M A J O R A R T I C L E H I V / A I D S
Increasingly Successful Highly Active
Antiretroviral Therapy Delays the Emergence of
New HLA Class I–Associated Escape Mutations
David J. H. F. Knapp,1Zabrina L. Brumme,1,2Sheng Yuan Huang,1Brian Wynhoven,1Winnie W. Y. Dong,1Theresa Mo,1
P. Richard Harrigan,1,3and Chanson J. Brumme1
1BC Centre for Excellence in HIV/AIDS, Vancouver;2Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia; and3Faculty of
Medicine, University of British Columbia, Vancouver, Canada
exert strong selective pressures on human immunodeficiency virus type 1 (HIV-1), leading to escape mutations
compromising virologic control. Immune responses continue to shapeHIV-1 evolution after HAART initiation, but
the extent and rate at which this occurs remain incompletely quantified. Here, we characterize the incidence and
clinical correlates of HLA-associated evolution in HIV-1 Pol after HAART initiation in a large, population-based
Methods.British Columbia HAART Observational, Medical Evaluation and Research cohort participants with
available HLA class I types and longitudinal posttherapy protease/reverse transcriptase sequences were studied
(n 5 619; median, 5 samples per patient and 5.2 years of follow-up). HLA-associated polymorphisms were
defined according to published reference lists. Rates and correlates of immune-mediated HIV-1 evolution were
investigated using multivariate Cox proportional hazard models incorporating baseline and time-dependent
plasma viral load and CD4 response data.
Results. New HLA-associated escape events were observed in 269 (43%) patients during HAART and occurred
at 49 of 63 (78%) investigated immune-associated sites in Pol. In time-dependent analyses adjusting for baseline
factors, poorer virologic, but not immunologic, response to HAART was associated with increased risk of
immune escape of 1.9-fold per log10viral load increment (P , .0001). Reversion of escape mutations following
HAART initiation was extremely rare.
Conclusions. HLA-associated HIV-1 evolution continues during HAART to an extent that is inversely related
to the virologic success of therapy. Minimizing the degree of immune escape could represent a secondary benefit
of effective HAART.
HLA class I–restricted cytotoxic T lymphocytes and highly active antiretroviral therapy (HAART)
HLA class I–restricted cytotoxic T lymphocytes (CTLs)
and highly active antiretroviral therapy (HAART)
shape human immunodeficiency virus type 1 (HIV-1)
evolution by selecting mutations that compromise
immune [1, 2] and therapy-induced [3, 4] virologic
control. The extent and rate at which immune pres-
sures drive HIV-1 evolution during HAART remain
HAART suppresses HIV replication. As a consequence
of antigen withdrawal, HIV-specific CTL responses
decline in frequency  (although they remain
present in the CTL population) . Ongoing im-
mune escape occurs in specific HLA-restricted epitopes
during HAART [7–9]. However, no cohort studies have
systematically investigated theincidenceand
Correspondence: Chanson J. Brumme, BSc, BC Centre for Excellence in HIV/AIDS,
603-1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6 (email@example.com).
? The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
Received 16 November 2011; accepted 16 February 2012; electronically pub-
lished 2 2012.8 March
Clinical Infectious Diseases 2012;54(11):1652–9
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reader. The posted materials are not copyedited. The contents of all sup-
plementary data are the sole responsibility of the authors. Questions or
messages regarding errors should be addressed to the author.
conceived and designed the study. D. J. H. F. K. and C. J. B. performed
data analysis. D. J. H. F. K., Z. L. B., P. R. H., and C. J. B. interpreted data
and wrote the manuscript. All authors participated in data collection and
Financial support. This work was supported by grants from the
Canadian Institutes of Health Research (CIHR) and GlaxoSmithKline
(GSK) (to P. R. H.) and a CIHR operating grant (MOP93536 to Z. L. B.).
C. J. B. is supported by a Vanier Canada Graduate Scholarship from the
CIHR (CGV-104812). P. R. H. is a CIHR-GSK Chair. Z. L. B. holds a CIHR
New Investigator Award.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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