ABSTRACT: Background: HIV infection of the central nervous system (CNS) is commonly associated with cognitive and motor impairment. The utility and limitations of currently employed antiviral drug combinations for the treatment of HIV infection of the CNS remain unclear because of the variability of drug penetration across the blood brain barrier, the long-lived nature of the infected target cells in the CNS and the evolution of distinct virus types in the CNS.
Objectives: To track the emergence of multi-drug resistant HIV in cerebrospinal fluid (CSF) relative to plasma virus following a switch in drug therapy.
Methods: The virological response measured by Roche Amplicor in CSF and plasma from two antiviral experienced, neurocognitively impaired but adherent patients was tracked following a switch in therapy. For patient A both early and late time-point paired specimens were available whereas only late time-points were available from patient B for sequence analysis. Sequencing of the protease and part of the reverse transcriptase from pol and C2-V3 from env was performed following replicate RT-PCR amplifications and cloning from samples of CSF and plasma.
Results: Both patients demonstrated an initial fall in viral RNA levels in CSF but not in plasma in response to changes in drug therapy. In both cases the CSF response was transient and was followed by a rebound in viral RNA levels. For patient A, the initial response of CSF viral load and subsequent failure of virological control was accompanied by a transition from genotypically 'drug susceptible' virus to mix of clones bearing either the 'drug susceptible' genotype or the identical resistance mutational pattern found in plasma virus. Ultimately there was a complete replacement of the 'drug susceptible' genotypes in the CSF by the drug resistant ones for both patients. This transition in the distribution of clonal pol sequences was also mirrored by the replacement of the distinct env genotype in plasma.
Conclusions: In the course of some combination drug therapies, multidrug resistant virus may be selected initially in the plasma/lymph compartment while virus in the CSF remains drug susceptible. The subsequent emergence of resistant virus in CSF represents the trafficking of resistant virus into the CNS rather than the evolution of resistance in an independent viral lineage. The fitness advantage conferred by drug resistance in the setting of drug therapy appears to dominate over advantage(s) conferred by envelope sequences adapted for the CNS.
