Immunological function restoration with lopinavir/ritonavir versus efavirenz containing regimens in HIV-infected patients: a randomized clinical trial.

CD4(+) count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4(+) count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4(+) count increase that was higher in the EFV group (ΔCD4(+) 88 vs. 315 cells/µl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4(+) gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4(+) and CD8(+) T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4(+) T cells and naive subsets of CD8(+) T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4(+) gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens.

HIV exposed seronegative individuals show antibodies specifically recognizing native HIV envelope glycoprotein.

BACKGROUND: Susceptibility to HIV transmission by sexual intercourse has been associated with cellular anti-HIV responses. We aimed to also evaluate potential systemic humoral responses against HIV in a group of HIV-exposed seronegative individuals (HESN) in stable relationship with HIV-infected partners. METHODS: We recruited 27 serodiscordant couples. HESN were classified according to HIV exposure into very low/low and moderate/high risk. Plasma from HESN and HIV partners were tested for neutralizing capacity and for the recognition of cell-surface expressed and recombinant forms of HIV envelope glycoproteins (Env). Healthy individuals (healthy control, n=11) were used as controls. RESULTS: Recognition of cell-surface expressed Env by both immunoglobulin (Ig)G and IgA was higher in plasma samples from HESN than in healthy controls (P=0.0062 and P=0.0144, respectively). IgG binding to Env was significantly increased in HESN after unmasking CD4-induced epitopes (P=0.001), suggesting a wide range of targeted epitopes. Remarkably, ELISA assays using trimeric gp140 or monomeric gp120 failed to detect significant differences in reactivity between groups. Neutralization analysis showed residual activity in only three HESN samples (11%), whereas 70% of HIV-infected partners showed neutralizing activity. Although anti-Env humoral responses were found in 85% of HESN, their magnitude was not associated with the estimated level of exposure or the detection of HIV-specific cellular immune responses. CONCLUSION: A high proportion of HESN show detectable plasma IgG or IgA recognizing different exposed and cryptic Env native epitopes unrelated to neutralizing capacity. Therefore, low but persistent HIV exposure induces new virus-specific systemic humoral responses or boosts preexisting natural antibodies.

Triple combination therapy for hepatitis C with telaprevir exhibits greater early antiviral activity than with boceprevir.

BACKGROUND: Achievement of early viral suppression is important in patients with chronic HCV infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far. METHODS: All consecutive individuals who initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV RNA (<25 IU/ml) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in). RESULTS: A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, body mass index, baseline HCV RNA, HCV subtype 1a (45% versus 42%) and IL28B-CC alleles (29% versus 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% versus 44%). Conversely, more patients on BOC than TLV had previously failed pegylated interferon plus ribavirin (82% versus 64%). RVR was achieved by 82% of patients on TLV versus 59% on BOC (P=0.001). Multivariate logistic regression analysis confirmed that TLV use was the strongest predictor of RVR (OR 3.54 [95% CI 1.23, 10.24]; P=0.02), others being HCV subtype 1b versus 1a (OR 3.26 [95% CI 1.17, 9.09]; P=0.02) and low baseline HCV RNA (OR 0.41 [95% CI 0.16, 1.03]; P=0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR. CONCLUSIONS: Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV RNA responses.

HIV Gag-specific immune response mediated by double negative (CD3(+)CD4(-)CD8(-)) T cells in HIV-exposed seronegative individuals.

Double negative (DN) T cells are CD3(+), CD4(-), CD8(-) cells with either T-cell receptors (TCR) αß or TCR γδ whose importance on protection against HIV infection is unknown. Since HIV-exposed seronegative individuals correspond to an ideal group in whom correlates of protection are expected, the role of these cells was studied in 13 HIV-serodiscordant couples in a stable relationship and reporting unprotected sexual intercourses. HIV-specific immune responses mediated by DN T-cells were evaluated by measuring intracellular IFNγ and MIP1ß (CCL4) production in response to HIV-Gag peptides. Thirty-five healthy controls not exposed to HIV were tested similarly and used to define a threshold for positive responses. Interestingly, Gag-specific DN T-cell responses were found in 3/13 (23%) HIV-exposed seronegative individuals (Group A), involving both DN/αß(+) and DN/γδ(+) T-cells through MIP1ß and IFNγ production. 4/13 (30%) of partners infected with HIV (Group B) also showed Gag-specific responses but were mediated exclusively by DN/γδ(+) T-cells, mainly through IFNγ production. DN T-cells in Group A individuals can display differential HIV-specific immune responses, which might contribute to the low susceptibility to infection with HIV shown by individuals in Group A.

Interferon-stimulated genes are associated with peginterferon/ribavirin treatment response regardless of IL28B alleles in hepatitis C virus/HIV-coinfected patients.

BACKGROUND: The interaction between interferon-stimulated genes (ISGs) expression, IL28B genotypes and hepatitis C treatment outcomes has been mainly evaluated in the liver tissue from hepatitis C virus (HCV)-monoinfected patients but with controversial results. Herein, we examined whether more easily accessible peripheral blood mononuclear cells (PBMCs) could be used for this purpose in HIV-HCV coinfected patients, a population in whom HCV-induced liver disease progression occurs more rapidly and treatment response is lower. METHODS: Gene expression profiles were examined using the human whole genome Agilent microarray platform in PBMCs collected from HIV/HCV-coinfected patients who had completed a course of peginterferon/ribavirin therapy with validated outcomes. Patients were split out according to the achievement of sustained virological response (SVR) and IL28B rs12979860 genotypes. The GeneSpringGX software was used to select genes differentially expressed in the different groups. RESULTS: Nineteen HIV/HCV-coinfected individuals receiving antiretroviral therapy and having undetectable plasma HIV-RNA were examined. Global gene expression profiles showed 42 genes differentially expressed according to treatment outcome and 56 according to IL28B genotype. Common genes were not found and functions differed for genes belonging to either group. Whereas at least 26 out of 37 repressed genes (70.3%) in SVR patients were ISGs, none of the 56 differentially expressed genes in carriers of distinct IL28B variants were ISGs (P < 0.0001). CONCLUSION: Baseline expression of ISGs in PBMCs from HCV/HIV-coinfected patients influence the response to peginterferon/ribavirin therapy, regardless of IL28B genotypes. PBMC specimens can reliably be used for evaluating ISGs expression in clinical practice.

A model to predict the response to therapy against hepatitis C virus (HCV) including low-density lipoprotein receptor genotype in HIV/HCV-coinfected patients.

OBJECTIVES: Accurate prediction of sustained virological response (SVR) to pegylated interferon-α (Peg-IFN) plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients could improve the management of these patients. We aimed to develop a model to predict SVR to Peg-IFN/ribavirin in HIV/HCV-coinfected individuals combining HCV genotype and baseline HCV RNA load with interleukin 28B and low-density lipoprotein receptor genetic variations. METHODS: Three hundred and twelve treatment-naive HIV/HCV-coinfected patients receiving Peg-IFN/ribavirin were analysed in an on-treatment approach. One hundred and eighty-one of them were included in the development group and 131 in the validation population. The predictive model was obtained from a logistic regression equation including the above-mentioned variables. The areas under the receiver operating characteristic (AUROC) curves (95% CI), sensitivity and specificity, as well as negative and positive predictive values, were calculated. RESULTS: SVR was achieved by 88 (48.6%) patients from the development group and 68 (51.9%) individuals from the validation group. The AUROC curve values (95% asymptotic CI) were 0.83 (0.77-0.89) for the development group and 0.84 (0.77-0.91) for the validation group. Using two cut-off values, maximum specificity and sensitivity were 89.7% and 96.6%, respectively, with a negative predictive value for SVR of 88.9% and a positive predictive value of 83.6%. Thirteen (7.2%) individuals were misclassified using these cut-off values. CONCLUSIONS: This model represents a reliable and easily applicable tool to individually evaluate the probability of achieving an SVR to Peg-IFN/ribavirin among HIV/HCV-coinfected patients.

Different impact of IL28B polymorphisms on response to peginterferon-α plus ribavirin in HIV-positive patients infected with HCV subtypes 1a or 1b.

BACKGROUND: HCV subtype 1a has emerged as a predictor of poor response to triple hepatitis C therapy including boceprevir or telaprevir, which largely has been attributed to a lower resistance barrier in HCV-1a compared to -1b. OBJECTIVES: We examined whether a lower efficacy of pegIFN/RBV on HCV-1a than HCV-1b could alternatively contribute to explain it. STUDY DESIGN: All chronic hepatitis C patients who had completed a course of pegIFN/RBV therapy at our institution were examined. For this study we selected individuals that were IFN-naïve and had been successfully subtyped as 1a or 1b. Moreover, only HIV-coinfected patients were included as they represented a more uniform population in terms of demographics and treatment exposure at our institution. The IL28B rs12979860 alleles were typed using the 5' nuclease assay. RESULTS: A total of 96 individuals were examined, 58 of whom harbored HCV-1a and 38 HCV-1b. IL28B allele distribution was as follows: 33 CC and 63 CT/TT. SVR was achieved by 64% of CC vs 30% of CT/TT patients (p=0.001). On the other hand, SVR was 53% in HCV-1b vs 34% in HCV-1a (p=0.08). Interestingly, the effect of IL28B variants on SVR was mainly recognized in HCV-1a (63% in CC vs 20% in CT/TT; p=0.001), being marginal on HCV-1b (64% in CC vs 46% in CT/TT; p=0.27). CONCLUSIONS: The rate of SVR to pegIFN/RBV therapy tends to be lower in HIV-infected patients with chronic hepatitis C due to HCV-1a than HCV-1b; being the impact of IL28B variants significantly stronger on HCV-1a than HCV-1b.

Impact of IL28B gene polymorphisms on interferon-λ3 plasma levels during pegylated interferon-α/ribavirin therapy for chronic hepatitis C in patients coinfected with HIV.

OBJECTIVES: The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-λ3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-α/ribavirin therapy. PATIENTS AND METHODS: A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-α/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-λ3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment. RESULTS: No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-λ3 plasma levels or in their median values. In contrast, median IFN-λ3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers [34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001], but not in CT/TT carriers. Unexpectedly, increases in IFN-λ3 at week 4 of therapy did not predict SVR. CONCLUSIONS: The exogenous administration of IFN-α may induce IFN-λ3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.

Differences in virological response to peginterferon-α plus ribavirin in HIV-positive patients coinfected with HCV subtypes 1a or 1b.

BACKGROUND: Both viral and host factors influence response to peginterferon-α plus ribavirin (pegIFNα/RBV) in patients with chronic hepatitis C. The impact of these variables is more pronounced in HIV/Hepatitis C virus (HCV)-coinfected individuals, in whom treatment response rates are lower. METHODS: Virological responses at multiple time points were assessed in all HIV/HCV-coinfected patients that completed a first course of pegIFNα/RBV. Viral responses were stratified by HCV geno/subtypes and IL28B rs12979860 variants. RESULTS: A total of 331 HIV/HCV-coinfected patients were analyzed. HCV geno/subtype distribution was as follows: HCV-1a in 97, HCV-1b in 62, HCV-3 in 122, and HCV-4 in 50. Age, gender, CD4 counts, plasma HIV RNA and liver fibrosis stage did not differ significantly across HCV geno/subtypes. In contrast, mean serum HCV RNA was greater in HCV-1a compared with the rest (P < 0.0001). The proportion of IL28B CC variants was higher in HCV-3 compared with the rest (P = 0.001). Virological responses were better in HCV-1b than HCV-1a at any given time point during therapy. IL28B variants significantly influenced virological responses across all HCV-1 subtypes, with the strongest effect seen in HCV-1a. In a multivariate linear regression analysis, both HCV-1b and IL28B CC variants were significantly associated with greater HCV RNA drops at weeks 4 (R = 0.52, p < 0.0001) and 12 (R = 0.49, P < 0.0001) of therapy. CONCLUSIONS: The response to pegIFNα/RBV therapy is lower in HCV-1a than HCV-1b in HIV/HCV-coinfected patients. The strongest influence of IL28B variants is seen in HCV-1a. This information may be relevant when using most directly acting antivirals in coinfected patients along with pegIFNα/RBV, given that selection of drug resistance occurs more frequently in HCV-1a than HCV-1b.

