Trends over time of virological and immunological characteristics in the Swiss HIV Cohort Study

The long-term outcome of antiretroviral therapy (ART) is not assessed in controlled trials. We aimed to analyse trends in the population effectiveness of ART in the Swiss HIV Cohort Study over the last decade.

Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration

Objectives  To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART). Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment. Results  Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008). Conclusion  Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children.

Short- and long-term immunological and virological outcome in HIV-infected infants according to the age at antiretroviral treatment initiation

The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both groups.

The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure

Objectives  To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. Results  Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. Conclusion  The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.

Cellular and immunological basis of the host-parasite relationship during infection with Neospora caninum

Neospora caninum is an apicomplexan parasite that is closely related to Toxoplasma gondii, the causative agent of toxoplasmosis in humans and domestic animals. However, in contrast to T. gondii, N. caninum represents a major cause of abortion in cattle, pointing towards distinct differences in the biology of these two species. There are 3 distinct key features that represent potential targets for prevention of infection or intervention against disease caused by N. caninum. Firstly, tachyzoites are capable of infecting a large variety of host cells in vitro and in vivo. Secondly, the parasite exploits its ability to respond to alterations in living conditions by converting into another stage (tachyzoite-to-bradyzoite or vice versa). Thirdly, by analogy with T. gondii, this parasite has evolved mechanisms that modulate its host cells according to its own requirements, and these must, especially in the case of the bradyzoite stage, involve mechanisms that ensure long-term survival of not only the parasite but also of the host cell. In order to elucidate the molecular and cellular bases of these important features of N. caninum, cell culture-based approaches and laboratory animal models are being exploited. In this review, we will summarize the current achievements related to host cell and parasite cell biology, and will discuss potential applications for prevention of infection and/or disease by reviewing corresponding work performed in murine laboratory infection models and in cattle.

Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis

BACKGROUND: Number of intratumoral mast cells predicts survival in various cancers. The prognostic significance of such mast cells in surgically treated prostate cancer is unknown. METHODS: Mast cell densities were determined in prostate cancer samples of more than 2,300 hormone-naïve patients using a tissue microarray format in correlation with clinical follow-up data. Mast cells were visualized immunohistochemically (c-kit). All patients were homogeneously treated by radical prostatectomy at a single institution. RESULTS: Mast cells were present in 95.9% of the tumor samples. Median mast cell number on the tissue spot was 9 (range: 0-90; median density: 31 mast cells/mm(2)). High mast cell densities were significantly associated with more favorable tumors having lower preoperative prostate-specific antigen (P = 0.0021), Gleason score (P < 0.0001) and tumor stage (P < 0.0001) than tumors with low mast cell densities. Prostate-specific antigen recurrence-free survival significantly (P = 0.0001) decreased with decline of mast cell density showing poorest outcome for patients without intratumoral mast cells. In multivariate analysis mast cell density narrowly missed to add independent prognostic information (P = 0.0815) for prostate-specific antigen recurrence. CONCLUSION: High intratumoral mast cell density is associated with favorable tumor characteristics and good prognosis in prostate cancer. This finding is consistent with a role of mast cells in the immunological host-defense reaction on prostate cancer. Triggering mast cell activity might expand immunotherapeutic strategies in prostate cancer.

Virological and immunological responses to efavirenz or boosted lopinavir as first-line therapy for patients with HIV

BACKGROUND: Efavirenz and lopinavir boosted with ritonavir are both recommended as first-line therapies for patients with HIV when combined with two nucleoside reverse transcriptase inhibitors. It is uncertain which therapy is more effective for patients starting therapy with an advanced infection. METHODS: We estimated the relative effect of these two therapies on rates of virological and immunological failure within the Swiss HIV Cohort Study and considered whether estimates depended on the CD4(+) T-cell count when starting therapy. We defined virological failure as either an incomplete virological response or viral rebound after viral suppression and immunological failure as failure to achieve an expected CD4(+) T-cell increase calculated from EuroSIDA statistics. RESULTS: Patients starting efavirenz (n=660) and lopinavir (n=541) were followed for a median of 4.5 and 3.1 years, respectively. Virological failure was less likely for patients on efavirenz, with the adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.78) then multiplied by a factor of 1.00 (0.90-1.12) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. Immunological failure was also less likely for patients on efavirenz, with the adjusted hazard ratio of 0.68 (0.51-0.91) then multiplied by a factor of 1.29 (1.14-1.46) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. CONCLUSIONS: Virological failure is less likely with efavirenz regardless of the CD4(+) T-cell count when starting therapy. Immunological failure is also less likely with efavirenz; however, this advantage disappears if patients start therapy with a low CD4(+) T-cell count.

