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Given international interest in "treatment as prevention" (TasP) and the pertinence of optimizing antiretroviral treatment (ART) regimens for TasP, 19 French HIV experts were interviewed on their criteria for ART if used specifically for prevention with HIV-positive persons. Through content analysis of the interview material, nine criteria were identified. The most endorsed criteria, collectively, suggest a choice of treatment based on "minimal interference" where negative impacts of ART are minimized and ease of treatment integration maximized in the lives of people living with HIV/AIDS (PLHIV) for both the short and long term. These criteria were the tolerance, side effects, and/or toxicity profile of ART, simplicity (e.g., of treatment schedule, dosage form) and the individualization of treatment (e.g., adapted to lifestyle). While virologic efficacy (i.e., a durable, undetectable viral load) was also deemed important, several experts specified that it was virtually assured with current treatments. To a much lesser extent, experts endorsed diffusion of ART into the genital compartments, a strong genetic barrier (against resistance), validated treatments (as opposed to new classes of ART), a rapid reduction in HIV viral load, and treatment cost. Pharmacologically, minimal interference calls for further improvements in the tolerance, side effects and toxicity profile of ART and in the simplicity of ART administration. Clinically, it means avoiding a one-size-fits-all approach to ART in TasP and engagement with and of PLHIV in ART selection and side effects management. Strategically, it emphasises keeping the health and quality of life of PLHIV at the forefront of a TasP-oriented public health intervention.

Early use of highly active antiretroviral treatment (ART) in people living with HIV for HIV prevention has gained legitimacy but remains controversial. Nineteen French HIV experts with diverse specializations (over half of whom were clinicians) were qualitatively interviewed on their views about ART irrespective of CD4 count of more than 500 cells/mm3for purposes of HIV prevention, which is not systematically recommended in France. Content analysis identified 2 broad categories: individual considerations (subcategories: patient health and well-being; patient preparedness and choice) and collective considerations (subcategories: HIV transmission risk; impact on the epidemic; cost). Uncertainty surrounded many experts’ considerations, and unity was lacking on key issues (eg, candidacy for early preventive treatment, expected clinical- and population-level effects). An umbrella theme labeled “Weighing the merits of early ART in the face of uncertainties” was identified. Our analyses raise doubts about the current acceptability of widespread implementation of early ART for HIV prevention in France.

The decision by blood agencies in many developed countries to defer the donation of blood by men who have sex with men was justified when it was first implemented, in 1983, given that there was no effective mechanism to screen for HIV infection until screening for HIV antibodies became available in

Evidence from animal models suggests that the expression of CD8alphaalpha homodimer on CD8(+) T cells plays a key role in the generation of long-lived memory cells. Here, we studied the quantitative alterations of CD8(+) T cell subsets expressing CD8alphaalpha, interleukin-7 receptor (IL-7Ralpha) and activation markers in HIV-1-infected individuals including aviremic, viremic and slow progressor subjects using eight-color flow cytometry. Compared to slow progressor subjects, expression of CD8alphaalpha was significantly reduced in aviremic and viremic patients and this reduction occurred mainly within central memory cell subsets and not in naive and effector memory compartments. Persistence of antigenemia leads to IL-7Ralpha loss mainly on central and pre-terminal memory CD8(+) T cell subsets in viremic patients but not in slow progressor subjects. Compared to aviremic and viremic patients, slow progressor subjects had lower levels of IL-7 and reduced activated cells. The expression of CD8alphaalpha was not significantly related to IL-7Ralpha although negative associations were evidenced within all CD8(+) T cell subsets. Collectively, these results further advance the characterization of immunophenotypic patterns of CD8(+) T cell subsets expressing CD8alphaalpha/IL-7Ralpha and provide new insights into the ability of HIV-1 infection to alter memory cell population.

Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS; also known as "B-cell factor belonging to the tumor necrosis factor family" [BAFF]). We have recently shown that, in human immunodeficiency virus (HIV)-infected individuals with rapid and those with classic disease progression, B-cell dysregulations were associated with increased BLyS expression in plasma and by blood myeloid DCs (mDCs), in contrast to aviremic HIV-infected individuals with slow disease progression (also known as "elite controllers"). In previous work with transgenic mice expressing HIV genes, B-cell dysregulations were concomitant with altered mDCs and dependent on HIV negative factor (Nef). We now report that HIV Nef is detected early after infection and despite successful therapy in plasma and BLyS-overexpressing blood mDCs of HIV-infected rapid and classic progressors, whereas it is low to undetectable in aviremic slow progressors. In vitro, HIV Nef drives monocyte-derived DCs toward BLyS overexpression through a process involving STAT1. Importantly, this is counteracted in the presence of all-trans retinoic acid. Nef thus contributes to high BLyS proinflammatory profiles in HIV-infected individuals.

Objectives To examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. Methods Thirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy. An enzyme-linked immunosorbent assay was used to determine IL-7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV-1. Results Pretreatment IL-7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r=−0.59, P

Summary CD40/CD40-ligand (CD40L) signalling is a key stimulatory pathway which triggers the tryptophan (Trp) catabolizing enzyme IDO in dendritic cells and is immunosuppressive in cancer. We reported IDO-induced Trp catabolism results in a T helper type 17 (Th17)/regulatory T cell (Treg) imbalance, and favours microbial translocation in HIV chronic infection. Here we assessed the link between sCD40L, Tregs and IDO activity in HIV-infected patients with different clinical outcomes. Plasmatic sCD40L and inflammatory cytokines were assessed in anti-retroviral therapy (ART)-naive, ART-successfully treated (ST), elite controllers (EC) and healthy subjects (HS). Plasma levels of Trp and its metabolite Kynurenine (Kyn) were measured by isotope dilution tandem mass spectrometry and sCD14 was assessed by enzyme-linked immunosorbent assay (ELISA). IDO-mRNA expression was quantified by reverse transcription–polymerase chain reaction (RT–PCR). The in-vitro functional assay of sCD40L on Treg induction and T cell activation were assessed on peripheral blood mononuclear cells (PBMCs) from HS. sCD40L levels in ART-naive subjects were significantly higher compared to ST and HS, whereas EC showed only a minor increase. In ART-naive alone, sCD40L was correlated with T cell activation, IDO-mRNA expression and CD4 T cell depletion but not with viral load. sCD40L was correlated positively with IDO enzymatic activity (Kyn/Trp ratio), Treg frequency, plasma sCD14 and inflammatory soluble factors in all HIV-infected patients. In-vitro functional sCD40L stimulation induced Treg expansion and favoured Treg differentiation by reducing central memory and increasing terminal effector Treg proportion. sCD40L also increased T cell activation measured by co-expression of CD38/human leucocyte antigen D-related (HLA-DR). These results indicate that elevated sCD40L induces immunosuppression in HIV infection by mediating IDO-induced Trp catabolism and Treg expansion.

Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naive, Successfully Treated (ST), and elite controllers (EC). In ART-naive patients, increased IDO activity/expression, together with elevated levels of TNF-alpha and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-na ve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.

Regulatory T cells (Tregs) have a dominant role in self-tolerance and control of autoimmune diseases. These cells also play a pivotal role in chronic viral infections and cancer by limiting immune activation and specific immune response. The role of Tregs in HIV pathogenesis remains poorly understood as their function, changes according to the phases of infection. Tregs can suppress anti-HIV specific responses and conversely can have a beneficial role by reducing the deleterious impact of immune activation. We review the frequency, function and homing potential of Tregs in the blood and lymphoid tissues as well as their interaction with dendritic cells in the context of HIV infection. We also examine the new insights generated by recombinant IL-2 and IL-7 clinical trials in HIV-infected adults, including the immunomodulatory effects of Tregs. Based on their detrimental role in limiting anti-HIV responses, we propose Tregs as potential targets for immunotherapeutic strategies aimed at decreasing Tregs frequency and/or immunosuppressive function. However, such approaches require a better understanding of the time upon infection when interfering with Treg function may not cause a deleterious state of hyperimmune activation.

It is recognized that AIDS involves multiple epidemics. As well as an epidemic of HIV, we are experiencing epidemics of fear and of stigmatization, scapegoating and discrimination associated with AIDS. In this paper, we investigate the nature of these reactions and the links between them. In doing so, we identify some of their causes. We likewise investigate counter-reactions, pre-eminent among which is the promotion of concepts of respect for persons and for human rights. We also examine the 'tools' used to elicit and manifest both these reactions and counter-reactions. In all cases, these 'tools' include choice of language--especially in the form of metaphor and rhetoric--and the use of symbolism. We conclude that in order to deal humanely and compassionately with AIDS and persons with AIDS, and, ultimately, to protect society (including, the fundamental principles and rules on which it is based), a primary requirement is to recognize that we are all living with AIDS, whether infected or affected by it; that is, in the context of AIDS, it is imperative that we overcome any divisions into 'them' and 'us'.

Background The level of HIV-1 integrated DNA in CD4 T cells was reported to predict the evolution of untreated HIV-1 infection independently of CD4 cell counts or plasma HIV-1 RNA levels. However, the relevance of reservoir level while on efficient antiretroviral therapy (ART) is still unknown. Objectives To evaluate factors that may contribute to the establishment and maintenance of HIV-1 reservoir size in ART-treated HIV-1-infected adults with complete suppression of viremia. Study design 35 subjects receiving ART with plasma HIV-1 RNA below the limit of detection for an average duration of 3.2 years were studied. A highly sensitive PCR was used to assess HIV-1 integrated DNA levels in sorted CD4 T cells. Results The mean HIV-1 integrated DNA was 300 ± 7 copies/10 6 CD4 cells (range 10–1408). In univariate analysis, the levels of HIV-1 proviral DNA appeared to be independent of duration of HIV-1-infection, duration on ART, time since HIV-1 viral load was undetectable, delay between HIV-1 infection and starting ART, or viral load before starting ART. Conversely, CD4 T cell nadir, CD4/CD8 ratio and, to lesser degree, CD4 T cell counts were inversely associated with HIV-1 proviral DNA levels. In multivariate analysis, only CD4 T cell nadir significantly predicted levels of HIV-1 proviral DNA ( P = 0.025). Conclusions CD4 T cell nadir strongly predicted reservoir size independently of other factors in HIV-1-infected adults with complete suppression of viremia. Collectively, these results indicate that the extent of CD4 T cell depletion before ART drives the size of the viral reservoir after prolonged therapy.

This review of the human immunodeficiency virus (HIV) epidemic shows that HIV has had and will have a major impact on dentistry, just as it has had on so many other aspects of medical practice and society. These areas include the prevention of HIV transmission in the dental care workplace, the early and safe care and treatment of those who are infected, and the protection of those who are vulnerable or made more vulnerable because of HIV infection. To do this, the dental professional must be educated about HIV and its diseases, their treatment, and what must be done to prevent HIV transmission. Early recognition and treatment of HIV-related oral diseases have become the norms of practice today. Although more and more dentists face potential exposure to HIV, excellent dental care can be provided while minimizing this risk.

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels

To estimate the cost-effectiveness ratio of highly-active antiretroviral therapy (HAART) in Canada.A before-and-after analysis to calculate incremental cost of life year gained (LYG) between 1991 and 1995 (pre-HAART period) and between 1997 and 2001 (HAART period) for non-AIDS and AIDS groups (CDC stage of HIV infection).For two Quebec HIV hospital clinics, mean inpatient (IP) days, outpatient (OP) visits and direct health care costs per patient-year (PPY) were calculated. Cox's proportional hazards models calculated disease progression, stratified by study periods and adjusted for gender, age at cohort entry, sexual orientation, injecting drug use and baseline CD4 cell count.For non-AIDS patients, mean IP days was 1.6 (pre-HAART period) compared with 0.8 PPY (HAART period); mean OP visits increased from 2.8 to 5.5 PPY. Total cost was US$ 4265 (pre-HAART period) and US$ 9445 PPY (HAART period) of which 66 and 84%, respectively were spent on antiretroviral drugs. Median progression time was 6.3 years in the pre-HAART period compared with 12.5 years in HAART period (log rank chi = 270, P0.0001). Incremental cost per LYG between periods was US$ 14 587. For AIDS patients, mean IP days decreased from 13.3 to 4.4 PPY between periods; OP visits increased from 8.3 to 9.2 PPY. Total costs increased from US$ 9099 to US$ 11 754 PPY, while expenditure on antiretroviral drugs increased from 29 to 72% of total cost. Median progression time was 3.8 years in the pre-HAART period, which increased to 13.3 years in the HAART period (log rank chi = 158, P0.0001); incremental cost per LYG between periods was US$ 12 813.HAART appeared a cost-effective intervention in Canada.

We investigated the effect of dyslipidemia associated with highly active antiretroviral therapy on cardiovascular risk and life expectancy among patients who had the human immunodeficiency virus. Dyslipidemia estimates were based on results from a phase 2 randomized trial that compared lipid changes after 32 weeks of therapy with atazanavir with those with nelfinavir (each in combination with stavudine and lamivudine). The resultant increased coronary risk was estimated using Framingham risk equations, and change in life expectancy (after adjustment for mortality due to human immunodeficiency virus) was based on the cardiovascular life expectancy model, which is based on a published Markov's model. Levels of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (+24% and +28%) than among those who used atazanavir (+4% and +1%). This dyslipidemia increased the risk of coronary disease by 50% over 10 years. The absence of dyslipidemia was estimated to preserve life expectancy 0.15 to 1.53 additional years depending on a patient's age, gender, and other risk factors. There are increasing reports of dyslipidemia and cardiovascular events associated with highly active antiretroviral therapy. Significant increases in blood lipid levels observed with some protease inhibitors are associated with an increase in calculated 10-year coronary risk. Accordingly, minimizing dyslipidemia associated with highly active antiretroviral therapy may preserve life expectancy among adults who have the human immunodeficiency virus.

Provision of nourishment to terminally ill patients has been a controversial topic in clinical medicine. Determination of the limits of palliative care requires an understanding of the disease process, as well as the boundaries of patient self-determination. With the advent of living wills, the determination of the patient to limit care, including nutrition support, has become socially acceptable. Difficulties arise when there are differences of opinion between the caregiver and the patient. The solutions to these conflicts are often decided in the courtroom, as demonstrated by the Cruzan and Quinlan cases. Living wills are often written to prevent unnecessary financial burdens in hopeless situations. As well, financial considerations influence the decisions made by caregivers in providing care to terminally ill patients. The following case report illustrates the conflict between patient self-determination and limitation of care for financial reasons. The use of substituted judgment within the Canadian health care system and the role of team meetings to resolve ethical decisions are discussed.

Cold stress by increasing circulating catecholamines may sensitize blood platelets to aggregate and release their constituents. This study investigates the effect of cold stress on the release of the platelet-specific protein beta-thromboglobulin into the coronary venous blood of 12 subjects with atherosclerotic coronary artery disease (CAD) and 7 subjects with angiographically normal coronary arteries (NCA). Cold pressor stress caused a greater increase in systolic arterial pressure in patients with CAD than in subjects with NCA (p less than 0.05). There was no significant difference between the platelet counts in the arterial or coronary venous blood either before or during cold stress. Arterial beta-thromboglobulin was higher in the group with CAD (77 +/- 18 ng/ml) than in subjects with NCA (49 +/- 12 ng/ml, p less than 0.01). Although there was no arteriovenous difference of beta-thromboglobulin at rest in either group, during cold stress, coronary venous beta-thromboglobulin increased in both the NCA (53 +/- 16 to 95 +/- 26 ng/ml, p less than 0.05) and CAD groups (76 +/- 13 to 117 +/- 53 ng/ml, p less than 0.025) despite no change in arterial beta-thromboglobulin. Release of beta-thromboglobulin, although not related to the presence of angiographic arterial disease, correlated with the systolic arterial pressure during cold stress (r = 0.66) and inversely with the platelet's ability to generate cyclic adenosine monophosphate (r = 0.69). The release of platelet constituents in the coronary circulation is provoked by cold stress and may play a role in stress-induced acute coronary occlusion in patients with atherosclerotic disease and in those with apparently normal vessels.

