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Improvement in CD4 T-Cell Counts Despite Virologic Treatment Failure: Role of Thymic Output D. LECOSSIER, F. CLAVEL, and A. J. HANCE* for the CRIV Bichat-Claude Bernard. Paris, France In an important minority of individuals infected with HIV-1, viral load fails to decline or rapidly rebounds following treatment with combined antiretroviral agents. Despite this apparent treatment failure, some, but not all, of these patients demonstrate substantial improvement in the absolute number of circulating CD4+ T-cells (so-called discrepant responses). Preliminary studies have shown that the viruses recovered from these individuals, which contain multiple drug resistance mutations, have decreased fitness in thymic tissue, suggesting that impaired viral replication in the thymus may permit the regeneration of T-cells despite persistently elevated viral load. To test this hypothesis, thymic output of T-cells was assessed in 18 patients who, after being treated for the first time with a protease inhibitor in conjunction with two reverse transcriptase inhibitors, subsequently experienced confirmed virologic failure (plasma HIV RNA >3 log10 copies/ml; with no more than a 0.5 log10 reduction in load compared to pretreatment levels). Patients were evaluated after at least 1 year of therapy. DNA was extracted from purified CD4 T cells, and DNA sequences corresponding to Va T-cell receptor excision circles (TREC) (an index of thymic output) and the albumin gene (a measure of total cell number) were quantified by real-time PCR and expressed as a ratio after normalization for the proportion of CD45RA+ ("naive") T-cells present. The improvement in the absolute number of CD4+ T-cells observed in these patients with persistant viremia was correlated with TREC/CD45RA (r=0.7, p<0.01): TREC/CD45RA were 56±16 units for patients whose CD4 T-cell count increased by >200 cells/µl (n=8), but only 16±3 units for patients whose CD4 T-cell count increased by <200 cells/µl (n=10). Viral load was not significantly different comparing the two groups. Thymic output has been shown to decrease with age. In this context, patients whose CD4+ T-cell count increased by <200 cells/µl tended to be older (45±7 years) than individuals whose whose CD4+ T-cell count increased by >200 cells/µl (36±7 years) (p<0.02). These findings indicate that improvement in CD4 cell counts observed in some patients with virologic failure after treatment is associated with better thymic output, and therefore support the idea that impaired viral fittness resulting from treatment may permit the restoration of thymic function, especially in younger patients. Key Words: Thymic output, Virologic failure |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |