) rs1801282 (Pro12Ala) polymorphism has been associated with lower risk of metabolic disturbance and atherosclerosis. The aim of this study was to analyze the association between the Pro12Ala polymorphism and cardiometabolic risk factors in human immunodeficiency virus (HIV)/Hepatitis C virus (HCV)-coinfected patients. Methods We carried out a cross-sectional study on 257 HIV/HCV coinfected patients. PPARγ2 polymorphism was genotyped by GoldenGate® assay. The main outcome measures were: i) serum lipids (cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), LDL-C/HDL-C, and atherogenic index (AI)); ii) homeostatic model assessment (HOMA-IR) values; iii) serum adipokines (leptin, adiponectin, resistin, plasminogen activator inhibitor-1(PAI-1), hepatic growth factor (HGF), and nerve growth factor (NGF)). Generalized Linear Models (GLM) with gamma distribution (log-link) were used to investigate the association between PPARγ2 polymorphism and continuous outcome variables. This test gives the differences between groups and the arithmetic mean ratio (AMR) in continuous outcome variables between groups. Results The rs1801282 CG/GG genotype was associated with low values of cholesterol (adjusted arithmetic mean ratio (aAMR) = 0.87 (95% of confidence interval (95% CI) = 0.79; 0.96); p = 0.004) and LDL-C (aAMR = 0.79 (95% CI = 0.68; 0.93); p = 0.004). Furthermore, rs1801282 CG/GG was associated with low values of HOMA-IR (aAMR = 0.69 (95% CI = 0.49; 0.98); p = 0.038) among patients with significant liver fibrosis (F ≥ 2). Moreover, rs1801282 CG/GG was also associated with low serum values of hepatic growth factor (HGF) (aAMR = 0.61 (95% CI = 0.39; 0.94); p = 0.028), and nerve growth factor (NGF) (aAMR = 0.47 (95% CI = 0.26; 0.84); p = 0.010). The serum levels of leptin, adiponectin, resistin, and PAI-1 did not show significant differences. Conclusions The presence of PPARγ2 rs1801282 G allele (Ala variant) was associated with a protective cardiometabolic risk profile versus CC genotype in HIV/HCV-coinfected patients. Thus, PPARγ2 rs1801282 polymorphism may play a significant role in the development of metabolic disorders in HIV/HCV coinfected patients, and might have an influence on the cardiovascular risk.