Short communication: Does interleukin-28B single nucleotide polymorphisms influence the natural history of hepatitis B?

Single nucleotide polymorphisms (SNP) nearby the IL28B gene have been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in both monoinfected and HIV-coinfected patients. However, its impact on spontaneous clearance of HBV (the pathogenesis of which is also related to interferon) is less known. A case-control study was performed. Cases were 49 HIV(+) patients with chronic hepatitis B (HBsAg(+) for more than 6 months) who had been genotyped for the rs12979860 SNP (protective CC genotype). One control for each case was chosen among HIV patients with anti-HBs and anti-HBc. Controls were matched for gender and coinfection with HCV. Most patients were male (90%) and the median (IQR) age was 42.6 (39-46.7) years. Eighteen (36.7%) were also coinfected by HCV. Among HBsAg(+) patients, 19 (41.3%) were HBeAg(+) and 13 (26.5%) were also infected with hepatitis delta (HDV). No differences were found in the distribution of the CC genotype between patients with chronic hepatitis B and those who spontaneously cured hepatitis B: 59.2% vs. 44.9%; p=0.3. Thus, the interleukin-28B (IL-28B) genotype does not seem to have a role in the development of chronic hepatitis B among HIV-infected patients.

Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.

BACKGROUND: A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia. RESULTS: A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR. CONCLUSIONS: This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.

Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C.

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.

The expansion ability but not the quality of HIV-specific CD8(+) T cells is associated with protective human leucocyte antigen class I alleles in long-term non-progressors.

Studies in long-term non-progressors (LTNP) have suggested that the quality of the CD8(+) response may involve protective human leucocyte antigen (HLA) class I alleles. However, studies examining the expansion ability of different functional CD8(+) T cells and their association with HLA class I alleles are lacking. LTNP, untreated typical progressors (TP) and patients successfully on highly active retroviral therapy (HAART) during 1 year (HP) were included. HLA class I typing was performed using a sequence-specific primer assay. Functional subsets of Gag- and Nef-specific CD8(+) cells were analysed based on the production of macrophage inflammatory protein (MIP)-1ß, tumour necrosis factor (TNF)-α and interleukin (IL)-2. Their expansion abilities were evaluated after 10-day culture in the presence of Gag and Nef human immunodeficiency virus (HIV) peptides. No differences were seen when comparing quantitative and qualitative HIV-specific CD8(+) T cell responses according to the presence/absence of protective HLA alleles (B*58 and B*27 supertypes) in each group. However, LTNP with protective HLA alleles showed a higher expansion ability of Gag-specific MIP(+) TNF(+) IL-2(+) T cells and Nef-specific MIP(+) TNF(+) IL-2(+) . HLA-B*5701+LTNP displayed a higher expansion ability of Gag and Nef-specific MIP(+) TNF(-) IL-2(+) T cells than HLA-B*5701-LTNP. This was not so for HLA-B*2705. No differences were seen in the expansion ability according to the presence/absence of protective HLA alleles in TP and HP. The expansion ability of polyfunctional CD8(+) T cells is modulated by HLA class I alleles and targeted protein. LTNP with HLA class I protective alleles (mainly B*5701) display better expansion ability of polyfunctional HIV-specific CD8(+) T cells than the rest, suggesting that factors other than HLA-B*5701 must contribute to the control of viral replication in other LTNP. Furthermore, these attributes of HIV-specific CD8(+) T are not restored by HAART; thus, adjuvant therapies and vaccines that induce and/or normalize the expansion ability of HIV-specific T cells are required.

Longitudinal assessment of interleukin 7 plasma levels in HIV-infected patients in the absence of and under antiretroviral therapy.

