Background: Detection of episomal HIV cDNA has been associated with greater levels of CD8 and CD4 T-cell activation in HIV-1-infected highly active antiretroviral therapy (HAART)-suppressed individuals. However, HAART intensification exclusively reduced CD8 T-cell activation.
Methods: We evaluated activation markers 12 weeks after raltegravir withdrawal in a previously described 48-week raltegravir intensification study. The subjects (n = 34) were subgrouped into 2-LTR+ (n = 12) or 2-LTR− (n = 22) subgroups according to delectability of 2-LTR episomes during the intensification period.
Results: The initial differences in CD8 T-cell activation between subgroups were lost after intensification. Linear mixed models revealed significant reductions in CD8 T-cell activation in both 2-LTR− and 2-LTR+ subgroups, suggesting that raltegravir impacts subjects irrespective of 2-LTR detection. Remarkably, a partial rebound in CD8 activation markers after raltegravir discontinuation was observed in the 2-LTR+ subgroup. This restored the differences between subgroups observed at study entry, particularly in terms of CD38 expression within CD8 memory T-cells. Conversely, CD4 T-cell activation remained unchanged in both subgroups during the study period, although an early and transient CD45RA− CD4 T-cell redistribution from tissues was apparent.
Conclusions: CD8 T-cell activation undergoes reversible changes during raltegravir intensification and discontinuation in patients showing detectable 2-LTR circles. The general decrease in CD8 T-cell activation and a transient CD45RA− CD4 T-cell redistribution in intensified individuals may reflect residual viral replication during apparently suppressive HAART.
*IrsiCaixa, Institut de Recerca de la SIDA, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain (M. J. Buzón is now with Infectious Disease Division, Massachusetts General Hospital, and Ragon Institute, of MGH, MIT, and Harvard. Boston, MA);
†Center for Epidemiological Studies on STI and HIV/AIDS of Catalonia, CEEISCAT-ICO-ASPC, Badalona, Spain;
‡“Lluita contra la SIDA” Foundation and University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain;
§Hospital Cli[Combining Acute Accent]nic-Idibaps, Barcelona, Spain;
‖Hospital Sant Pau, Barcelona, Spain;
¶Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; and
#ICREA, Barcelona, Spain.
Correspondence to: Dr. Julià Blanco, IrsiCaixa—Institut de Recerca de la SIDA, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, University Hospital Germans Trias i Pujol, Ctra de Canyet, s/n. 08916 Badalona (Barcelona), Spain (e-mail: email@example.com).
Supported by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” (RD06/0006), by the European Community's Seventh Framework Program under the project “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)” grant agreement n°223131, by funding from the NIH to M. S. and by an unrestricted grant from Merck Sharp & Dohme (MSD). J. B. is a researcher from the Institut de Recerca en Ciéncies de la Salut Germans Trias i Pujol supported by the ISCIII and the Health Department of the Catalan Government (Generalitat de Catalunya). M. J. B., and M. M. were supported by Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya and European Social Fund.
J.M. Llibre has received research funding, consultancy fees, or lecture sponsorships from Abbott, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck, Pfizer, ViiV Healthcare, and Roche. M. Stevenson has been a consultant for Merck and has received research support from Tibotec. J. M. Gatell has received grant support or lecture or advisory fees from Merck, Roche, GlaxoSmith Kline, Bristol–Myers Squibb, Tibotec, Pfizer, Gilead, Abbott, and Boehringer-Ingelheim. B. Clotet has served as a consultant on advisory boards or participated in speakers' bureaus or conducted clinical trials with Boehringer-Ingelheim, GlaxoSmithKline, Gilead, Janssen, Merck, Pfizer, and ViiV. J. Martinez-Picado has received research funding, consultancy fees, or lecture sponsorships from GlaxoSmithKline, Merck, and Roche. J. Blanco has received research funding, consultancy fees, or lecture sponsorships from GlaxoSmithKline, ViiV, and Merck. All the other authors declare no competing interests. This study was presented in part at the 16th Conference on Retroviruses and Opportunistic Infections; Montreal, Canada; 2009 (abstracts 423-a and 574), at the 17th Conference on Retroviruses and Opportunistic Infections; San Francisco, CA, USA; 2010 (abstract LB-100) and at the 18th Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; 2011 (abstract 281).
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Received July 25, 2012
Accepted January 22, 2012