IMPAIRED TELOMERASE ACTIVITY IN UNINFECTED HEMATOPOIETIC PROGENITORS IN HIV-1-INFECTED PATIENTS

Background: Haematopoietic progenitor cells (HPC) of HIV-l-infected pa tients are severely compromised in their replication and clonogenic ca pacities, and show an enhanced propensity to apoptosis, despite the la ck of productive or latent HIV-1 infection. Objective: To investigate telomerase enzyme levels in CD34+ HPC isolated from HIV-1-infected pat ients, because the absence of telomerase activity has been found to be correlated with a diminished replication potential. Methods: Telomera se levels were measured by a PCR-based telomeric repeat amplification protocol. CD34+ HPC isolated from the peripheral blood of 11 HIV-1-inf ected patients were compared with CD34+ HPC isolated from peripheral b lood (nine subjects) or bone marrow (six subjects) from 15 healthy don ors. Telomerase levels were also studied in normal HPC after exposure to either gp120 or transforming growth factor (TGF)-beta 1. Results: C D34+ HPC isolated from either peripheral blood or bone marrow from hea lthy donors expressed a high level of telomerase activity. On the cont rary, CD34+ HPC isolated from HIV-1-seropositive patients did not expr ess any detectable telomerase activity in nine patients, and a clearly reduced enzymatic activity in two patients. Furthermore, telomerase a ctivity in normal CD34+ HPC exposed to recombinant gp120 was significa ntly reduced, and to a higher extent than in CD34+ HPC exposed to reco mbinant TCF-beta 1. Conclusions: This is the first study to demonstrat e severely impaired telomerase activity in uninfected CD34+ HPC isolat ed from HIV-1-infected patients. The mechanism underlying this impairm ent probably involves the interaction of HIV-1 envelope glycoprotein g p120 with the cell membrane. These results may add to our understandin g of the pathogenesis of the lesion of the HPC compartment. (C) 1998 L ippincott-Raven Publishers.