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13th International AIDS ConferenceDurban, South Africa - July 9-July 14, 2000 |
Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrB488)
Giovannetti A, Kuonen D, Mazzetta F, Iebba F, Lusi AE, Rosso R, Pierdominici M, Aiuti F
A. Giovannetti, Viale dell'Universite 37, 00185 Rome, Italy, Tel.: +39 64 997 20 17, Fax: +39 64 46 62 09, E-mail: giovannetti@uniroma1.it
BACKGROUND: The continue loss of CD4 T cells that characterize the HIV infection can result in deletions of CD4 T cell clones whereas the persistent antigen stimulation lead to expansions of HIV-specific CD8 T cell clones. Suppression of HIV replication by higly active antiretroviral therapy (HAART) results in increased CD4 cell count and decreased levels of HIV antigens. However the HAART-induced effects on T-cell repertoire (TCR) diversity has not at present fully investigated.
METHODS: The CD4 and CD8 TCR repertoire of 20 HIV-infected patients has been investigated by flow cytometry before and after HAART evaluating the expression of 21 BV gene products. To assess the extent of TCR perturbation, a control group of seronegative donors was studied. Values greater than three standard deviation above the mean of normal controls were used to establish a skewed usage of BV genes. In selected patients the CDR-3 fragment size of 21 BV subfamilies was also investigated by using polymerase chain reaction and capillary gel electrophoresis on an automated DNA sequencer.
RESULTS: A perturbed CD4/TCR repertoire was observed, before the onset of therapy, in 17 out of 20 patients. The extent of perturbation was inversely related to CD4 cell count, being greater in patients with lower CD4 counts. At baseline the CD8/TCR repertoire was also altered although to a lesser extent. After three months of therapy the number of expansions was diminished in CD4 while it was increased in the CD8 T subset. However, these changes were statistically not significant as demonstrated by stratified data permutation analysis. At time +6 the extent of both CD4 and CD8 BV perturbation was similar to that observed at time +3 with a trend to return at the pre-therapy determinations. A policlonal profile of the CDR3 region was observed whithin the CD4 subset, for the major part of BV subfamilies investigated whereas oligoclonal peaks were seen in quite all BV subfamilies within the CD8 subset. No significant changes of CD8 CDR-3 profiles were observed up to 12 months of therapy whereas an improvement of CD4 CDR-3 profiles was observed.
CONCLUSIONS: These results indicate that the HAART-induced rise of CD4 count associates with discrete changes of CD4, but not CD8, TCR BV repertoire thus suggesting that the increased production of CD4 cell during early phases of HAART may be mainly due to peripheral proliferation of pre-existing clones. A longer period of treatment is probably needed to achieve a complete recovery of immune functions.
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