17 research outputs found
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Prevention of Infection Due to Pneumocystis spp. in Human Immunodeficiency Virus-Negative Immunocompromised Patients
Pneumocystis was initially identified in the lungs of rats as a stage in the life cycle of Trypanosoma cruzi (in 1909 by Chagas and in 1910 by Carini). The first case of Pneumocystis infection in humans was described by van der Meer and Brug in 1942 (167); Jirovec has been credited with describing epidemic in- fection in humans in the 1950s (85). Pneumocystis carinii was thought to be a protozoan parasite based on morphologic appearance, proposed life cycle, and antimicrobial susceptibil- ities. Subsequent phylogenic analyses using rRNA sequences suggested that the organism was more closely related to the fungi despite the absence of ergosterol in the cell wall (34). Animal models of Pneumocystis pneumonia have been highly predictive of the clinical experience with human infection and are extensively used in studies of disease pathogenesis and therapy. However, some molecular and immunologic studies suggest that Pneumocystis associated with human disease is distinct from the strains found in animal models. This distinc- tion has resulted in a suggested reclassification of organisms isolated from humans as Pneumocystis jiroveci while P. carinii remains the designation of rodent-derived organisms (161). The use of this name remains controversial (72). Some back- ground information about the biology of infection is useful in considering strategies for the prevention or treatment of Pneu- mocystis pneumonia. This review refers to both P. carinii pneu- monia and P. jiroveci pneumonia as PCP (161)
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Genome-wide inactivation of porcine endogenous retroviruses (PERVs)
The shortage of organs for transplantation is a major barrier to the treatment of organ failure. While porcine organs are considered promising, their use has been checked by concerns about transmission of porcine endogenous retroviruses (PERVs) to humans. Here, we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all 62 copies of the PERV pol gene and demonstrated a > 1000-fold reduction in PERV transmission to human cells using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine- to-human xenotransplantation
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Identification of Exogenous Forms of Human-Tropic Porcine Endogenous Retrovirus in Miniature Swine
The replication of porcine endogenous retrovirus subgroup A (PERV-A) and PERV-B in certain human cell lines indicates that PERV may pose an infectious risk in clinical xenotransplantation. We have previously reported that human-tropic PERVs isolated from infected human cells following cocultivation with miniature swine peripheral blood mononuclear cells (PBMC) are recombinants of PERV-A with PERV-C. Here, we report that these recombinants are exogenous viruses in miniature swine; i.e., they are not present in the germ line DNA. These viruses were invariably present in miniature swine that transmitted PERV to human cells and were also identified in some miniature swine that lacked this ability. These data, together with the demonstration of the absence of both replication-competent PERV-A and recombinant PERV-A/C loci in the genome of miniature swine (L. Scobie, S. Taylor, J. C. Wood, K. M. Suling, G. Quinn, C. Patience, H.-J. Schuurman, and D. E. Onions, J. Virol. 78:2502–2509, 2004), indicate that exogenous PERV is the principal source of human- tropic virus in these animals. Interestingly, strong expression of PERV-C in PBMC correlated with an ability of the PBMC to transmit PERV-A/C recombinants in vitro, indicating that PERV-C may be an important factor affecting the production of human-tropic PERV. In light of these observations, the safety of clinical xenotrans- plantation from miniature swine will be most enhanced by the utilization of source animals that do not transmit PERV to either human or porcine cells. Such animals were identified within the miniature swine herd and may further enhance the safety of clinical xenotransplantation
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HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression
Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA