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335 The Sequence of Events Leading to Progression in Members of the Sydney Blood Bank Cohort
B. L. Herring1, W. Dyer2, N. Deacon3, M. Churchill3, N. K. Saksena1, J. Learmont2, M.-R. Birch, J. Zaunders4, and A. L. Cunningham*1
1WMI, Westmead, Australia; 2Sydney Red Cross Blood Bank, Australia; 3Macfarlane Burnet Ctr., Fairfield, Victoria, Australia; and 4St. Vincent's Hosp., Darlinghurst, Australia
Background: The Sydney Blood Bank cohort is a unique group of 5 long-term surviving recipients and a single donor (D36) who were infected with an HIV nef/LTR deletion variants by blood transfusion 10 to 20 years ago. Recently the donor and 1 recipient (C98) have exhibited declining CD4 counts and increasing viral loads and have commenced retroviral therapy. Another recipient (C54) shows a slight decline in CD4 counts but no increase in viral load (a "possible progressor"). The remaining 3 recipients (C135, C49, and C64) have undetectable viral loads and normal CD4 counts. A detailed study of virologic and immunological events including changes in the nef/LTR region and envelope (env) quasispecies (QS) diversity and divergence was undertaken to identify the sequence of events associated with progression.
Methods: Patient samples were selected from stored PBMC, culture, and plasma samples (1992 to 2000) from the donor and all recipients. CD4+ and CD8+ T-cell counts and CTL responses to HIV-1 gag, pol, and env were determined. Nef/LTR regions were amplified and sequenced to define changes in deletions. The QS was examined by sequencing and HTA using probes prepared from the earliest time point plasma and PBMC samples from each recipient. Additional probes were prepared from D36 corresponding to time points where changes in quasispecies were observed by HMA.
Results: Further nef/LTR deletions were only observed in C98 and D36, increasing the replicative capacity of the virus correlating with increases in viral load and progression in these 2 patients. HTA analysis indicated that early time point variants from all patients were similar. Progressive divergence over the next 5 to 10 years was observed in D36 and C98 with sharp increments following the expansion of deletions in nef/LTR. Increases in viral load and CTL activity to pol, env, and gag followed, and finally decreases in CD4 counts were observed. C54 showed no extension of nef/LTR deletions but reversible increases in QS diversity and divergence correlated with CTL increases. Absent p24-specific T-lymphocyte proliferation were observed at all time points in D36 and C54. One of the nonprogressors (C49) had no changes in the QS, viral load or CTL throughout the period of study. The other nonprogressors had no amplifiable HIV DNA.
Conclusions: Therefore, the sequence of events in the progressors were nef/LTR deletions, QS changes then viral load and CTL changes and finally CD4 count changes.
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