486-M. Individuals with Discordant Immunological Responses Following Combination Antiviral Therapy Have Elevated Levels of T-Cell Receptor Excision Circles Despite Increased Levels of T-Cell Proliferation

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Session 69 Poster Session
Immunopathogenesis Issues Addressed by Therapeutic Interventions
Session Time: 4:30-6:30 pm
Room 4E-F

486-M.

Individuals with Discordant Immunological Responses Following Combination Antiviral Therapy Have Elevated Levels of T-Cell Receptor Excision Circles Despite Increased Levels of T-Cell Proliferation
S. Lewin*^1,2, A. Solomon¹, P. U. Cameron¹, S. M. Crowe^3,4, and J. Hoy²
¹Univ. of Melbourne; ²Royal Melbourne Hosp;³Burnet Inst.; and ⁴Alfred Hosp., Melbourne, Australia

Background: Many HIV-1-infected patients treated with combination antiviral therapy develop rebounds in viral load (VL) in association with improvement in CD4+ T-cell counts. Recent evidence suggests that protease-inhibitor (PI)-resistant viruses replicate less efficiently in thymic tissue favoring sustained T-cell production in the presence of PI-resistant viruses.
Methods: We performed a cross-sectional study of HIV-1-infected individuals (n=35) who had been compliant with combination antiviral therapy (including either a PI or NNRTI) for at least 12 months. Peripheral blood mononuclear cells (PBMC) were separated into purified CD4+ and CD8+ naďve (CD45RA+) and memory (CD45RA-) T cells. Thymic function was assessed by quantification of T-cell receptor excision circles (TREC) in each T-cell population using real-time PCR. T-cell proliferation and apoptosis were assessed by intracellular staining for Ki67 and TUNEL respectively.
Results: Individuals were classified according to degree of viral suppression, rate of change in CD4 (using least-squares linear regression) and absolute change in CD4 count. Individuals were classified into 3 groups: those with persistent viral replication and an increasing CD4 count (discordant immunological responders, DIR, n=15), persistent viral replication and a falling CD4 count (non-responders, NR, n=5), and suppressed viral replication and an increasing CD4 count (complete responders, CR, n=15). CD4 counts were significantly lower in NR compared with CR and DIR (p<0.05). There was no significant difference in viral load (VL) between DIR and NR. VL was undetectable (<400 copies/mL) in all CR. There was no significant difference in TREC in CD4+ or CD8+ naďve T cells in DIR and CR but there was a trend toward lower TREC in NR. The percentage of Ki67 staining in CD4+ and CD8+ memory T cells was significantly lower in CR compared with DIR (p<0.01) and NR (p<0.05). There was no significant difference in change in percentage of Ki67 staining in CD4+ and CD8+ naďve cells between each patient group.
Conclusions: Despite persistent viral replication and increased T cell proliferation in DIR taking either a PI or NNRTI, CD4 and TREC levels are not reduced. Impaired replication of drug resistant virus in thymic tissue or reduced apoptosis of recent thymic emigrants may explain DIR following treatment of HIV infection.

Š2002 9^th Conference on Retroviruses and Opportunistic Infections