BACKGROUND: Cross-sectional studies in HIV-positive patients have suggested that interleukin 7 (IL-7) may increase in parallel to CD4 decline during the natural course of HIV infection. We tested this hypothesis in a longitudinal study examining the evolution of IL-7 and CD4 counts in 2 different scenarios. METHODS: IL-7 and CD4 counts were regularly monitored in 30 drug-naive patients during a follow-up period of 46 ± 14 months in the absence of therapy and in 42 patients who started highly active antiretroviral therapy and maintained undetectable viremia for 2 years. Multivariate linear regression analysis was used to ascertain what factors were associated with IL-7 variations during follow-up. RESULTS: In antiretroviral therapy-naive patients, CD4 counts significantly decreased (P < 0.0001), whereas plasma HIV-RNA and IL-7 levels remained fairly stable. In patients on highly active antiretroviral therapy, CD4 counts significantly increased (P < 0.0001) and IL-7 tended to decrease (P = 0.1). There was no correlation between CD4 and IL-7 variations either in the naive or in the treated population. The only parameter significantly associated with IL-7 variation during follow-up was its baseline level that showed a negative correlation. CONCLUSIONS: In HIV patients with low or moderate degree of immunodeficiency, CD4 counts and plasma IL-7 levels do not evolve in parallel, suggesting that other factors different from CD4 counts must be involved in the upregulation of IL-7 observed in HIV infection.

HCV-specific T-cell responses in HIV/hepatitis C virus-coinfected patients on highly active antiretroviral therapy are comparable to those observed in hepatitis C virus-monoinfected individuals.

BACKGROUND: Cellular responses against hepatitis C virus (HCV) are impaired in HIV/HCV-coinfected patients showing uncontrolled viral replication and immune suppression. Very few studies have explored to what extent HCV-specific response improves as a consequence of control of HIV replication by highly active antiretroviral therapy. We compared HCV-specific T-cell responses between HIV/HCV-coinfected patients, showing complete viral suppression, and HCV-monoinfected patients. METHODS: HCV-specific T-cell responses were examined in 50 interferon-naive patients with chronic hepatitis C: 27 HCV-mono-infected and 23 HIV/HCV-coinfected on highly active antiretroviral therapy and undetectable HIV load. Production of interferon-γ and tumor necrosis factor-α was simultaneously measured in response to genotype-matched overlapping peptides spanning the whole HCV proteome by flow cytometry. Differences between groups were tested using nonparametric tests. RESULTS: More than half of patients presented CD4+ (60%) or CD8+ (57%) response to at least one HCV protein with no significant differences between both groups. Intensity and breadth of response were also similar between groups. The functional profile of response was represented, in both groups, mainly by monofunctional subsets, although there were some differences between CD4+ and CD8+ T-cell response. CD8+ response was mediated almost exclusively by monofunctional interferon-γ+ cells, whereas bifunctional interferon-γ+ tumor necrosis factor-α+ cells showed a moderate contribution to CD4+ response. Most of the CD8+ response was mediated by interferon-γ, whereas tumor necrosis factor-α was the highest contributor to CD4+ response. CONCLUSIONS: Our study demonstrates that in HIV/HCV-coinfected patients with maximal HIV suppression under highly active antiretroviral therapy, several characteristics of anti-HCV T-cell response are similar to those found in HCV-monoinfected patients, suggesting that control of HIV replication might improve HCV-specific T-cell response in HIV/HCV-coinfected patients.

IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin.

BACKGROUND: A single nucleotide polymorphism (SNP) upstream of the IL28B gene (rs12979860) predicts sustained virological response (SVR) to peginterferon-ribavirin therapy in chronic hepatitis C patients. There is scarce information regarding the influence of this IL28B SNP on early viral kinetics during therapy, particularly in patients coinfected with HIV, in whom treatment response is lower than in hepatitis C virus (HCV)-monoinfected patients. METHODS: We selected 196 HIV/HCV-coinfected individuals who had completed a course of peginterferon-ribavirin therapy, and a validated outcome for SVR. Association of IL28B SNPs with rapid, early and end-of-treatment virological responses [rapid virological response (RVR), early virological response (EVR) and end of treatment virological response, respectively] was assessed in univariate and multivariate analyses. RESULTS: Rate of SVR in the study population was 54%. Frequency of the IL28B CC genotype was 44%. The distribution of HCV genotypes was as follows: HCV-1 57%, HCV-2 1%, HCV-3 30% and HCV-4 12%. Compared to CT/TT, the CC genotype was associated with significantly higher rates of all on-treatment viral outcomes, after adjusting for other predictors of viral response as serum HCV-RNA, HCV genotype and liver fibrosis staging. IL28B CC genotype kept its predictive power of SVR in patients who did not achieve RVR or cEVR. The association between IL28B SNP and viral kinetics and treatment outcomes was significant only for HCV genotypes 1 and 4. CONCLUSION: IL28B CC genotype is a strong predictor of virological response to therapy in HIV/HCV-coinfected patients. This effect is mediated by an increase in viral clearance during the first 12 weeks of treatment and is mainly seen in patients infected with HCV genotypes 1 and 4.

