Long-term antifungal treatment improves health status in patients with chronic pulmonary aspergillosis: a longitudinal analysis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is an infectious disease that progressively destroys lung tissue. To date, no longitudinal data on the efficacy of antifungal treatment on health status in CPA patients exist. METHODS: Using the standardized St George's Respiratory Questionnaire, the health status of 122 patients with was assessed at baseline and quarterly over 12 months. The score range was 0-100, where higher score indicates worse heath status, and a change of ≥4 was deemed the minimal clinically important difference. Lung function, body mass index, Medical Research Council dyspnea scale, disease severity, and demographic data were reported. RESULTS: Mean age of patients was 59 years, and 45% were female. Overall, patients with CPA had substantial health status impairment at baseline. After treatment, 47%-50% gained substantial health improvement with a mean reduction of score of 14 at both 6 and 12 months, whereas 32% deteriorated with a mean rise of score of 11 and 14 after 6 and 12 months of treatment and observation, respectively, and 21% were not much different (stable). Patients gained therapeutic benefit irrespective of their illness severity where >50% of those who had "poor" and "very poor" status at baseline improved with score reduction of ≥4 after 6 months of treatment. Replicating this analysis using a health status category, we found that at least 50% of patients with a "poor/very poor" health status category at baseline improved significantly to "fair" or "good/very good" categories. Side effects burdened health status considerably. In multivariate analysis, dyspnea and disease severity significantly defined health status impairment. CONCLUSIONS: Antifungal therapy improved health status and prevented CPA progression in most patients.

Monocyte derived dendritic cells from HIV-1 infected individuals partially reconstitute CD4 T-cell responses.

OBJECTIVES: The study tests the hypothesis that monocyte derived dendritic cells from HIV-1 infected individuals are normal and can restore impaired CD4 T-cell antigen specific responses. DESIGN: Monocyte derived dendritic cells were isolated from individuals at three different stages of HIV-1 infection with a wide spectrum of viral load and CD4 T-cell counts, and from healthy volunteers. The cell surface phenotype and allogeneic stimulatory potential of these dendritic cells was documented. CD4 T-cell responses to HIV p24, tetanus toxoid and purified protein derivative were measured using either unfractionated peripheral blood mononuclear cells, or purified dendritic cell/T-cell cultures. RESULTS: Dendritic cells from all three HIV-1 infected groups did not differ from each other or from healthy volunteers in terms of cell surface phenotype or allogeneic stimulatory potential using T cells from healthy volunteers. Dendritic cells from immunosuppressed antiretroviral naive individuals enhanced the autologous recall proliferative responses both to HIV-1 p24, and third party antigens tetanus toxoid and purified protein derivative, both in terms of the proportion of responding individuals, and median proliferation. CONCLUSION: Antigen presentation by dendritic cells partially restores impaired antigen specific CD4 T-cell responses associated with HIV-1 infection. Immunization strategies which target dendritic cells may therefore offer significant advantages in the ability to stimulate HIV-specific protective immune responses.

Development of the antibody response in acute HIV-1 infection.

BACKGROUND: Cytotoxic T lymphocytes have been shown to reduce viraemia during acute HIV-1 infection; however the role of neutralizing antibodies in this process is unclear. One confounding factor may be artefacts introduced by viral culture. OBJECTIVE: To assess the development of autologous neutralizing and non-neutralizing antibodies following acute HIV-1 infection using recombinant viruses with envelopes amplified directly from patient peripheral blood mononuclear cells, thereby avoiding in vitro selection. METHODS: Disease progression in four homosexual men was monitored from acute infection for up to 2.5 years, in the absence of antiretroviral therapy. Antibodies to viral envelope protein were quantified by enzyme-linked immunosorbent assay. Development of neutralizing antibodies was monitored using a quantitative infectivity reduction assay, sequential serum, recombinant viruses and target cells with defined receptor expression. RESULTS: The time to development of neutralizing antibodies after onset of symptoms was 3, 5, 7 and 16 months in the four patients. There was no correlation between development of neutralizing antibodies and the resolution of viraemia in any of the patients. However, antibodies to the envelope were detectable as early as 2 weeks after onset of symptoms. CONCLUSIONS: Neutralizing antibodies do not contribute to the control of viraemia in acute HIV-1 infection. However, antibodies to the envelope could be detected at the time of reduction in plasma viraemia and so other effector functions of antibodies may play a role in viral clearance.

Association of strong virus-specific CD4 T cell responses with efficient natural control of primary HIV-1 infection.

OBJECTIVE: To investigate whether there are differences in the virus-specific CD4 T cell response during primary HIV-1 infection in patients who naturally (without antiretroviral intervention) control viral replication with differing efficiencies. METHODS: CD4 T cell responses to recombinant HIV proteins (Gag p24 and p55 and Env gp160) and an inactivated HIV-1 preparation were analysed using interferon-gamma ELISPOT assays (with CD8-depleted peripheral blood mononuclear cells) and by intracellular interferon-gamma staining and fluorescent-activated cell sorting. RESULTS: Strong HIV-specific CD4 T cell responses were detected from the earliest time-points analysed in primary infection in patients who naturally established low persisting viral loads. By contrast, HIV-specific CD4 T cell responses were weaker (at or just below the limit of detection in our assays) at similar time-points in patients who went on to establish high persisting viral loads. Statistical analysis revealed a highly significant difference (P < 0.001) between the magnitudes of the Gag p24-specific response at the earliest time-point analysed in primary infection in the two sets of patients. CONCLUSIONS: Strong HIV-specific CD4 T cell responses are associated with efficient natural control of primary HIV-1 infection.

Dendritic cells in viral pathogenesis: protective or defective?

Dendritic cells (DC) are potent antigen-presenting cells that are critical in the initiation of immune responses to control and/or eliminate viral infections. Recent studies have investigated the effects of virus infection on the biology of DC. This review summarizes these changes, focusing on both the DC parameters affected and the viral factors involved. In addition, the central role of DC biology in the pathogenesis of several viral families, including herpesviruses, paramyxoviruses and retroviruses, is explored. The field of pathogen recognition by DC is addressed, focusing on its role in protecting the host from viral infection, as well as the ability of viruses to exploit such host receptor ligation and signalling to their replicative advantage. The hypothesis is proposed that virus and host have evolved a symbiotic relationship to ensure both viral transmission and host survival.

Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection.

Specific CD8 T-cell responses to human immunodeficiency virus type 1 (HIV-1) are induced in primary infection and make an important contribution to the control of early viral replication. The importance of neutralizing antibodies in containing primary viremia is questioned because they usually arise much later. Nevertheless antienvelope antibodies develop simultaneously with, or even before, peak viremia. We determined whether such antibodies might control viremia by complement-mediated inactivation (CMI). In each of seven patients studied, antibodies capable of CMI appeared at or shortly after the peak in viremia, concomitantly with detection of virus-specific T-cell responses. The CMI was effective on both autologous and heterologous HIV-1 isolates. Activation of the classical pathway and direct viral lysis were at least partly responsible. Since immunoglobulin G (IgG)-antibodies triggered the CMI, specific memory B cells could also be induced by vaccination. Thus, consideration should be given to vaccination strategies that induce IgG antibodies capable of CMI.

Intracellular accumulation of human immunodeficiency virus protease inhibitors.

Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.