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Disease Progression in HIV-1–Infected Viremic Controllers

Groves, Katherine C. MBChB, BMedSci*,†; Bibby, David F. BSc, PhD; Clark, Duncan A. BSc, PhD; Isaksen, Are BSc; Deayton, Jane R. FRCP, PhD*,‡; Anderson, Jane MBChB, FRCP, PhD; Orkin, Chloe MBChB, FRCP, MD; Stagg, Andrew J. BSc(Hons), PhD*; McKnight, Áine MiBiol, MSc, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: December 1st, 2012 - Volume 61 - Issue 4 - p 407–416
doi: 10.1097/QAI.0b013e318269c414
Basic and Translational Science

Background: The mechanism of CD4+ T-cell decline in HIV-1 infection is unclear, but the association with plasma viral RNA load suggests viral replication is involved. Indeed, viremic controller patients with low viral RNA loads typically maintain high CD4+ T-cell counts. Within a local cohort of 86 viremic controllers, we identify a subgroup (18 “discord controllers”) with low CD4+ T-cell counts that present clinical uncertainty. The underlying mechanism accounting for CD4+ T-cell decline in the face of low or undetectable plasma (RNA) viral load remains unresolved. The objective of this study was to investigate the viral and host immune system dynamics in discord controllers by measuring cellular HIV-1 DNA load, T-cell populations, and T-cell activation markers.

Methods: We compared discord controllers (viral RNA load <2000 copies/mL, <450 CD4+ T-cells/mm3) with typical controllers (viral RNA load <2000 copies/mL, >450 CD4+ T-cells/mm3) and progressors (viral RNA load >10,000 copies/mL, <450 CD4+ T-cells/mm3). We quantified CD4+/CD8+ naive/central memory/effector memory subsets (CD45RA/RO ± CD62L), activation levels (CD38+HLA-DR+), and HIV-1 DNA load.

Results: Discord controllers resembled progressors showing high viral DNA load, depletion of naive CD4+ T-cells, and higher activation in all CD4+ T-cell subsets, compared with typical controllers. They were similar to typical controllers with lower CD8+ T-cell activation compared with progressors.

Conclusions: Our data are consistent with a relationship between CD4+ T-cell activation and disease progression. HIV-1 DNA load may be a better marker of viral replication and disease progression than viral RNA load. Lower level CD8+ T-cell activation correlates with low viral RNA load but not with disease progression or viral DNA load.

*Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London

Department of Virology, Barts and the London NHS Trust

HIV Clinical Research, Grahame Hayton Unit, Barts and the London NHS Trust

the Centre for the Study of Sexual Health and HIV, Homerton University Hospital NHS Foundation Trust.

Correspondence to: Áine McKnight, MiBiol, MSc, PhD, Blizard Institute, Queen Mary's School of Medicine and Dentistry (e-mail:

Professor McKnight and Dr Stagg are joint senior authors.

Supported by MRC Senior Non-Clinical Fellowship awarded to A.M. (G117/547), Wellcome Trust grant (WT075853MA), Barts and the London Charity Grant (MMBG1E7R), BHIVA SpR Research Grant (MMBG1F2R).

Presented at the 15th Conference on Retroviruses and Opportunistic Infections, February 3–6, 2008, Boston, MA (poster 352) and the AIDS Vaccine Conference, October 19–22, 2009, Paris, France (poster).

The authors have no conflicts of interests to disclose.

Received August 16, 2011

Accepted July 13, 2012

© 2012 Lippincott Williams & Wilkins, Inc.