Malaria prophylaxis policy for travellers from Europe to the Indian Subcontinent.

Analysis of malaria imported into eight European countries from the Indian Sub-continent (ISC) (India, Pakistan, Bangladesh and Sri Lanka) led to a consensus statement on the use of chemoprophylaxis within TropNetEurop. The proportion of cases from the ISC in 2004 ranged from 1.4%-4.6% of total imported cases. Plasmodium falciparum cases reported from the eight countries was only 23 (13% of all cases from the region). Total malaria reports between 1999-2004 fell from 317 to 180. The risk of malaria in UK residents visiting the region was > 1 case per 1,000 years exposed. The group recommended non-selective prescribing of chemoprophylaxis for visitors to India, Pakistan, Bangladesh and Sri Lanka should be dropped.

The Fas/FasL system and T cell apoptosis in HIV-1-infected lymphoid tissue during highly active antiretroviral therapy.

Apoptosis has been proposed as a mechanism responsible for T cell depletion in HIV-1 infection. In the present study we have phenotyped apoptotic T cells in tonsillar lymphoid tissue from 11 HIV-1-infected patients by flow cytometry light-scatter characteristics during 48 weeks of highly active antiretroviral therapy (HAART). We found that the decline in tonsillar viral load was associated with a decrease in the proportion of apoptotic CD4+ and CD8+ T cells. CD4 cell apoptosis was predominantly seen within the memory CD28+ Fas+ FasL+ population. The increased level of apoptotic CD8+ T cells was found among activated Fas+ memory cells irrespective of CD28 and FasL expression. These T cell subsets were expanded in untreated infection, but normalized with therapy. We conclude that HIV-1 triggers FasL-mediated apoptosis of uninfected CD4+ T cells, whereas CD8+ T cell apoptosis is driven by chronic immune activation. Virus suppression reverses both of these mechanisms, contributing to immune reconstitution during HAART.

Residual human immunodeficiency virus type 1 infection in lymphoid tissue during highly active antiretroviral therapy: quantitation and virus characterization.

HIV-1 can persist in infected patients despite undetectable plasma viremia. To characterize the residual viral load, repetitive blood and tonsillar samples were collected from 11 HIV-1-positive individuals before and during 96 weeks of therapy with zidovudine, lamivudine, and indinavir. HIV-1 RNA in tonsils was quantified by RT-PCR and infectious HIV-1 provirus by the limiting dilution assay. Genotypic resistance analyses and biological characterization were performed on plasma virus, blood, and tonsillar isolates. Tonsillar infectious HIV-1 provirus and HIV-1 RNA declined by 2 and 3 log(10), respectively, but 10(3)-10(4) cells, less than 0.5% of the total body CD4(+) T cell population carrying infectious HIV-1 provirus, remained involved in active viral replication of drug-sensitive R5 viruses. Thus, the dominant HIV-1 residual infection consists of < or = 10(6) latently infected CD4(+) cells. Plasma HIV-1 RNA decline of > 1.5 log(10) during the first 2 weeks of therapy may indicate low levels of this latent reservoir. Whereas the reservoir of latently infected cells remains stable, actively replicating HIV-1 continuously declines during prolonged antiretroviral therapy. Thus, although viral eradication seems unlikely, antiretroviral therapy may induce an extended period of virologic latency in HIV-1-positive individuals.

Eradication of non-typhoid salmonellae in acute enteritis after therapy with ofloxacin for 5 or 10 days.

Eradication of non-typhoid salmonellae was evaluated in a randomized, double-blinded study of 49 patients with acute enteritis after therapy with ofloxacin 400 mg once daily for 5 or 10 days. Early eradication of salmonellae was found in 57% of patients in the 5 day therapy group and in 74% of patients in the 10 day therapy group. This difference was larger among severely ill patients. Together with our previous study of ofloxacin therapy for 3 days or placebo, this shows that early eradication of non-typhoid salmonellae increases with duration of ofloxacin therapy without an increase in persistence of salmonellae in stools or development of resistant strains.

Normalization of CD4+ cell numbers and reduced levels of memory CD8+ cells in blood and tonsillar tissue after highly active antiretroviral therapy in early HIV type-1 infection.