Zidovudine impairs immunological recovery on first-line antiretroviral therapy: collaborative analysis of cohort studies in southern Africa

OBJECTIVES Zidovudine (ZDV) is recommended for first-line antiretroviral therapy (ART) in resource-limited settings. ZDV may, however, lead to anemia and impaired immunological response. We compared CD4+ cell counts over 5 years between patients starting ART with and without ZDV in southern Africa. DESIGN Cohort study. METHODS Patients aged at least 16 years who started first-line ART in South Africa, Botswana, Zambia, or Lesotho were included. We used linear mixed-effect models to compare CD4+ cell count trajectories between patients on ZDV-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4+ cell count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4+ cell count and hemoglobin level, age, sex, type of regimen, viral load monitoring, and calendar year. RESULTS A total of 72,597 patients starting ART, including 19,758 (27.2%) on ZDV, were analyzed. Patients on ZDV had higher CD4+ cell counts (150 vs.128 cells/μl) and hemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be women than those on other regimens. Adjusted differences in CD4+ cell counts between regimens containing and not containing ZDV were -16 cells/μl [95% confidence interval (CI) -18 to -14] at 1 year and -56 cells/μl (95% CI -59 to -52) at 5 years. Impaired immunological recovery was more likely with ZDV compared to other regimens (odds ratio 1.40, 95% CI 1.22-1.61). CONCLUSION In southern Africa, ZDV is associated with inferior immunological recovery compared to other backbones. Replacing ZDV with another nucleoside reverse transcriptase inhibitor could avoid unnecessary switches to second-line ART.

Hepatitis B virus infection is associated with impaired immunological recovery during antiretroviral therapy in the Swiss HIV cohort study

Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients worldwide. It is unclear whether HIV-related outcomes are affected by HBV coinfection. We compared virological suppression and immunological recovery during antiretroviral therapy (ART) of patients of different HBV serological status in the Swiss HIV Cohort Study. CD4 cell recovery during ART was significantly impaired in hepatitis B surface antigen-positive patients and in those with anti-hepatitis B core antigen alone compared with HBV-uninfected patients, despite similar virological efficacy of ART. CD4 increase in patients with resolved HBV infection was similar to that in HBV-uninfected individuals.

Early follicular testosterone level predicts preference for masculinity in male faces — But not for women taking hormonal contraception

It has been shown that women’s preference for masculinity in male faces changes across the menstrual cycle. Preference for masculinity is stronger when conception probability is high than when it is low. These findings have been linked to cyclic fluctuations of hormone levels. The purpose of the present study is to further investigate the link between gonadal steroids (i.e. testosterone, estradiol, and progesterone) and masculinity preference in women, while holding the cycle phase constant. Sixty-two female participants were tested in their early follicular cycle phase, when conception probability is low. Participants were shown face pairs and where asked to choose the more attractive face. Face pairs consisted of a masculinized and feminized version of the same face. For naturally cycling women we found a positive relationship between saliva testosterone levels and masculinity preference, but there was no link between any hormones and masculinity preference for women taking hormonal contraception. We conclude that in naturally cycling women early follicular testosterone levels are associated with masculinity preference. However, these hormonal links were not found for women with artificially modified hormonal levels, that is, for women taking hormonal contraception.

Complement dependent early immunological responses during ex vivo xenoperfusion of hCD46/HLA-E double transgenic pig forelimbs with human blood.

BACKGROUND Besides α1,3-galactosyltransferase gene (GGTA1) knockout, several transgene combinations to prevent pig-to-human xenograft rejection are currently being investigated. In this study, the potential of combined overexpression of human CD46 and HLA-E to prevent complement- and NK-cell-mediated xenograft rejection was tested in an ex vivo pig-to-human xenoperfusion model. METHODS α1,3-Galactosyltransferase knockout heterozygous, hCD46/HLA-E double transgenic (transgenic) as well as wild-type pig forelimbs were ex vivo perfused with whole, heparinized human and autologous pig blood, respectively. Blood samples were analyzed for the production of porcine and/or human inflammatory cytokines as well as complement activation products. Biopsy samples were examined for deposition of human and porcine C3b/c, C4b/c, and C6 as well as CD62E (E-selectin) and CD106 (VCAM-1) expression. Apoptosis was measured in the porcine muscle tissue using TUNEL assays. Finally, the formation of thrombin-antithrombin (TAT) complexes was measured in EDTA plasma samples. RESULTS No hyperacute rejection was seen in this model. Extremity perfusions lasted for up to 12 h without increase in vascular resistance and were terminated due to continuous small blood losses. Plasma levels of porcine cytokines IL1β, IL-6, IL-8, IL-10, TNF-α, and MCP-1 as well as human complement activation markers C3a (P = 0.0002), C5a (P = 0.004), and soluble C5b-9 (P = 0.03) were lower in blood perfused through transgenic as compared to wild-type limbs. Human C3b/c, C4b/c, and C6 as well as CD62E and CD106 were deposited in tissue of wild-type limbs, but significantly lower levels (P < 0.0001) of C3b/c, C4b/c, and C6 deposition as well as CD62E and CD106 expression were detected in transgenic limbs perfused with human blood. Transgenic porcine tissue was protected from xenoperfusion-induced apoptosis (P < 0.0001). Finally, TAT levels were significantly lower (P < 0.0001) in transgenic limb as compared to wild-type limb xenoperfusions. CONCLUSION Transgenic hCD46/HLA-E expression clearly reduced humoral xenoresponses since all, the terminal pathway of complement activation, endothelial cell activation, muscle cell apoptosis, inflammatory cytokine production, as well as coagulation activation, were all downregulated. Overall, this model represents a useful tool to study early immunological responses during pig-to-human vascularized xenotransplantation in the absence of hyperacute rejection.