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

492-M. Intrinsic Decay Rate of Lymphocyte Reservoirs of HIV-1 M. C. Strain1, D. Havlir1,2, H. Gunthard3, C. Ignacio1, T. Macaranas1, O. A. Daly4, M. Fischer3, M. Opravil3, A. J. Leigh-Brown1,2, H. Levine1, S. Kwok5, C. Christopherson5, D. Smith1, C. Spina1,4, D. D. Richman1,4, and J. K. Wong*1 1Univ. of California, San Diego; 2Antiviral Res. Ctr., San Diego, CA; 3Univ. Hosp., Zurich, Switzerland; 4VA San Diego Healthcare System, CA; and 5 Roche Molecular Diagnostics, Alameda, CA Background: Long-lived, cellular reservoirs of HIV are an obstacle to eradication of infection despite highly active antiviral therapy (HAART). Assessment of clearance rates of cellular reservoirs is complicated by possible replenishment by residual replication. Methods: 9 chronically HIV patients who had received 0.5-1.5 years of non-suppressive antiviral therapy including 3TC followed by suppressive therapy with PI + NRTI (n=6) or PI + NNRTI (n=3) (plasma HIV RNA <50c/ml) were studied over a 2- to 4-year period. All subjects had developed the M184V mutation in both plasma and PBMC with non-suppressive therapy. 4 subjects remained on 3TC as part of HAART. HIV DNA was quantified from serial PBMC by PCR. Quantitative DNA sequencing was performed using a dye primer system to determine the proportion of wildtype and 184V mutant and was used to estimate the individual decay rates of HIV DNA with the wildtype and mutant genotypes. Clonal virus isolated from 5 patients at late time points were sequenced for comparison. We postulated that cells with 184V virus would have been infected more recently than those with 184WT virus. Moreover, residual replication would replenish the 184V population in patients continuing 3TC while those receiving no 3TC would preferentially replenish the 184WT population. Results: For patients without intermittent viremia, including those continuing 3TC, clearance of HIV DNA with 184V was more rapid (T1/2:43-138 weeks, median 61 weeks) than for the 184WT (T1/2:82-infinite, median 1540 weeks). One patient with intermittent viremia who continued 3TC had a 184V half-life of 417 weeks, consistent with the effects of replenishment by residual replication. Sequences of clonal virus isolated by microculture showed that the retention of wildtype virus was not due to disproportionately defective 184WT forms. Conclusions: Cellular reservoirs of HIV have heterogeneous activation and clearance rates. While these reservoirs can be replenished by residual replication, subsets of cells with replication competent virus persist during HAART which have intrinsically slow turnover rates that are unlikely to be affected by more potent antiviral suppression.

©2002 9th Conference on Retroviruses and Opportunistic Infections