Antiretroviral therapy increases the number of both CD4+ and CD8+ T cells in the blood of HIV-1-positive patients with advanced disease. In the present study, we have examined the kinetics of CD4+ and CD8+ T cell restoration in blood and lymphoid tissue in asymptomatic HIV-1-positive individuals with high CD4+ cell counts during highly active antiretroviral treatment. Tonsillar biopsies and blood samples were collected at baseline and at regular intervals during the following 48 weeks and from HIV-1-negative controls. Mononuclear cells from blood and tonsils were phenotyped and quantified by three-color flow cytometry. After 48 weeks of therapy, blood CD4+ cell counts in the HIV-1-infected group were comparable to those found in uninfected controls. Naive CD4+ T cells in blood increased during the initial 2 weeks in parallel with reduced plasma viremia. Both naive and memory CD4+ T cells in blood reached normal numbers by week 48, whereas the CD4+ naive/memory cell ratio in tonsils was within normal range throughout the study. The level of memory CD8+ T cells in blood declined during the first 8 weeks in parallel with a reduction in the tonsillar memory CD8+ T cells. Naive CD8+ T cells in the blood increased after 4 weeks, while the level of naive CD8+ T cells in tonsils remained unaltered. Our data indicate that in the early stages of HIV-1 infection antiretroviral therapy normalizes CD4+ cell counts and causes a decrease in the level of memory CD8+ cells in blood and lymphoid tissue, suggesting reduced CD8+ cell turnover in response to reduced viral replication.

Changes in tonsillar tissue in early HIV-1 infection and during 3 years of antiretroviral therapy.

Tonsillar tissue from individuals in the early stages of HIV-1 infection was studied during the natural course of infection and during antiretroviral therapy with and without a protease inhibitor in order to investigate markers of clinical progression and evaluate the effects of therapy. Tonsillar biopsies and blood samples were collected at regular intervals during 3 years and clinical observations were noted. Tonsillar morphology was evaluated and the fragmentation of the follicular dendritic cell network was quantified by standardised follicular fragmentation rate (FR) analysis. Lymphocyte subsets were phenotyped by flow cytometry, and viral load was calculated by limiting dilution assay. The FRs were higher in the HIV-1-infected individuals than in the uninfected controls, although tonsillar tissue from both groups contained follicular fragmentation. During HIV-1 infection, the FR increased and the tonsillar CD4/CD8 ratio declined. During maximum viral suppression, FR approached that of controls while tonsillar T cell subsets and blood CD4 cell counts normalised. Even when virus suppression was incomplete, tonsillar improvements were observed in parallel with a resolution of the HIV-1-related dermatological disorders. However, persistent viral replication paralleled distortion of the tonsillar architecture. We suggest that a normalisation of the lymphoid tissue may have important functional and clinical implications in HIV-1 infection.

Activation of CD8 T cells normalizes and correlates with the level of infectious provirus in tonsils during highly active antiretroviral therapy in early HIV-1 infection.

OBJECTIVES: To study the effects of antiretroviral therapy on T cell activation in blood and tonsils from HIV-1 infected individuals in relation to CD4 cell count, plasma viremia, and infectious HIV-1 provirus. DESIGN: A 48-week study of viral load and T cell subsets in blood and tonsils from 12 HIV-1-positive individuals with a mean CD4 cell number of 400 x 10(6) cells/l treated with a combination of zidovudine, lamivudine, and indinavir. METHODS: Tonsil biopsies and blood samples were collected at regular intervals. Lymphocytes were phenotyped and quantified by three-color flow cytometry; infectious provirus was quantified by a limiting dilution assay. HIV-1-negative individuals were included as controls. RESULTS: The fraction of tonsillar CD8 T cells expressing CD69, CD38, or HLA-DR in the patients with suppressed virus replication declined to levels comparable with that in controls by 48 weeks and showed a strong positive correlation with tonsillar infectious provirus and plasma viremia. The level of CD4 T cell activation was within normal range in tonsils throughout the study. The fraction of HLA-DR+ cells within CD4 and CD8 T cells in blood declined rapidly in parallel with plasma viremia but remained slightly higher compared with that in uninfected individuals. CONCLUSION: Antiretroviral therapy normalizes tonsillar CD8 T cell activation in HIV-1-positive individuals in parallel with suppression of viral replication, indicating reduced CD8 cell turnover. Normal tonsillar CD4 T cell activation suggests limited CD4 cell turnover in early HIV infection. Activated CD8 T cells in lymphoid tissue is superior to that in blood as an immunological marker for the virological response to antiretroviral therapy.

Correlates of apoptosis of CD4+ and CD8+ T cells in tonsillar tissue in HIV type 1 infection.

The immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased death by apoptosis of T cell subsets. In the present study, we have examined correlates of apoptosis of CD4+, CD8S+CD28+, and CD8+CD28- T cells in tonsillar lymphoid tissue in persons with HIV-1. Single-cell suspensions of tonsillar lymphocytes were analyzed by flow cytometry to determine the fraction of cells showing typical characteristics of apoptosis as well as the expression of activation markers within the live and the apoptotic cell populations. The proportion of cells carrying infectious provirus was quantified by limiting dilution analysis. Compared with uninfected controls, apoptosis of both CD4+ and CD8+ T cells was enhanced in HIV-1 infection and was higher among CD8+ than among CD4+ T cells. Apoptosis of CD28-cells was more prevalent than apoptosis of CD28+ cells for both CD4+ and CD8+ T cells. Occurrence of apoptosis of CD4+ T cells correlated with provirus levels and proportional expression of the activation marker HLA-DR. Apoptosis of CD8+CD28+ cells correlated with expression of the activation markers CD69 and HLA-DR while apoptosis within CD8+CD28- cells did not correlate with any of the studied parameters. Although apoptosis was much more prevalent among CD8+ than CD4+ T cells, CD8+ T cells still accumulated in tonsillar lymphoid tissue in persons with HIV-1. Our data may be interpreted to suggest that apoptosis of CD4+, CD8+CD28+, and CD8+CD28- cells in tonsillar tissue is regulated by different mechanisms and the results are of importance to our understanding of the immunopathogenesis of HIV-1 infection.

Correlates of latent and productive HIV type-1 infection in tonsillar CD4(+) T cells.

Correlates of virus load and characteristics of virus-producing cells in tonsillar tissue were investigated. Our results suggest that when less than 1:100 tonsillar CD4(+) T cells from individuals infected with HIV type-1 (HIV-1) contain replication competent provirus, the level of CD4(+) T cells in tonsils is comparable to that observed in uninfected individuals. Virus load at or above this level was associated with low CD4 cell numbers in tonsillar tissue. Only a few percent of all infected T cells in tonsillar tissue were active virus producers, with minor differences observed between individuals. Plasma viremia was found to correlate with infectious virus load in tonsillar tissue. With less than 1:1,000 of CD4 cells in lymphoid tissues being involved in active virus production, direct cytopathic effect by HIV-1 on infected CD4 cells is unlikely to fully explain the immunodeficiency seen in AIDS.

CD8+ T cells from HIV type 1-seronegative individuals suppress virus replication in acutely infected cells.

CD8+ lymphocytes (CD8 cells) have been shown to inhibit replication of the human immunodeficiency virus (HIV) in vitro when cocultured with HIV-infected CD4+ lymphocytes (CD4 cells). This suppressive effect on HIV replication in experimentally infected CD4 cells has so far been demonstrated only for CD8 cells from HIV-seropositive individuals. In the present study we have investigated if CD8 cells from HIV-negative individuals can also suppress HIV replication in experimentally infected CD4 cells. Positively selected CD4 cells were infected with phenotypically different primary isolates of HIV type 1 and 2 (HIV-1 and HIV-2). Graded numbers of CD8 cells were added to the infected cultures. The T cells were activated by antibodies directed against the CD3 molecule or the T cell receptor. Culture supernatants were harvested for HIV p24 quantitation and the CD8 suppression of HIV replication was calculated by comparing p24 levels from parallel cultures in the presence or absence of CD8 cells from different donors. We show that CD8 cells from unexposed HIV-seronegative blood donors are able to control HIV-1 and HIV-2 replication in experimentally infected autologous CD4 cells. The antiviral activity of CD8 cells from and HIV-naive individual was reproducible over time and the suppressive effect was comparable to that seen with CD8 cells from HIV-positive individuals. The infected cells were not eliminated from the cultures. The suppressive effect of CD8 cells varied depending on the dose and biological phenotype of the virus used for infection. Thus, exposure to HIV in vivo is not a prerequisite for CD8 cells to exert a suppressive effect on HIV replication in acutely infected cells.

Reduced CD4 cell counts in blood do not reflect CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1 infection.