By lysine-Sepharose chromatography, approximately 20% of normal plasma samples yield epsilon-aminocaproic acid (EACA) eluates which are opalescent, rather than clear, suggesting the presence of an additional, non-plasminogen component. This material has been isolated and characterized as a plasma lipoprotein of the very low density (VLDL) class on the basis of density ( less than 1.006 g/ml), size (greater than or equal to 5 X 10(7) daltons by gel filtration), electrophoretic mobility (pre-beta), chemical composition (mean cholesterol:triglyceride protein ratio, 1:3.4:1) and immunochemical evidence for apoproteins B, C, and E. Uniform particles, 100-200 Angstroms in diameter, were seen by electron microscopy. In contrast with VLDL in general, this lipoprotein co-chromatographed with plasminogen on lysine-Sepharose, where its binding was plasminogen-dependent, and from which it was eluted by EACA, but at lower concentrations than was plasminogen, suggesting a lysine-binding process. This plasminogen-binding lipoprotein (PBLP) was found in both male and female plasma samples, and increased post-prandially. Its properties suggest that it is a unique subclass of plasma VLDL. Although its isolation explains a laboratory phenomenon, and it exhibits interesting interactions with an important plasma zymogen, its function remains to be determined.

HIV antigens were searched for in the thymus, lymph nodes, bone marrow, and spleen of AIDS patients, by means of immunofluorescence technique. Human IgG against HIV and monoclonal antibodies against viral gag P24 protein yielded strong cytoplasmic fluorescence of cells in sections of the thymus, lymph nodes and spleen. Some cells containing HIV antigens were morphologically multinucleated giant cells. They reacted with monoclonal antibodies against helper/inducer T-cells (OKT4+), and were complexed with antibody or with complement as demonstrated by double-staining immunofluorescence technique. A large number of inflammatory cells infiltrated the thymus in areas containing cells expressing HIV antigens. These studies demonstrated an association of HIV virus with cytopathic and immunopathogenic reactions in lymphatic organs of AIDS patients, and are consistent with previous results, as well as indicative of a primary aetiologic role for the virus.

Infection of a newly described human T lymphoid cell line, CEM-CL10, with three different variants of HIV-1 resulted in cytopathic effects followed by cell lysis. Following primary lytic infection, proviral DNA could not be detected by Southern blot analysis in the outgrowth of the surviving CEM-CL 10 cells 60 days after initial exposure to HIV-1. These surviving cells could be further grown as a separate line, derived from CEM-CL10, and were found to be resistant to subsequent infection by HIV-1. A marked decrease in CD4 antigen expression was observed in these latter cells but not of the CD3 and transferrin receptor antigens. This decline in cell surface CD4 expression was correlated with both an absence of specific CD4 mRNA and with changes in structure of the CD4 gene. Both the HIV-1-sensitive CEM-CL10 cell line and its CD4(-), HIV-1-resistant derivative line, will be made available to interested investigators.

To determine if vesicular rosettes (VR), tubuloreticular structures (TRS), and "test-tube and ring-shaped forms" (TRF) are characteristic ultrastructural features of the syndromes of acquired immune deficiency (AIDS) or of unexplained persistent lymphadenopathy (PLS), the authors studied lymph nodes from nine patients with PLS, two patients with AIDS, and seven controls by electron microscopy. An average of 122 lymphocytes per case were photographed. VR were present in only 0.37% of lymphocytes in 4 of 11 index cases and were mimicked by grouped vesicles and degenerating multivesicular bodies (MVB). TRS were found in 10 of 11 index cases, compared with only one of seven controls (P less than 0.01). In the index cases, they were more frequent in AIDS (mean 21%) than in PLS lymphocytes (mean 4%) (P less than 0.05). MVB were found in all index cases and five of seven controls and were more frequent in index lymphocytes (mean 19%) than in controls (mean 5%) (P less than 0.01). TRF were found in one Haitian male with AIDS, where they were present in 4% of lymphocytes. VR are infrequent and indistinct. MVB probably reflect the reactivity of the lymphocytes. TRF is not a feature of PLS. The authors conclude that there are no pathognomonic ultrastructural markers of AIDS or PLS but that TRS are characteristic of both syndromes and occur frequently enough to be supportive to the diagnosis of AIDS and PLS.