984 • JID 2009:200 (15 September) • Pereyra et al
M A J O R A R T I C L E
Persistent Low-Level Viremia in HIV-1 Elite
Controllers and Relationship to Immunologic
Florencia Pereyra,1,2Sarah Palmer,3,7Toshiyuki Miura,1,6Brian L. Block,1Ann Wiegand,3Alissa C. Rothchild,1
Brett Baker,1Rachel Rosenberg,1Emily Cutrell,1Michael S. Seaman,4John M. Coffin,5and Bruce D. Walker1,6
1The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard,
Division of Infectious Diseases,
and Microbiology, Tufts University, Boston Massachusetts;
Control and Karolinska Institute, Solna, Sweden
2Brigham and Women’s Hospital,
5Department of Molecular Biology
4Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, and
3HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health,
6Howard Hughes Medical Institute, Chevy Chase, Maryland; and
7Virology Department, Swedish Institute for Infectious Disease
lication to levels below the limits of detection by commercial assays, but the actual level of viremia in these
individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with
specific immunologic parameters.
Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-
transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1–specific immuneresponses
and longitudinal CD4+T cell counts were examined.
The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2–14 copies/mL). A
longitudinal analysis of 31 elite controllers demonstrated 2–5–fold fluctuations in viremia in the majority of
individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1–specific neutralizing
antibodies and Western blot reactivity but not with CD8+T cell responses. Absolute CD4+T cell decrease was
more common among individuals with detectable viremia (
Low-level viremia is present in the majority of elite controllers and is associated with higher
HIV-1–specific antibody responses. Absolute CD4+T cell loss is more common among viremic individuals, sug-
gesting that even very low-level viremia has negative consequences over time.
Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus rep-
).P p .04
In light of the recent failure of a prophylactic human
immunodeficiency virus type 1 (HIV-1) vaccine trial
, the rationaleforcurrentTcell–basedHIV-1vaccine
approaches has been questioned. Understandingthere-
lationships between low-level viremia, adaptive im-
mune responses, and disease progression is of im-
Received 29 January 2009; accepted 21 April 2009; electronically published 4
Potential conflicts of interest: none reported
Presented in part: 15th Conference on Retroviruses and Opportunistic Infections,
Boston, Massachusetts, February 2008 (abstract 349).
Financial support: National Institutes of Health (AI28568 and AI30914 to B.D.W.),
the Bill and Melinda Gates Foundation, the International AIDS Vaccine Initiative, and
the Mark and Lisa Schwartz Foundation.
Reprints or correspondence: Florencia Pereyra,MD,RagonInstitute,Massachusetts
General Hospital, 149 13th St, Charlestown, MA 02129 (firstname.lastname@example.org).
The Journal of Infectious Diseases
? 2009 by the Infectious Diseases Society of America. All rights reserved.
portance, particularly in situations of natural HIV-1
control that are relevant to vaccine approaches based
on protection from disease progression. Such situations
of control of HIV-1 are seen in elite controllers, indi-
viduals who spontaneously control virus replication
without antiretroviral drugs, to levels below the limits
of detection by commercial assays . Although some
recent studies have indicated low-level viremia in these
persons, the relationship to immunologic parameters,
including CD4+T cell decrease remains to be deter-
We previously reported that low-level viremia can
be detected by ultrasensitive quantitative polymerase
chain reaction (PCR) in elite controllers and is associat-
ed with the expression of immunoregulatory receptors
that affect CD4+T cell function . In that study,
the relationship between low-level viremia and other
immunologic parameters was not examined. Low-lev-
el viremia and its relationship to HIV-1 antibody lev-
by guest on February 2, 2016
990 • JID 2009:200 (15 September) • Pereyra et al
or that the assays used fail to quantify critical defects in effector
Taken together, our data demonstrate that, using an assay
250-fold more sensitive than current commercial assays, most
elite controllers have persistent low-level plasma viremia and
that humoral immune responses but not CD8+IFN-gELISPOT
responses correlate withthelevelofviremia.Moreover,weshow
that CD4+T cell loss is more common among elite controllers
with detectable virus levels, suggesting that future studies using
this assay could help identify elite controllers who are at risk
for this complication.
We thank the patients, investigators, and clinical and laboratory staff of
the International HIV Controllers Study (http://www.hivcontrollers.org)
for their important contributions to this research study.
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