OBJECTIVE: To investigate whether the loss of CD4 cells seen in peripheral circulation of HIV-1-positive individuals reflects a similar depletion of CD4 cells from lymphoid tissue. DESIGN: CD4 and CD8 cells in tonsillar mononuclear cell suspensions were quantified relative to tonsillar B cells, as these were thought to remain numerically unchanged in the course of HIV infection. Results were related to the CD4 cell counts in blood and to the clinical status of the patients. METHODS: Blood samples and tonsillar tissue were obtained from 13 HIV-1-seropositive individuals and six seronegative controls. B cells and T-cell subsets in mononuclear cells were quantified using a three-colour flow cytometry protocol. Histological sections were morphologically classified and B-cell areas were quantified by morphometry. RESULTS: The B-cell fraction was confirmed to be relatively unchanged in asymptomatic HIV-1-seropositive individuals compared with controls. The tonsillar CD4 : B-cell ratios in asymptomatic individuals was similar to those seen in controls, whereas the CD4 : B-cell ratios in symptomatic HIV-1-infected individuals were greatly reduced. The tonsillar CD4 : CD8 cell ratios in HIV-1-infected individuals were much lower than those seen in controls, in the asymptomatic group due to a considerable expansion of the tonsillar CD8 cell subset, and in the symptomatic group also due to a loss of CD4 cells. CONCLUSIONS: We found no evidence of CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1-infected individuals despite low CD4 cell counts in blood. Loss of CD4 cells from this lymphoid tissue seems to occur as a late-stage phenomenon correlated with the onset of clinical symptoms.

Dynamics of HIV-1 replication following influenza vaccination of HIV+ individuals.

Levels of HIV-1 have been reported to increase in peripheral blood after influenza vaccination of HIV+ individuals. In this study we have evaluated the dynamics of these changes. Ten HIV-1+ individuals classified in revised CDC clinical categories B and C as well as five seronegative healthy controls were vaccinated with the recommended influenza strains. HIV viral RNA and proviral DNA were sequentially quantified in serum and blood lymphocytes, respectively. Nine of the 10 HIV+ individuals had an increase in the frequency of infected CD4 cells 2 weeks after influenza vaccination. Individuals with low viral load had a rapid increase in viraemia and a small increase in frequency of infected cells in peripheral blood. In contrast, individuals with high viral load had a small drop in viraemia followed by a significant rise in the rate of infected cells. The observed change may resemble those taking place during intercurrent infections in HIV+ individuals. The effects of the relative increases in infectious virus after the transient viraemic phase should be further investigated to evaluate potential risks of vaccination.

Serum antibodies to viral pathogens and Toxoplasma gondii in HIV-infected individuals.

Sera from 38 HIV-infected individuals were examined longitudinally for antibodies to viruses that may increase morbidity in HIV infection, as well as commensal viruses and Toxoplasma gondii. HTLV infection was seen in Norway for the first time as four patients had antibodies to HTLV-II and one had antibodies to HTLV-I. Antibodies to hepatitis B virus (HBV) were found in 47.2%, while 21.6% of the patients had antibodies to hepatitis C virus (HCV). There was no evidence of acquisition of HBV or HVC during the mean observation period of 2 years. A titre increase in CMV antibody with time was observed for 7 out of 21 patients and a decrease for 2 patients. For Epstein-Barr virus, herpes simplex, varicella-zoster, rubella and measles viruses, human polyomavirus BK as well as for Toxoplasma gondii, antibody prevalences and titres were within the range seen in normal populations. Also, no longitudinal changes were observed in titres of these antibodies, indicating that humoral immunity remained intact during the study period. The high prevalences of HTLV-I/II, HBV and HCV antibodies in HIV-infected patients reflect common modes of virus transmission, and the fluctuations in CMV antibody titre are indicative of reactivations. Such coinfections may influence disease progression.

HIV infection and Norwegian general practitioners: does fear affect knowledge?

The objective was to study the dimensionality of knowledge among general practitioners in Norway about transmission of HIV and what factors influence the degree of knowledge. Data were collected by a mailed questionnaire. Independent variables were experience of HIV, acquisition of knowledge and confidence in information on HIV from the central authorities and perception of own knowledge, skills of practice and fear of oneself or one's family contracting the HIV infection. Analysis of variance and multiple classification analysis were applied to measure the effect of independent variables on knowledge about transmission of HIV. The general practitioners in three counties (Oslo, Møre og Romsdal and Troms), constituting one-quarter of the Norwegian general practitioner population were selected (n = 578). The response rate was 65%, and the results are assumed to be representative of Norwegian general practitioners. Four dimensions of knowledge about transmission of HIV were identified by factor analysis. The two most important, transmission through 'body fluids' and transmission by 'needle sticks', were subsequently converted into sum scores and used as dependent variables. Forty-five per cent of the respondents were uncertain about ways in which HIV is not transmitted through 'body fluids'. There was an association between knowledge about transmission through 'body fluids' and the variables county background, confidence in the information about HIV and fear of contracting HIV. In the multiple classification analysis these three variables explained 11% of the variation in knowledge about transmission through 'body fluids'. Only confidence and fear significantly predicted the degree of knowledge, and among the 11% who had no confidence in the information received the effect of fear on knowledge increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)