Immune Reconstitution after Receipt of Highly Active Antiretroviral Therapy in Children with Advanced or Progressive HIV Disease and Complete or Partial Viral Load Responsea
Andrea KovácsGrace MontepiedraVincent J. CareySavita PahwaAdriana WeinbergLisa M. FrenkelEdmund V. CapparelliLynne MofensonElizabeth SmithKenneth McIntoshSandra Burchett
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Abstract:
We assessed CD4 cell recovery in 175 children with advanced human immunodeficiency virus disease who had received a 4-drug antiretroviral regimen and were categorized as viral load (VL) responders (VLRs), partial VLRs, or non-VLRs. Median CD4 cell counts increased from baseline to week 48, and, among children with maximal follow-up, increases in CD4 cell counts were sustained to week 96 among VLRs and partial VLRs but not among non-VLRs. For VL rebounders still in the study, CD4 cell counts remained increased for 32 weeks after VL rebound. Sustained immunologic benefits can be achieved even with partial VL response in children with advanced disease.Keywords:
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Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra−/− mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10–dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection.
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The study of virus infections in experimental animals has led to the definition of the individual components of the host response, and their relative roles in the resolution of the infection. However, these immune responses can be perturbed by direct virus infection of immunocompetent cells, and effective responses may produce tissue damage for exmple by immune complex formation and T cell-mediated destruction of infected cells. This virus immunopathology assumes particular importance when the virus itself is relatively non-cytopathic and in the case of peristent infections.
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Human immunodeficiency virus type 2 (HIV-2) is less pathogenic than HIV type 1 (HIV-1), but the mechanisms underlying this difference have not been defined. We developed an internally controlled quantitative reverse transcriptase-polymerase chain reaction to measure HIV-2 viral load and determined levels of plasma virus in a cohort of registered commercial sex workers in Dakar, Senegal. The assay has a lower limit of detection of 100 copies/mL and is linear over 4 logs. HIV-2 viral RNA was detectable in 56% of all samples tested; the median load was 141 copies/mL. Levels of viral RNA in the plasma were inversely related to CD4+ cell counts. HIV-2 and HIV-1 viral loads were compared among the seroincident women in the cohort; the median viral load was 30x lower in the HIV-2-infected women (P<.001, Wilcoxon rank sum test), irrespective of the length of time infected. This suggests that plasma viremia is linked to the differences in the pathogenicity of the 2 viruses.
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Objective To assess the occurrence of viral load greater than 50 copies/ml in patients on highly active antiretroviral therapy (HAART) having achieved less than 50 copies/ml and the chance of whether a viral load greater than 50 copies/ml would lead to a sustained and increasing viral load. Design A cohort of 553 patients on HAART with viral loads of less than 50 copies/ml were followed. Results Over a median of 56 weeks 35% of patients experienced a transient increase and 8% virological failure (two consecutive viral loads of > 400 copies/ml). Transient increases and virological failure were more common in those with greater drug experience, and those with initial raised viral load values of more than 400 copies/ml were more likely to have a sustained increase and become virological failures. Conclusion Transient increases in viral load are common, mainly in the 50–400 copies/ml range, and the majority of subsequent viral load estimations show a return to less than 50 copies/ml. A single raised viral load should lead to adherence support and intensified monitoring. Subsequent treatment decisions can then be based on evidence of true virological rebound and failure.
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Background: Plasma viral load has been shown to be a meaningful prognostic marker for disease progression in untreated, HIV-1 subtype B-infected subjects in United States and Western Europe and therefore used as a prognostic marker for disease progression. Because of high expenses of commercially available viral load assays, the role of viral load in disease progression has not been evaluated in HIV-1 subtype C-infected patients in India. Methods: We developed an inexpensive real-time reverse transcriptase-polymerase chain reaction assay to quantify viral load in plasma of HIV-1 subtype C-infected subjects from India and used it in a longitudinal analysis of viral load and CD4 cell number in HIV-infected subjects from Calcutta, India. Results: The real-time reverse transcriptase-polymerase chain reaction assay can quantify plasma viral load with a linear range of detection from 102 to 109 HIV-1 RNA copies per input. Longitudinal analysis of viral load in a cohort of 39 subjects over an average period of approximately 3 years indicates that 1-log increase in HIV-1 RNA level was associated with a decline of 67 CD4 cell count. Furthermore, HIV-1 RNA level between 500 and 50,000 copies per milliliter would predict a 12.9% decrease in CD4 cell count per year, whereas HIV-1 RNA levels above 50,000 copies HIV-1 RNA per milliliter would predict a 25.3% decrease in CD4 cells per year. In addition, we estimated that the mean incubation period of disease development, as defined by the loss of CD4 below 200, is 8.2 years. Conclusion: Our report on the level of viral load on predicting CD4 decline in Indian subjects with HIV-1 provides an additional important tool to the physicians for treating and planning a therapeutic strategy to control HIV-1 infection in India.
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HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs.We recruited donor partners of persons who presented with acute or recent (<6 months) HIV infection. Transmission was confirmed by phylogenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection.We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r = 0.55, P = 0.006).The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection.
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PERSPECTIVES ON PEDIATRIC HUMAN IMMUNODEFICIENCY VIRUS INFECTIONS EDITED BY PHILIP A. PIZZO, M.D., AND CATHERINE M. WILFERT, M.D.: PDF Only
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