HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV).

BACKGROUND: Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. MATERIALS AND METHODS: The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. RESULTS: Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. CONCLUSIONS: Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.

An epidemiological and retrospective study in a cohort qualified for SARS-CoV-2 vaccination in the region of Lower Silesia, Poland.

BACKGROUND: Since the beginning of the coronavirus disease (COVID-19) pandemic, numerous infections have been observed with various symptoms and degrees of severity. Not all patients have had a confirmation of infection made using reverse transcription polymerase chain reaction (RT-PCR) or antigen tests. It has been observed that some people, including convalescents or those without knowledge of a past infection, perform serological tests to detect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. OBJECTIVES: We aimed to evaluate the levels of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies in a cohort of convalescents and in individuals not previously infected, who were willing to get vaccinated. We also aimed to assess several socio-clinical factors associated with participants' humoral responses. MATERIAL AND METHODS: We recruited 298 individuals from the region of Lower Silesia who were willing to get vaccinated for SARS-CoV-2. The participants were divided into 2 groups: convalescents (group I) and participants without a past infection (group II). Several seropositive individuals in group II were identified, and they were transferred to group I, resulting in a final distribution of 171 individuals in group I and 127 individuals in group II. For serological testing, the QuantiVac anti-SARS-CoV-2 (IgG) enzyme-linked immunosorbent assay (ELISA) was used. RESULTS: The results showed the presence of anti-SARS-CoV-2 IgG antibodies in participants from group I, with an average number of 190.3 IU/mL. Twenty-three participants (13.45%) did not have a detectable level of antibodies despite a previous SARS-CoV-2 infection. In 21 participants (12.28%), antibodies were detected despite no previous symptoms of infection (average level: 145.0 IU/mL). CONCLUSION: Older participants were more likely to experience a symptomatic SARS-CoV-2 infection, and the severity of the symptoms was related to higher antibody titers seen later after COVID-19. Numerous individuals from group II were unaware of past SARS-CoV-2 infections. In several participants, antibodies were not detected despite a previous infection.

The Role of Plasminogen Activator Inhibitor 1 in Predicting Sepsis-Associated Liver Dysfunction: An Observational Study.

Sepsis-associated liver dysfunction (SALD) is associated with a poor prognosis and increased mortality in the intensive care unit. Bilirubin is one of the components of Sequential Organ Failure Assessment used in Sepsis-3 criteria. Hyperbilirubinemia is a late and non-specific symptom of liver dysfunction. This study aimed to identify plasma biomarkers that could be used for an early diagnosis of SALD. This prospective, observational study was conducted on a group of 79 patients with sepsis and septic shock treated in the ICU. Plasma biomarkers-prothrombin time, INR, antithrombin III, bilirubin, aspartate transaminase (AST), alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, albumin, endothelin-1, hepcidin, plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, and interferon-gamma inducible protein (10 kDa) were analysed. Plasma samples were obtained within 24 h after having developed sepsis/septic shock. Enrolled patients were followed for 14 days for developing SALD and 28 days for overall survival. A total of 24 patients (30.4%) developed SALD. PAI-1 with a cut-off value of 48.7 ng/mL was shown to be a predictor of SALD (AUC = 0.671, sensitivity 87.3%, and specificity 50.0%) and of 28-day survival in patients with sepsis/septic shock (p = 0.001). Measuring PAI-1 serum levels at the onset of sepsis and septic shock may be useful in predicting the development of SALD. This should be verified in multicenter prospective clinical trials.

How Humoral Response and Side Effects Depend on the Type of Vaccine and Past SARS-CoV-2 Infection.

