Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting for thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation

The boosting of didanosine by allopurinol permits a halving of the didanosine dosage.

info:eu-repo/semantics/publishe

Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine

The association between human immunodeficiency virus type I (HIV-1) RNA load changes and the emergence of resistant virus variants was investigated in 24 HIV-1-infected asymptomatic persons during 2 years of treatment with zidovudine by sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L), and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first month, followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modeling suggests that this resurgence is caused by host-parasite dynamics, and thus reflects infection of the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of treatment, the RNA load returned to baseline values, which was associated with the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite the relative loss of RNA load suppression, selection toward mutations at RT codons 215 and 41 continued. Identical patterns were observed in the mathematical model. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance

Effects of recombinant human granulocyte colony‐stimulating factor on leucopenia in zidovudine‐treated patients with AIDS and AIDS related complex, a phase I/II study

Summary. Twelve male patients, eight with the acquired immunodeficiency syndrome (AIDS) and four with AIDS related complex (ARC), who had zidovudine associated neutropenia (<1 x 109 neutrophils/l) were treated with recombinant human granulocyte colony‐stimulating factor (G‐CSF) in a phase I/II study. Treatment consisted of daily subcutaneous injections with G‐CSF in a weekly increasing dose of 0·4, 2, 5 or 10 μg/kg body weight until a neutrophil count of more than 3 x 109 neutrophils/l was observed. This effective dose was continued for up to 4 weeks, followed by 4 weeks observation period without G‐CSF treatment. Two patients (both with ARC) reached target neutrophil counts at the lowest G‐CSF dose, whereas nine patients needed 2 μg/kg. One patient discontinued treatment before he reached target neutrophil counts. Mean(±SD) neutrophil counts before and after 1 and 4 weeks of effective dose treatment were 0·65(±0·188) × 109, 6·016(±2·595) x 109 and 5·54(±4·237) x 109/l respectively (P<0·01). The number of monocytes increased from 0·171(±0·113) to 0·501(±0·274) and 0·474(±0·374) x 109/l after 1 and 4 weeks of treatment (P<0·01). Other haematologic parameters did not change significantly. Two weeks post‐treatment the numbers of neutrophils and monocytes had returned to pre‐treatment values. Mild side effects consisting of bone, joint or muscle pain were observed in three patients. Two patients (both with AIDS) did not complete the study. One patient stopped treatment because of fever and malaise, attributable to a generalized cytomegalovirus (CMV) infection and one patient had to stop zidovudine treatment because of severe thrombocytopenia. We conclude that G‐CSF increases the number of circulating neutrophilic granulocytes in zidovudine‐treated patients at relatively low doses and with few side‐effects