This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.

Human immunodeficiency virus type 1 (HIV-1) RNA that persists in the lymphoid tissue of patients despite treatment with highly active antiretroviral therapy (HAART) may represent extracellular virions or intracellular RNAs residing within HIV-infected cells. To further characterize residual viral transcription, tonsil biopsy specimens from patients receiving long-term HAART, untreated patients, and patients undergoing 2 weeks of structured treatment interruption were analyzed by polymerase chain reaction quantification of virion-encapsidated RNA, intracellular unspliced HIV RNA (HIV UsRNA), multiply spliced HIV RNA encoding tat and rev (HIV MsRNA), and HIV DNA. Tonsil biopsy specimens from viremic patients harbored high amounts of virions, which primarily stemmed from local production, as indicated by a strong correlation of extracellular tonsillar RNA with intracellular HIV-1 nucleic acid levels but not with plasma viremia, and as shown by phylogenetic analysis of clonal env sequences from lymphoid tissue and plasma. In patients receiving HAART, intracellular HIV UsRNA persisted at significantly decreased levels, whereas HIV MsRNA and lymphoid virion levels were depleted. Thus, residual lymphoid HIV-1 RNA in patients receiving HAART indicates attenuated viral transcription in HIV-1-infected cells that lack virion production.

No abstract

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

The 1-week-on-1-week-off schedule, as tested in the Staccato study, showed an unacceptably high failure rate and was therefore terminated.