Since the end of December 2020, it has been possible to vaccinate against COVID-19. Our aim was to evaluate and compare the effectiveness of the vaccines available at the time of the mass vaccination program in Poland and also to look into the most common adverse side effects. Patients' anti-SARS-CoV-2 antibodies levels were checked before vaccination and after the first and after the second/last dose by the anti-SARS-CoV-2 QuantiVac ELISA (IgG) (EUROIMMUN MedicinischeLabordiagnostica AG; Luebeck; Germany) test. Before each blood collection, all patients filled out a questionnaire regarding experienced side effects. We observed that 100% of patients responded to the vaccinations. After the first dose, convalescents had much higher levels of anti-SARS-CoV-2 antibodies than naive patients, although after the second dose, 61 out of 162 convalescents (37.7%) had lower results than before. The comparison of immunological responses in the convalescents group after the first dose and in the naive group after the second dose showed that convalescents had higher antibody titers, which may suggest the possibility of changing the vaccination schedule for convalescents. The highest antibody titers after both the first and second doses were observed after Moderna shots. Fever was identified as a significant factor regarding higher levels of antibodies after the first and second doses of the vaccine.

Asymptomatic Human Immunodeficiency Virus-1 Infection with High CD4+ T Cell Count Does Not Alter Iron Metabolism or Hepcidin Levels: The Pilot Study.

INTRODUCTION: The purpose of the study was to assess hepcidin levels and iron metabolism in otherwise healthy human immunodeficiency virus-1 (HIV-1)-infected males and the influence of antiretroviral therapy on hepcidin production, as data in this group are scarce. METHODS: A total of 89 HIV-1-infected males, 42 on effective antiretroviral therapy (ART)-group A, 47 treatment-naïve-group B, and 27 healthy controls-group C, were enrolled. Erythrocytes parameters, iron metabolism parameters, hepcidin, highly sensitive C-reactive protein (hsCRP), interleukin 6 (IL-6), and soluble transferrin receptor (sTfR) levels were assessed. Conditions related to inflammatory activity, systemic metabolic diseases and iron supplementation were exclusion criteria. Convenience sampling was used. RESULTS: Median age in HIV-1 group was 33 years, and 27 years in the control group. Median CD4+ T-cell count was 724 cells/µl in group A, and 488 cells/µl in group B (p = 0.0000). Nadir CD4+ T-cell count was 397 cells/µl in group A and 475 cells/µl in group B (p = 0.0001). Median value of HIV-1 viral load (VL) in group B was 16 900 copies/mL. The hepcidin value was lower in group A than in groups B (p = 0.0008) or C (p = 0.0004), without differences between groups B and C. The hepcidin value correlated with ferritin in groups A (r2 = 0.16; p = 0.008) and B (r2 = 0.39; p = 0.000), but not in group C (r2 = 0.11; p = 0.09). In group A, the hepcidin value correlated with current CD4+ count (r = 0.48, p = 0.0012), but there was no correlation in group B. There were no correlations of hepcidin values with CD4+ T cell nadir in group A (p = 0.371) or in group B (p = 0.477); ART period (p = 0.614); VL in group B (p = 0.71). No abnormalities of iron metabolism, hsCRP, IL-6, or sTfR were noted. CONCLUSIONS: Asymptomatic HIV-1 infection does not cause clinically important iron metabolism alterations or increased hepcidin production. Hepcidin values decrease on effective antiretroviral therapy.

Prevalence and genotype distribution of human papillomavirus infection among HIV-infected men who have sex with men living in Lower Silesia, Poland.

Introduction: Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and is associated with the risk of anogenital and oropharyngeal cancers. Men who have sex with men (MSM) are at a high risk of HPV infection. However, little up-to-date data are available regarding the prevalence of HIV and HPV co-infection in MSM in Poland. Aim: To evaluate the prevalence, genotype distribution and risk factors for HPV infection among HIV-positive MSM living in Lower Silesia. Material and methods: A total of 54 HIV-positive and 28 HIV-negative MSM participated in the study. The polymerase chain reaction was performed to detect HPV from oral and anal swabs. A self-applied written questionnaire was conducted to collect sociodemographic and behavioural data. Results: The prevalence rates of oral and anal HPV infection were higher in HIV-infected MSM than in HIV-negative MSM. Statistical analysis showed that the prevalence of high oncogenic genotypes, HPV 16 and HPV 18, at the anal site was significantly higher in patients with lower CD4 cell counts, in addition, HPV 18 infection was significantly more frequent in patients with higher levels of HIV RNA. Moreover, HPV 33 and HPV 52 at the anal site were significantly more common in patients with lower nadir CD4. Conclusions: This is the first report of HPV infection among Polish HIV-infected MSM. Our results show that HIV-related immunodeficiency is associated with a higher prevalence of high-risk HPV infections, therefore early detection of HIV infection and initiation of antiretroviral therapy might reduce the risk of HPV-related diseases.

