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HIV infection is characterized by progressive immunodeficiency: HIV-infected peripheral blood mononuclear cells (PBMCs) cannot properly react to stimulation with allo-antigens and mitogens. In this study, we examined interferon-γ (IFN-γ)-mediated pathways and the proliferative response of mitogen-stimulated HIV-infected PBMCs in vitro. PBMCs of 30 HIV-infected patients were stimulated with the mitogens concanavalin A (Con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM). Mitogen stimulation induced expression of IFN-γ, GTP cyclohydrolase I (GCH-I), and indoleamine (2,3)-dioxygenase (IDO) resulting in enhanced neopterin formation and tryptophan degradation by HIV-infected and control PBMCs. IFN-γ concentrations correlated with neopterin levels and tryptophan degradation. Proliferative responses to PHA and PWM cytokine were lower in HIV patients, with IFN-γ formation predicting proliferative responses. Higher mRNA expression of IFN-γ, GCH-I and IDO after 6 h was related to better proliferative responses in HIV-infected PBMCs. In conclusion, induction of IFN-γ and subsequent enzymes appears to importantly influence the proliferative response of HIV-infected PBMCs in vitro, suggesting a prominent role of the cytokine in the development of immunodeficiency. [ABSTRACT FROM AUTHOR]

Abstract: Design: We evaluated whether an increase in haemoglobin levels in the first 6 months of effective anti-retroviral therapy (ART) is associated with a decrease in immune activation. To reduce confounding factors only men (n = 35) and patients not receiving agents known to enhance haematopoiesis or patients without diseases that might suppress haematopoiesis were included. Simultaneously parameters of iron metabolism and cofactors for haematopoiesis were analysed. Results: A median baseline haemoglobin level of 139 g L-1 increased to 149 g L-1 at month 6 of ART (P < 0.001). At baseline low haemoglobin levels were strongly associated with high neopterin concentrations (r = - 0.64, P < 0.001), and much less correlated to high HIV-1 RNA levels (r = - 0.41, P < 0.05) and to a lower CD4+ cell count (r = 0.33, P < 0.05). The change of neopterin levels during the study period correlated with the relative change in haemoglobin levels, r = - 0.35, P = 0.03, whereas no such correlations were found for the change of HIV-1 RNA levels and the CD4 cell count. A logistic regression analysis revealed that the change of neopterin and soluble transferrin receptors concentrations are independently associated with an increase of haemoglobin levels of more than 15 g L-1 . Conclusion: Our study supports a cause–effect relationship between immune activation and anaemia in HIV-infected patients. Treatment of patients with ART decreases virus load, which may thereby result in silencing of immune effector activity thus ameliorating anaemia by reversing the anti-proliferative effects of cytokines towards erythroid progenitors and the iron withdrawal strategy of the immune system. [ABSTRACT FROM AUTHOR]

We assessed the value of HIV–1 RNA level compared to soluble immune activation markers, namely neopterin, β[sub 2] –microglobulin and soluble TNF receptor 75 (sTNFR–75), to predict the change in the number of CD4+ T cells over a 1–year period, the development of AIDS, and survival (median follow–up 54 months). The study population comprised a cohort of 47 individuals for the analysis of the change in CD4+ T cells and survival (20 died), and a subgroup of 31 individuals with a baseline CD4+ T cells above 200×10[sup 6] /l for the development of AIDS (11 developed AIDS). HIV–1 RNA was measured from stored sera by quantitative PCR. The CD4+ T cell count obtained at study entry strongly correlated with baseline serum HIV–1 RNA levels (r = –0.47), and to a lesser extent with neopterin (r = –0.41) and β[sub 2] –microglobulin (r = –0.29). The percentage change in CD4+ T cells over a 1–year period correlated with HIV–1 RNA levels (r = –0.32, p = 0.03), however, stronger correlations were found for neopterin, β[sub 2] –microglobulin and sTNFR–75 (r = –0.51, r = –0.41, r = –0.42; p<0.01). No progression to AIDS or death was observed in individuals with baseline HIV–1 RNA levels below 20,000 copies/ml (10 of 31 and 15 of 47 individuals, respectively). A Cox’s proportional hazard model to predict AIDS revealed that HIV–1 RNA, the change in CD4+ cells over a 1–year period and sTNFR–75 levels independently predict AIDS; the change in CD4+ cells, the absolute CD4+ T cell count and neopterin were jointly significant to predict death. All results were adjusted for nucleoside monotherapy. In conclusion, to improve the predictive power, quantitation of HIV–1 RNA as a 'natural history marker’ may be supplemented by measurement of sTNFR–75 for 'early’–stage disease progression and neopterin for 'late’–stage disease progression. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Objectives: Phylogenetic analyses of 2 or more countries allow to detect differences in transmission dynamics of local HIV-1 epidemics beyond differences in demographic characteristics. Methods: A maximum-likelihood phylogenetic tree was built using pol -sequences of the Swiss HIV Cohort Study (SHCS) and the Austrian HIV Cohort Study (AHIVCOS), with international background sequences. Three types of phylogenetic cherries (clusters of size 2) were analyzed further: (1) domestic cherries; (2) international cherries; and (3) SHCS/AHIVCOS-cherries. Transmission group and ethnicities observed within the cherries were compared with the respective distribution expected from a random distribution of patients on the phylogeny. Results: The demographic characteristics of the AHIVCOS (included patients: 3′141) and the SHCS (included patients: 12′902) are very similar. In the AHIVCOS, 36.5% of the patients were in domestic cherries, 8.3% in international cherries, and 7.0% in SHCS/AHIVCOS cherries. Similarly, in the SHCS, 43.0% of the patients were in domestic cherries, 8.2% in international cherries, and 1.7% in SHCS/AHIVCOS cherries. Although international cherries in the SHCS were dominated by heterosexuals with men who have sex with men being underrepresented, the opposite was the case for the AHIVCOS. In both cohorts, cherries with one patient belonging to the transmission group intravenous drug user and the other one non–intravenous drug user were underrepresented. Conclusions: In both cohorts, international HIV transmission plays a major role in the local epidemics, mostly driven by men who have sex with men in the AHIVOS, and by heterosexuals in the SHCS, highlighting the importance of international collaborations to understand global HIV transmission links on the way to eliminate HIV. [ABSTRACT FROM AUTHOR]

Vaccination against seasonal influenza is recommended for all HIV-infected persons. Few data have been reported on the effect of repeated annual vaccination in this population. We measured haemagglutination inhibition antibody responses and investigated seroprotection rates in 344 HIV-infected adults before and 12 weeks after influenza vaccination with a trivalent subunit vaccine. 68.3% of patients were male, the median age was 45 years. 83.7% had a viral load < 50 copies/mL. The median CD4 count was 604/µL. 304 patients (88.4%) had received influenza vaccinations in previous years. Seroprotection rates for A/H1N1 and B were over 90% in all age groups before vaccination and close to 100% after vaccination. For A/H3N2, seroprotection rates were lowest in individuals below 30 years both before and after vaccination (22.2% and 50.0%) and higher in older age groups (48.4% and 83.9% in people over 60 years). GMT fold increases were not significantly different across the age groups (3.0 to 4.2, p = 0.425). Previous influenza vaccinations were associated with higher seroprotection rates before and after vaccination (62.2% and 84.2% in patients with 8 or more previous vaccinations vs. 15.0% and 57.5% without previous vaccinations, respectively). Individuals with detectable viral load, elevated immune activation (urine neopterin ≥ 250 µmol/mol creatinine), and higher CD4 nadir (≥200 cells/µL) showed a trend towards inferior immune responses to vaccination, whereas gender and CD4 count did not have an effect. The lower seroprotection rates observed in younger individuals may be explained by the higher proportion of patients without HIV treatment and with fewer previous encounters with influenza strains. Good seroprotection rates can be achieved in elderly HIV-infected patients and after repeated annual vaccinations. [ABSTRACT FROM AUTHOR]

The article investigates the plasma of patients through interferon-y-mediated pathways and evaluates for associations with the proliferative responses of Peripheral Blood Mononuclear Cells (PBMCs) to mitrogens in vitro. Result shows that the in vitro proliferative capacity of PBMC was associated with viral load, CD4 counts and also tryptophan degradation. It was then concluded that the higher the degree of immune activation in vivo, the lower is the proliferative capacity of PBMC in vitro.

Antiretroviral therapy (ART) has a significant impact on HIV-1 RNA levels, the CD4 cell count, and immune activation. We examined whether these changes are associated with a change in the rate of tryptophan degradation (expressed as the kynurenine to tryptophan ratio, kyn/trp) as an estimate for the activity of interferon-γ inducible enzyme indoleamine (, )-dioxygenase (IDO). Plasma levels of tryptophan, kynurenine, and neopterin were measured pretherapy and 6 months postinitiation of therapy in 45 patients with HIV-1 RNA levels of less than 1000 copies/ml 6 months after initiation of ART. Before ART, the patients had decreased tryptophan and increased kynurenine concentrations compared to healthy controls. During ART, average tryptophan levels increased; in the same time kynurenine and kyn/trp decreased (P < 0.001), although not to normal levels. Since pretherapy tryptophan concentrations correlated inversely with neopterin, and kynurenine correlated with viral load and neopterin but not with CD4 cell count, the data support the view that HIV production may induce immune activation and consequently tryptophan is degraded at a higher rate. In agreement, kyn/trp positively correlated with neopterin (rs = 0.60, P < 0.001), with virus load (rs = 0.37, P = 0.013), and very weakly with CD4+ cells counts (rs = 0.30, P = 0.049). The change in the kyn/trp ratio during ART correlated more strongly with the change in neopterin levels (rs = 0.49, P = 0.001) than with the change in HIV RNA levels and weakly with the CD4 cell count. The data underscore the fact that both neopterin production and tryptophan degradation are triggered by immune activation. Tryptophan degradation is increased in HIV infection and partially reversed under ART. The data agree with the concept that immune activation is the common background of IDO activation which may be an important factor underlying T-cell hyporesponsiveness. [Copyright &y& Elsevier]