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Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards

Murray, John M.a,b,*; McBride, Kristinb,*; Boesecke, Christophb,c; Bailey, Michelled; Amin, Janakib; Suzuki, Kazuod; Baker, Davide; Zaunders, John J.d; Emery, Seanb; Cooper, David A.b,d; Koelsch, Kersten K.b,d,*; Kelleher, Anthony D.b,d,*; on behalf of the PINT STUDY TEAM

doi: 10.1097/QAD.0b013e328350fb3c
Basic Science

Objective: We investigated the dynamics of HIV RNA and HIV DNA levels after the commencement of raltegravir-based antiretroviral therapy (ART) in primary (PHI) and chronically HIV-infected (CHI) individuals (the PINT study).

Design: We recruited 8 PHI and 8 CHI ART-naive individuals who commenced a 1-year combination regimen of Truvada and the integrase inhibitor raltegravir.

Methods: Nonlinear mixed effects modelling was used to determine multiphasic decay of plasma HIV RNA levels (pVL), as well as dynamics of total, episomal [2-long terminal repeats (LTR)] and integrated HIV DNA in CD4+ T cells from peripheral blood.

Results: Although pVL decreased faster through first and second phase for PHI individuals there was no difference in the final level reaching a mean of 9 copies/ml by week 16 that was maintained thereafter. Total HIV DNA and integrated HIV DNA levels from CHI patients were significantly higher than from PHI patients. However, at no time did 2-LTR levels differ between groups. Of note, 2-LTR circles exhibited an initial increase peaking at week 3 followed by biphasic decay with a half-life of 29 days. Second phase integrated HIV DNA levels were significantly correlated with duration of infection and consistent with this form of infection occurring at approximately 100 000 integration events per day in the absence of ART, achieving its 50% level 2 years after infection.

Conclusions: Integrated HIV DNA levels accumulate with duration of untreated HIV infection. The relatively short half-life and high levels of 2-LTR circles after 1 year support continued HIV transmission during ART.

aSchool of Mathematics and Statistics, University of New South Wales

bThe Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia

cDepartment of Internal Medicine I, University of Bonn, Bonn, Germany

dSt Vincent's Hospital, Sydney, Centre for Applied Medical Research

eEast Sydney Doctors, Darlinghurst, New South Wales, Australia.

*These authors contributed equally to this study.

Correspondence to Associate Professor John M. Murray, School of Mathematics and Statistics, University of New South Wales, Sydney 2052, NSW, Australia. Tel: +61 2 9385 7042; fax: +61 2 9385 7123; e-mail: J.Murray@unsw.edu.au

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Received 20 September, 2011

Revised 15 December, 2011

Accepted 23 December, 2011

© 2012 Lippincott Williams & Wilkins, Inc.