The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin.

Background: Tryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT1A and 5-HT2A, and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain. Methods: The study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery-Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement. Results: Of the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (ß = -0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery-Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively). Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: The present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.

Alterations in the metabolism of tryptophan in patients with chronic hepatitis C six months after pegylated interferon-α 2a treatment.

BACKGROUND: Risk of depression and suicide in patients on interferon remains also after the treatment, the pathogenesis of which is still unclear. We aimed to determine the influence of the PEG-IFN-α2a on tryptophan metabolism along the kynurenine pathway during treatment and up to 6 months after the end of treatment. METHODS: We evaluated 101 patients with chronic hepatitis C treated with PEG-IFN-α2a, and 40 controls, so as to determine the activation of indolamine 2,3-dioxygenase (IDO) and tryptophan (TRP) and their metabolites' concentrations/levels: kynurenine (KYN), kynurenic acid (KYNA) and anthranilic acid (AA). The subjects were evaluated before and after weeks 2, 4, 8, 12, 24, 48, as well as 6 months after the end of the treatment. RESULTS: In the group of patients treated 24 weeks, six months after the end of treatment IDO activity was significantly higher compared to baseline (69.5 vs 57.2 ß = 0.21 P = 0.000); TRP concentration was significantly lower compared to baseline (30.0 vs 35.6 ß=-0.21 P = 0.001); KYNA concentration was significantly higher compared to baseline (37.2 nmol/L vs 29.4 nmol/L ß = 0.22 P = 0.02), and AA concentration was significantly higher compered to baseline (51.0 nmol/L vs 38.4 nmol/L ß = 0.22 P = 0.05) In the group of patients treated 48 weeks six months, after the end of treatment both the IDO activity and KYNA concentration were significantly higher compared to baseline (respective values - IDO: 78.8 vs 56.2 ß = 0.14 P = 0.02; KYNA: 39.2 nmol/L vs 27.0 nmol/L ß = 0.26 P = 0.000). CONCLUSIONS: This is the first report of a prolonged activation of IDO six months after the end of PEG-IFN-α2a treatment. The clinical significance of the finding can be implicated in the pathophysiology of depressive episodes.

Transmission Networks of HCV Genotype 1a Enriched With Pre-existing Polymorphism Q80K Among HIV-Infected Patients With Acute Hepatitis C in Poland.

BACKGROUND: Hepatitis C virus (HCV) resistance-associated variants (RAVs) have been shown to adversely affect treatment response of direct-acting antivirals. Identifying pre-existing RAVs and transmission networks among HIV/HCV genotype 1 (G1)-infected patients from Poland will assist in shaping surveillance strategies for HCV. METHODS: NS3 and NS5A sequences were obtained from samples of 112 direct-acting antiviral-naive G1 patients (45 G1a and 67 G1b), of which 74 were chronically infected and 38 were diagnosed with acute hepatitis C (AHC). RAVs were identified using geno2pheno, and 98 concatenated NS3/NS5A alignments were constructed to identify transmission clusters using a maximum likelihood approach. RESULTS: G1a was notably more prevalent compared with G1b among men-having-sex-with-men (MSM) (60.0% vs. 31.3%, P = 0.004), AHC cases (46.7% vs. 25.4%, P = 0.019), and patients diagnosed with syphilis (52.2% vs. 24.5%, P = 0.009). The overall NS3/NS5A RAVs frequency was 14.3% with variants occurring more often in G1a compared with G1b (27.5% vs. 5.2%, P = 0.005), mostly for NS3 due to the high prevalence of polymorphism Q80K. NS5A RAVs were only found in 2.9% of sequences. Significant clustering was observed for 73.5% of the Polish sequences, however, more common in G1a MSM compared with G1b (50.0% vs. 25.9%, P = 0.02). The identified clusters contained sequences originating from up to 5 Polish cities, located within a mean distance of 370 km. CONCLUSIONS: Close clustering of Polish strains suggests the presence of compartmentalized epidemics of MSM that fuel the spread of G1a variants. Particularly patients with AHC form a national transmission network, including clusters enriched with the NS3 Q80K polymorphism.

