Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1
• High, but not low to moderate, HLA antibody levels are associated with platelet refractoriness.In the Trial to Reduce Alloimmunization to Platelets (TRAP) study, 101 of 530 participants became refractory to platelet transfusions without evidence of HLA or human platelet antigen (HPA) antibodies. We used a more sensitive bead-based assay to detect and quantify HLA antibodies and a qualitative solid-phase enzyme-linked immunosorbet assay for HPA to determine whether low-level antibodies could predict refractoriness in longitudinal panels from 170 lymphocytotoxicity assay (LCA) 2 and 20 LCA Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 3299. Disclosures The authors, Associate Editor Mortimer Poncz, and CME questions author Charles P. Vega, Associate Professor and Residency Director, Department of Family Medicine, University of California-Irvine, declare no competing financial interests. Learning objectives Upon completion of this activity, participants will be able to:1. Describe alloimmunization due to HLA after platelet transfusion. 2. Analyze the significance of human platelet antigen (HPA) antibodies (Abs) in cases of alloimmunization after transfusion. 3. Evaluate the performance of newer tests for HLA Ab and HPA Ab. 4. Assess the role of HLA Ab and HPA Ab among patients refractory to treatment with platelet transfusions.
Recent-infection testing assays/algorithms (RITAs) have been developed to exploit the titer and avidity of HIV antibody evolution following seroconversion for incidence estimation. The Vitros Anti-HIV 1؉2 assay (Ortho-Clinical Diagnostics) was approved by the FDA to detect HIV-1 and HIV-2 infections. We developed a less-sensitive (LS) and an avidity-modified version of this assay to detect recent HIV infection. Seroconversion panels (80 subjects, 416 samples) were tested to calculate the mean duration of recent infection (MDR) for these assays. A panel from known long-term (2؉ years) HIV-infected subjects on highly active antiretroviral therapy (HAART) (n ؍ 134) and subjects with low CD4 counts (AIDS patients [n ؍ 140]) was used to measure the false-recent rate (FRR) of the assays. Using a signal-to-cutoff ratio of 20 and the LS-Vitros assay gave a RITA MDR of 215 days (95% confidence interval [95% CI], ؎65 days) and using an avidity index (AI) of 0.6 gave an MDR of 170 days (؎44 days), while a combination of the two assays yielded a MDR of 146 days (؎38.6) and an FRR of 8%. Misclassifying subjects with known long-term infection as recently infected occurred in 14% of AIDS patients and 29% (95% CI, 22, 38) of HAART subjects and 3% (95% CI, 0.8, 7.2) and 42% (95% CI, 33, 51), respectively, for the LS-and avidity-modified Vitros assays, with a misclassification rate of 15% (95% CI, 11, 20) overall using a dual-assay algorithm. Both modified Vitros assays can be used to estimate the length of time since seroconversion and in calculations for HIV incidence. Like other RITAs, they are subject to high FRR in subjects on HAART or with AIDS. While the detection of recent HIV infections is useful for individual patient counseling and management, it is essential for calculating the HIV incidence in a population. Monitoring incidence is important for tracking the epidemic and essential in evaluating the need for and effectiveness of HIV prevention programs (2). Incidence calculations can be done through longitudinal studies of cohorts or serial cross-sectional population serological surveys; these can be difficult and expensive to conduct and are prone to biases (1,4,15). To overcome this limitation, crosssectional incidence testing was devised to capture individuals who were acutely infected; however, the short mean duration of recent infection (MDR) of detecting infection limited the effectiveness of this method (3). By diluting plasma samples from HIV-infected individuals and lengthening the MDR of detection of the assay, a larger number of recently infected individuals could be identified in HIV antibody detection assays (18). HIV investigators and public health laboratories developed the serological testing algorithm for recent HIV seroconversion (STARHS) to differentiate recent from established HIV infection in cross-sectional cohorts (17). The early approaches of the STARHS algorithm used a sensitive HIV antibody test to accurately identify individuals who were infected within weeks of infection, followed by a l...
HIV-specific antibodies become detectable and continue to increase in frequency during primary infection. The effects of early antiretroviral treatment (ART) and its discontinuation on the evolution of this immune response have not been systematically analyzed. To investigate the associations between antibody titer, viral load, and ART, we used a less-sensitive enzyme-linked immunosorbant assay (LS-EIA) to measure changes in HIV-1-specific antibody levels in treated and untreated subjects undergoing primary infection. In this longitudinal study, antibody levels gradually increased in therapy-naive subjects, reaching a plateau approximately 40 weeks postinfection. In contrast, antibody titers remained low among subjects receiving ART. Subjects who discontinued ART exhibited a more rapid rise in antibody titers than therapy-naive subjects, suggesting the presence of an enhanced B cell response. These results demonstrate that early ART prevents the typical evolution of the HIV-1-specific antibody response and can alter the expected kinetics of this response in subjects discontinuing therapy.
These findings suggest that declining antibody levels during ART reflect lower levels of antigen production and/or viral replication in the persistent HIV reservoir. Results of relatively inexpensive and quantitative HIV antibody assays may be useful indirect markers that enable efficient monitoring of the viral reservoir and suppression during functional-cure interventions.
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