Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Abstract

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays1,2. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells3,4 and from semen5. A reservoir of latently infected cells established early in infection6 may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy3,4,5. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of ‘covert’ virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

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Figure 1: Detection of 2-LTR replication intermediates of HIV-1.
Figure 2: Stability of 2-LTR circles in vitro and in vivo.
Figure 3: Relationship between 2-LTR circle frequency and interval during which plasma viral RNA was undetectable in plasma (fewer than 50 copies/ml).
Figure 4: High-input virus co-culture assays for replication-competent HIV-1.

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Acknowledgements

We thank P. Himlan, L. Mangini, C. Jaffarian, B. Cullen and L. O'Reilly for patient recruitment and scheduling; M. McManus for data management; C. Waterworth and G. Sontag of Imperial College and research associates in the laboratory of pediatric immunology at UMass Medical School for technical assistance; N. Bakker for manuscript preparation; and B. Mellor for assistance in preparation of the figures. Jurkat-CCR5 cells were obtained from M. Emerman. This work was supported in part by National Institutes of Health grants RR11589, HL57880 (M.S.) AI 32391 (K.L.), and AI32907 (J.L.S.). M. Sharkey is the recipient of a National Institutes of Health training grant (T32 AI07272). K. Luzuriaga is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.

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Correspondence to Mario Stevenson.

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Sharkey, M., Teo, I., Greenough, T. et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat Med 6, 76–81 (2000). https://doi.org/10.1038/71569

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