Stage of liver fibrosis in patients with congenital bleeding disorders and infected with hepatitis C virus.

INTRODUCTION: Hepatitis C virus (HCV) is the major cause of chronic liver disease in patients with hemophilia. However, since liver biopsy should not be routinely used in these patients, the accurate assessment of the stage of fibrosis has been limited so far. OBJECTIVES: The aim of this study was to determine the stage of liver fibrosis in HCV­infected patients with hemophilia by using noninvasive methods of fibrosis assessment, and to analyze the influence of risk factors on liver fibrosis. PATIENTS AND METHODS: The study included 71 HCV­infected patients with hemophilia and other congenital bleeding disorders. Patients were divided into 3 groups: HCV-RNA negative after successful treatment, HCV-RNA negative after spontaneous elimination of infection, and HCV­RNA positive. Liver fibrosis was measured with shear wave elastography and FibroTest. The risk factors for liver fibrosis were analyzed, including demographic factors, HCV genotype, coinfections, and comorbidities. RESULTS: Cirrhosis or significant fibrosis (METAVIR score >F2) was observed in 26.8% of the patients. The stage of fibrosis was associated with age and estimated duration of infection (P <0.001). Active and past HBV infection did not affect fibrosis. The stage of liver fibrosis was lower in patients with spontaneous clearance of HCV (P = 0.007). CONCLUSIONS: Patients in our study had a similar stage of liver fibrosis to that reported by other studies on hemophilia. The older age and long duration of infection are the main risk factors for advanced fibrosis. Noninvasive methods such as shear wave elastography and FibroTest may allow a proper assessment of the fibrosis stage in hemophilia patients, particularly when used together and in correlation with other clinical parameters. They may also be useful in other groups of HCV­infected patients.

Co-Infection of the Hepatitis C Virus With Other Blood-Borne and Hepatotropic Viruses Among Hemophilia Patients in Poland.

BACKGROUND: The prevalence of HCV infection in people with hemophilia is substantially higher than that in the general population (63% - 98%). Multiple transfusions and substitutive therapy have also been linked to a high risk of HBV and HIV transmission. However, the prevalence of other blood-borne viral infections in this population is less well known. OBJECTIVES: This study aimed to assess the prevalence of co-infection with HBV and other blood-borne viruses in Polish HCV-infected hemophiliacs. METHODS: Seventy-one individuals, the majority of whom were male (94.36%), who had congenital bleeding disorders (60 had hemophilia A, five had hemophilia B, and six had other factor deficiencies) and HCV infection, which was defined as the presence of positive anti-HCV antibodies, were included in this study. The study group was divided into two subgroups according to the year in which blood donors were first tested for HBsAg in Poland. The serological markers were screened using commercially available enzyme immunoassays according to the manufacturer's instructions. The molecular tests were performed using real-time PCR technology with commercial assays according to the manufacturer's instructions. RESULTS: The spontaneous elimination rate of HCV RNA was 29.6%. The HCV genotype 1 was detected in 28 patients (65.1%), genotype 2 in one patient (2.3%), genotype 3 in 11 patients (25.6%), genotype 4 in two patients (4.7%), and a mixed infection with genotypes 1 and 4 was detected in one person (2.3%). Fifty-three patients (74.6%) were anti-HBc positive. Among the seven HBsAg(+) patients, three individuals were HBV-DNA positive. No occult hepatitis B was detected. In six HBsAg positive patients, the HCV RNA was positive, while one patient was also infected with HIV. The prevalence rate of past infection with HAV in the study group was 30.9%, with a tendency for a higher prevalence in older patients. The prevalence of CMV and EBV infection was high and similar to that seen in the general population. All the patients were HGV and HTLV-1 negative. CONCLUSIONS: The diagnostics and management of infections with hepatotropic viruses, particularly HBV, are neglected in hemophilic patients. All patients with coagulation disorders and a history of exposure to non-inactivated blood products should be screened for blood-borne infections. The prevalence of other potentially blood-borne viral infections exhibited a pattern similar to that observed in the general population.

