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We have performed the first molecular analysis of a time course of infection by a papillomavirus. The Hershey isolate of the human papillomavirus type 11 was used to infect human foreskin tissues, which were then implanted under the renal capsules of nude mice. The xenografts were recovered every 2 weeks for 14 weeks, fixed in formalin, and embedded in paraffin. Four-micrometer serial sections were examined by light microscopy for morphological changes, by immunocytochemistry for virion antigen production, and by in situ hybridization with 3H-labeled RNA probes for viral DNA replication and expression of the major mRNA species. After a lag period, probes spanning the E4 and E5 open reading frames, which are present in all E region viral mRNAs, generated the first detectable signals at week 4. Signals of other E region probes were minimally detected at week 6. Between weeks 6 and 8, there was an abrupt change in the implant such that cellular proliferation, viral DNA replication, and E and L region mRNA transcription were robust and reached a plateau. By weeks 10 to 12, the experimental condylomata were morphologically and histologically indistinguishable from naturally occurring condylomata acuminata. These findings suggest that cellular hyperproliferation and the morphologic features of condylomata are direct results of viral genetic activities. Unlike other DNA viruses, the E region transcripts increased with cell age and cellular differentiation and persisted throughout the entire experiment. In particular, the mRNA encoding the Eli^E4 and perhaps E5 proteins remained overwhelmingly abundant. In contrast, viral DNA replication, L region mRNA synthesis, and virion antigen production were restricted to the most differentiated, superficial cells.

Summary. The relationships of haenioglobin concentration and blood pH to red cell 2,3‐dipliosphoglycerate and oxygen binding by haenioglobin have been studicd in healthy subjects and subjects with hypoproliferative anaemia with or without severe chronic renal disease. Red cell 2,3‐DPG was inversely correlated with haemoglobin deficit and directly and equally strongly associated with blood pH in anaemic subjects without chronic renal disease. In subjects with chronic renal disease receiving regular haemodialysis, predialysis pH was not increased despite severe anaemia, and red cell 2,3‐DPG was not significantly elevated, except in subjects who had a sustained alkalosis due to the use of sodium bicarbonate. In hypoproliferative anaemia, the incrcmcnt in pH was associated with the decrease in haenioglobin concentration such that 80% of the increase in p50 measured at standard conditions which occurred with anaemia was explicable by the relationship of (a) pH with haemoglobin concentration, (b) red cell 2,3‐DPG with pH, and (c) pso std with red cell 2,3‐DPG. However, p50 at the pH and base excess present in vivo was similar in all anaemic subjects whether an increase in red cell 2,3‐DPG occurred or not. Blood alkalosis and the accumulation of 2,3‐DPG cancelled each other's effect on oxygen binding by haemoglobin. Hence, increased red cell 2,3‐DPG and p50 compensated for the alkalosis of hypoproliferative anaemia, not for the deficit in haemoglobin concentration.