Impact of Thymectomy on the Peripheral T Cell Pool in the Context of SIV Infection

The thymus is the primary lymphoid organ responsible for T cell production. It is of particular interest in the context of human immunodeficiency virus (HIV)-l infection, in which the progressive loss of CD4+ T cells leads to immunodeficiency and opportunistic infection. CD4+ T cell loss is thought to result from direct and indirect killing of C D 4 cells in the periphery as well as from pathogenic effects of the virus on the thymus. However, it is not fully understood which is the greater factor in viral-induced CD4+ T cell decay. The development of an assay to detect T cell receptor excisional circles (TREC) as a marker for recent T cell receptor (TCR) recombination in the thymus has proved to be an invaluable tool for the study of recent thymic emigrants. Here we describe the development of this technique in the rhesus macaque model and use this method in combination with other techniques to study the role of the thymus in maintenance of the peripheral T cell pool. This study has two major goals: to define the role of the thymus in peripheral T cell homeostasis in the juvenile rhesus macaque (Macaca mulatto) and to assess the significance of thymic output in the context of simian immunodeficiency virus (SIV) infection. To this end, we have studied the impact of surgical thymectomy on the peripheral T cell pool in a cohort of macaques. W e present evidence that thymic output in the juvenile macaque is measurable but quantitatively insignificant in the context of the total T cell pool. While SIV infection does have pathogenic effects on the thymus, these effects play a minimal role in the overall destruction of the peripheral T cell pool

Validation of a Diagnostic Microarray for Human Papillomavirus: Coverage of 102 Genotypes

Papillomaviruses have been implicated in a variety of human diseases ranging from common warts to invasive carcinoma of the anogenital mucosa. Existing assays for genotyping human papillomavirus are restricted to a small number of types. Here, we present a comprehensive, accurate microarray strategy for detection and genotyping of 102 human papillomavirus types and validate its use in a panel of 91 anal swabs. This array has equal performance to traditional dot blot analysis with the benefits of added genotype coverage and the ability to calibrate readout over a range of sensitivity or specificity values

Measuring Recent Thymic Emigrants in Blood of Normal and HIV-1–Infected Individuals before and after Effective Therapy

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed α1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that α1 circle numbers in blood remain high for the first 10–15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, α1 circle numbers in HIV-1–infected adults were significantly reduced; however, there were many individuals with normal α1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on α1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in α1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as α1 circle numbers are normal in a substantial subset of HIV-1–infected individuals

Dramatic Rise in Plasma Viremia after CD8+ T Cell Depletion in Simian Immunodeficiency Virus–infected Macaques

To determine the role of CD8+ T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8+ T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo

Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients.

This article synthesizes the current data regarding the implication of voriconazole in the development of skin cancer in organ transplant recipients (OTRs) and offers suggestions for additional research. According to Organ Procurement and Transplantation Network data, 28 051 solid organ transplants were performed in 2012. Due to advancements in immunosuppression and management of infectious diseases, survival of OTRs has substantially increased. Voriconazole is a widely prescribed antifungal medication used for prophylaxis and for treatment of invasive fungal infections in OTRs. Case reports describing skin cancer associated with voriconazole exposure emerged shortly after US Food and Drug Administration approval of the drug, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole-induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide. Here we discuss the current data and potential mechanisms of voriconazole-associated photosensitivity and carcinogenesis and identify areas that require further research

Validation of a diagnostic microarray for human papillomavirus: coverage of 102 genotypes.

Papillomaviruses have been implicated in a variety of human diseases ranging from common warts to invasive carcinoma of the anogenital mucosa. Existing assays for genotyping human papillomavirus are restricted to a small number of types. Here, we present a comprehensive, accurate microarray strategy for detection and genotyping of 102 human papillomavirus types and validate its use in a panel of 91 anal swabs. This array has equal performance to traditional dot blot analysis with the benefits of added genotype coverage and the ability to calibrate readout over a range of sensitivity or specificity values