Risk factors for chronic kidney disease do not influence the serum levels of asymmetric dimethylarginine in HIV-1-infected patients without significant renal disease.

INTRODUCTION Chronic kidney disease (CKD) is one of the consequences of human immunodeficiency virus-1 (HIV-1) infection. The disease increases the risk of progression to acquired immunodeficiency syndrome and death and complicates antiretroviral therapy. The prevalence of CKD in HIV-1-infected patients is difficult to estimate and depends on the diagnostic criteria for CKD. OBJECTIVES The aim of the study was to evaluate the usefulness of a single measurement of serum asymmetric dimethylarginine (ADMA) levels in the diagnosis of kidney damage in patients infected with HIV-1.  PATIENTS AND METHODS The study included 119 HIV-1-infected individuals (88 males [74%]), both on antiretroviral treatment and treatment-naive, with a negative history of kidney disease, and 31 healthy volunteers. We analyzed demographic characteristics as well as data on concomitant diseases, antiretroviral regimen, serum ADMA concentrations, parameters of renal function, CD4+ cell count, and HIV-1 viral load. RESULTS No significant impairment of renal function was observed. Mean serum ADMA levels in all HIV-1-infected patients, as well as in treatment-naive patients and treated patients, were significantly higher (P <0.0001; P = 0.0001; P <0.0001; respectively) compared with those in the control group. The difference between treatment-naive and treated HIV-1-infected patients was nonsignificant. ADMA levels were not correlated with the mean duration of antiretroviral therapy, antiretroviral drugs used, or other risk factors for CKD. CONCLUSIONS A single measurement of ADMA levels is not useful for the diagnosis of CKD in patients without significant renal pathology or as an indicator of kidney damage related to antiretroviral therapy. The significance of repeated measurements of ADMA levels in renal function assessment requires further research.

Distribution and time trends of HIV-1 variants in Poland: Characteristics of non-B clades and recombinant viruses.

The spread of HIV-1 subtypes varies considerably both worldwide and within Europe, with non-B variants commonly found across various exposure groups. This study aimed to analyse the distribution and temporal trends in HIV-1 subtype variability across Poland. For analysis of the subtype distribution, 1219 partial pol sequences obtained from patients followed up in 9 of 17 Polish HIV treatment centres were used. Subtyping was inferred using the maximum likelihood method; recombination was assessed using the bootscanning and jumping profile hidden Markov model methods. Subtype B dominated in the studied group (n=1059, 86.9%); in 160 (13.1%) sequences, non-B variants were present [A1 (n=63, 5.2%), D (n=43, 3.5%), C (n=22, 1.8%), and F1 (n=2, 0.2%)]. In 25 (2.1%) cases circulating recombinant forms (CRFs) were found. Five A1 variants (0.4%) were unique AB recombinant forms (URF) not previously identified in Poland. Non-B clades were notably more common among females (n=73, 45.6%, p<0.001) and heterosexual individuals (n=103, 66.5%, p<0.001) and less frequent among men who have sex with men (MSM) (n=27, 17.42%, p<0.001). HIV-1 viral load at diagnosis was higher among non-B cases [median: 5.0 (IQR: 4.4-5.6)] vs. [median: 4.8 (IQR: 4.3-5.4) log copies/ml for subtype B (p<0.001)] with a lower CD4(+) lymphocyte count at baseline [median: 248 (IQR: 75-503) for non-B vs. median: 320 (IQR: 125-497) cells/µl for subtype B; p<0.001]. The frequency of the non-B subtypes proved stable from 2008 (11.5%) to 2014 (8.0%) [OR: 0.95 (95% CI: 0.84-1.07), p=0.4], with no temporal differences for exposure groups, gender, age and AIDS. Despite the predominance of subtype B, the variability of HIV in Poland is notable; both CRFs and URFs are present in the analysed population. Non-B variants are associated with heterosexual transmission, more advanced HIV disease and have stable temporal frequencies.