Long-term non-progressors display a greater number of Th17 cells than HIV-infected typical progressors.

Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p=0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p=0.001 and p=0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.

Host factors involved in low susceptibility to HIV infection.

There are individuals who despite being exposed to HIV, in some cases repeatedly and over long periods, remain without HIV seroconversion. These individuals are called HIV-exposed seronegatives, and have been reported among commercial sex workers, men having sex with men, injection drug users, hemophiliacs who received contaminated blood preparations, healthcare workers with accidental percutaneous exposure to HIV-infected blood, infants born to HIV-infected mothers, and individuals having HIV-positive heterosexual partners. Genetic and immunological mechanisms have been involved in the production of this resistance to HIV acquisition. Genetic factors have been linked to genes encoding chemokine receptors and their natural ligands as well as genes of the major histocompatibility complex. Immunological factors are grouped within both innate and adaptive immunity. The study of HIV-exposed seronegatives provides a unique opportunity to understand the mechanisms of natural protection against HIV infection. The better understanding of this protection may lead to novel preventive and immunotherapeutic approaches, including vaccines.

Elevated TGF-ß1 levels might protect HCV/ HIV-coinfected patients from liver fibrosis.

BACKGROUND: HIV accelerates hepatitis C virus (HCV)-induced liver fibrosis by mechanisms not well understood. As HIV dysregulates transforming growth factor-ß1 (TGF-ß1) and T regulatory (Treg) cells, both of which are involved in hepatic fibrogenesis, herein we describe their influence on liver fibrosis staging in patients with chronic hepatitis C with and without HIV coinfection. METHODS: Eighty-eight subjects (42 HIV/HCV co-infected patients, 20 HCV-monoinfected patients, and 26 healthy controls) were examined. Treg cells (CD4+Foxp3+) were measured in peripheral blood using flow cytometry. An enzyme immunoassay was used to measure TGF-ß1 in plasma. Liver fibrosis staging was estimated using elastometry and advanced liver fibrosis was considered for ≥ 9·5 kPa (F3-F4 Metavir estimates). RESULTS: Treg cells were increased in HIV/HCV-coinfected patients compared with HCV-monoinfected patients (P = 0·004), whereas TGF-ß1 levels were similar in both groups of patients. While Treg cells levels were similar in both null-mild and advanced liver fibrosis patients, a high level of TGF-ß1 was found in patients with low levels of liver fibrosis compared with those with advanced liver fibrosis [14·9 ng mL(-1) (5·6-37·9) vs. 5·5 ng mL(-1) (1·9-7·9) respectively P = 0·007]. In a multivariate logistic regression model, elevated TGF-ß1 levels were significantly associated with not having advanced liver fibrosis [OR: 0·13 (95% CI: 0·02-0·71), P = 0·019]. CONCLUSIONS: While Treg cells do not influence liver fibrosis staging, elevated TGF-ß1, probably through its anti-inflammatory effects, might protect HCV/HIV-coinfected patients from liver fibrosis.

Interleukin-28B gene polymorphisms do not influence the susceptibility to HIV-infection or CD4 cell decline.

The critical role of interleukin-28B (IL28B)/interferon-λ3 (IFN-λ3) polymorphisms on the susceptibility to hepatitis C virus infection and the response to peginterferon-ribavirin therapy has encouraged exploration of similar effects on other viruses. Given that IFN-λ mediates anti-HIV-1 activity, the protective role of IL28B polymorphisms was examined in 29 seronegative individuals at risk for HIV-infection and in 68 HIV-positive carriers with and without rapid progression of immunodeficiency. No protective role of IL28B polymorphism was found examining both HIV-disease progression and HIV-protection.