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Session 13 Oral Abstract Session Antiretroviral Chemotherapy: Combination Therapy, Drug Resistance, and Treatment Interruption Session Time: Tuesday, 10 am - 12:30 pm Room 4B

11:30   47. Drug Resistant Replication Competent HIV-1 Occurs Initially in the CD45RO Subset of CD4 T Cells and Subsequently in CD45RA CD4 Lymphocytes Following Antiretroviral Therapy S. Rose*, E. Perez, S. Lamers, J. Sleasman, and M. Goodenow Univ. of Florida Coll. of Med., Gainesville Background: CD4 T cells are classified based on expression of CD45RA or CD45RO. Cell phenotypes reflect differences in cell half-lives, activation, and HIV-1 susceptibility. HIV-1 is found predominantly in the CD45RO CD4 subset of T cells that have a short life-span. CD4 lymphocytes and macrophages that are long-lived also serve as targets for virus infection and replication. During acute infection in children, HIV-1 within the CD45RA subset of CD4 T cells accounts for a significant proportion of infection in peripheral CD4 lymphocytes. Combination therapy in infected children can produce dramatic increases in CD4 T cells that are new targets for viral infection. Methods: A longitudinal study involved 6 children who had immunological reconstitution, but incomplete suppression of virus replication, during combination therapy containing a protease inhibitor. Enriched CD4 T-cell subsets expressing CD45RO or CD45RA were selected by immunomagnetic beads. Protease genotypes were determined following amplification of HIV-1 sequences from plasma RNA and cell-associated DNA. Viruses from both the CD45RA and CD45RO subsets replicated in co-culture with PBMC. Gag-pol genotypes of the replicating virus were determined using cultured DNA. Results: Protease resistant genotypes were detected first in plasma, then CD45RO, followed by the CD45RA. Homogeneous populations of resistant viruses emerged in plasma before appearing in the CD45RO cells by 8-12 weeks of therapy. Viruses with wild type protease alleles persisted within CD45RA cells for >3 months before genotypic resistance appeared. Viruses harbored in both the CD45RA and CD45RO CD4 T cells were replication competent and distinguishable by gag-pol genotype. Conclusions: Drug resistant viruses emerge in temporal succession in different peripheral blood compartments that reflect diverse half-lives. Cells producing plasma virus represent a minority of infected peripheral blood cells or are sequestered in tissues. Viruses within CD45RA cells are a dynamic population which turn over more slowly than viral populations in plasma or CD45RO cells. CD45RA cells provide an important reservoir for drug resistant HIV-1 in patients who achieve reconstitution of CD4 lymphocytes.

©2002 9th Conference on Retroviruses and Opportunistic Infections