The effects of killer cell immunoglobulin-like receptor (KIR) genes on susceptibility to HIV-1 infection in the Polish population.

Killer cell immunoglobulin-like receptors (KIR) are the most polymorphic receptors of natural killer (NK) cells. Their activity diversifies the functions of NK cells in the antiviral immune response, so the presence of certain KIR may affect transmission of HIV-1. The aim of the study was to evaluate the influence of KIR genes on the susceptibility to HIV-1 infection in the Polish population depending on the route of exposure. We determined the frequencies of activating (2DS1, 2DS2, 2DS3, 2DS4f, 2DS4del, 2DS5, 3DS1) and inhibitory (2DL1, 2DL2, 2DL3, 2DL5, 3DL1) KIRs in HIV-1-positive patients (n = 459), individuals exposed to HIV-1 but uninfected (EU, n = 118) and in uninfected, healthy blood donors (BD, n = 98). Analysis was performed using stepwise logistic regression. Apart from KIRs, CCR5-∆32, and CCR2-64I, alleles were also analyzed, as we knew or suspected that these features could affect susceptibility to HIV infection. The regression confirmed the protective effect of CCR5-∆32 (OR = 0.25, p = 0.006) and CCR2-64I (OR = 0.59, p = 0.032) against HIV infection. Among KIR genes, 2DL3 was found to be a protective factor (OR = 0.30, p = 0.015). A similar effect was seen for 3DS1 but only in intravenous drug users (IDUs) (OR = 0.30, p = 0.019), not in sexually exposed people. 2DL5 was found to be a factor facilitating HIV infection (OR = 2.13, p = 0.013). A similar effect was observed for 2DL2 but only in females (OR = 2.15, p = 0.040), and 2DS1 in IDUs (OR = 3.03, p = 0.022). Our results suggest a beneficial role of KIR3DS1 and 2DL3 supporting resistance to HIV infection and a harmful effect of 2DS1, 2DL5, and 2DL2 genes promoting HIV acquisition.

The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis C outcome.

BACKGROUD: Cytokine response against hepatitis C virus (HCV) is likely to determine the natural course of infection as well as the outcome of antiviral treatment. However, the role of particular cytokines remains unclear. The current study analyzed activation of cytokine response in chronic hepatitis C patients undergoing standard antiviral treatment. METHODS: Twenty-two patients were treated with pegylated interferon and ribavirin. Twenty-six different cytokine transcripts were measured quantitatively in peripheral blood mononuclear cells (PBMC) before and after therapy and correlated with therapy outcome as well as with clinical and liver histological data. RESULTS: We found that patients who achieved sustained virological response (SVR) showed higher pretreatment cytokine response when compared to subjects in whom therapy was unsuccessful. The differentially expressed factors included IL-8, IL-16, TNF-α, GM-CSF, MCP-2, TGF-ß, and IP-10. Serum ALT activity and/or histological grading also positively correlated with the expression of IL-1α, IL-4, IL-6, IL-10, IL-12, IL-15, GM-CSF, M-CSF, MCP-2 and TGF-ß. CONCLUSION: Pretreatment activation of the immune system, as reflected by cytokines transcripts upregulation, positively correlates with treatment outcome and closely reflects liver inflammatory activity.

Depression and neuroticism in patients with chronic hepatitis C: correlation with peripheral blood mononuclear cells activation.

BACKGROUND: Hepatitis C virus (HCV) infection is commonly associated with cognitive dysfunction and depression, which could be related to direct brain infection. Viral sequences and proteins were found in brain macrophage/microglia cells and these cells were reported to be activated. Since blood leukocytes cross blood-brain barrier, activation state of peripheral blood mononuclear cells (PBMC) could reflect the state of brain immune cells. OBJECTIVE: The aim of the study was to determine whether depression and neuroticism in chronic HCV infection correlates with the expression of key cytokines and chemokines in PBMC. DESIGN: We studied 24 HCV-positive patients undergoing treatment with interferon and ribavirin. Patients were tested for depression using Beck Depression Inventory (BDI) and Montgomery Åsberg Depression Rating Scale (MADRS), while neuroticism was assessed by the Revised Eysenck Personality Inventory (N/EPO-R). Transcripts representing 28 various cytokines and chemokines were measured by real-time quantitative PCR in PBMC. RESULTS: Prior to therapy BDI and MADRS positively correlated with viral load while neuroticism correlated with IL-3, IL-8 and M-CSF transcription levels. Six months after therapy there was positive correlation between depression and/or neuroticism scores and the levels of proinflammatory cytokines TNF-α and IL-12 transcripts, as well as IL-8, IL-10, IL-16, MCP-1, MCP-2, MIP-1-alpha, MIP-1-beta, and TGF-beta, and IFN-ß transcripts. CONCLUSION: Activation of PBMC, as measured by the level of cytokine and chemokine transcripts, correlates with depression and neuroticism scores. These findings suggest a pivotal role of immune cells activation in depression and possibly neurocognitive dysfunction among chronic hepatitis C patients.

Replication of hepatitis C virus in peripheral blood mononuclear cells in patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin.

INTRODUCTION: Hepatitis C virus (HCV) is a primarily hepatotropic virus, but hepatocytes are not the only localization of its replication. It is still unclear if extrahepatic HCV replication, measured as the detection of HCV RNA negative strand in peripheral blood mononuclear cells (PBMCs) before initiation of treatment, has an influence on therapy response. Detection of HCV RNA in extrahepatic sites for assessment of therapy efficacy is not routinely used in clinical practice. The aim of the study was to evaluate whether the replication of HCV in PBMCs affects the rate of sustained virological response (SVR). MATERIALS AND METHODS: The study group comprised 55 patients with chronic hepatitis C, originally treatment naive. They were treated with pegylated interferon (PEG-IFN) alpha 2a and ribavirin, with the standard dosing schedule. Parallel serum samples for HCV RNA and PBMC samples for HCV RNA negative strand were obtained at baseline, at the end of treatment and 24 weeks after finishing therapy. RESULTS: Undetectable HCV RNA in serum at the end of therapy was found in 48 patients (87.3%), while 33 patients (60.0%) achieved sustained virological response (SVR) (51% for HCV genotype 1 and 78% for genotype 3, respectively). Fifteen individuals (31.3%) were relapsers. Factors associated with significantly higher rate of SVR were young age, mild or no fibrosis and infection with HCV genotype 3. HCV RNA negative strand in PBMCs before treatment was found in 21.8% (12 out of 55 patients). HCV RNA negative strand was detected at baseline more frequently in patients who later achieved SVR. Relapse appeared significantly more often in patients with negative strand at the end of therapy: in 2 out of 15 individuals compared to 0 out of 33 patients (p=0.03). CONCLUSIONS: Presence of negative HCV RNA strand in PBMCs before treatment may be suggested as a potential marker of good treatment response. Detection of negative strand at the end of therapy is a predictor of relapse.