Sheds Light on Residual Viral Load
Residual low-level HIV plasma viremia correlates with
size of the CD4 T-cell reservoir, but not immune activation
amounts of HIV genetic material can be detected in most people
with HIV even after many
years on effective combination antiretroviral
therapy (ART). Viral DNA, or provirus, can remain latent
inside resting CD4 T-cells, as well as anatomic areas such
as the brain and gut, creating a reservoir that is impervious
to current antiretroviral drugs.
these cells can become activated in various ways, causing
latent HIV to start replicating again. This is why even people
with "undetectable" viral load must remain on treatment.
Various strategies towards a cure for HIV aim to activate
resting T-cells in order to purge or flush out the virus.
described in the July
1, 2011, Journal of Infectious Diseases, Tae-Wook
Chun and Anthony Fauci from the National Institute of Allergy
and Infectious Diseases and colleagues looked at associations
between residual plasma viremia, CD4 cell reservoir size,
and levels of immune activation.
described, Chun and Fauci's team has carried out some
key studies in the area of HIV latency. In the mid-1990s they
started treating a small cohort of patients whose HIV infection
was diagnosed very early. Based on the half-life of latently
infected CD4 T-cells and the decay of plasma HIV levels, they
suggested that people who start treatment during primary infection
might eliminate all virus in resting CD4 cells with 7.7 years
More recently, however, Chun and colleagues reported that
while patients who started ART early had significantly less
HIV DNA in their resting CD4 T-cells than those who started
treatment later, all still had a small amount of residual
virus, and even 1 patient with an extremely low level still
experienced viral rebound after an experimental ART interruption.
In the present study the researchers assessed plasma viremia
using very sensitive tests that could measure down to 0 copies/mL.
They tested samples from 127 participants on ART who had undetectable
plasma viral load for extended periods, as measured by standard
clinical assays (limit of detection of 50 copies/mL). They
used an automated system that ran the tests in quadruplicate
for each individual.
of participants with "undetectable" viral load
< 50 copies/mL had detectable plasma viremia (1-49
copies/mL) according to the sensitive tests.
had no measurable plasma HIV RNA.
median residual viremia level was 2.7 copies/mL.
plasma HIV level correlated with the size of the CD4 T-cell
viral reservoir, or cells carrying proviral DNA.
Individuals with undetectable plasma viremia according
to the sensitive tests had fewer CD4 cells carrying HIV
DNA, on average, than those with detectable plasma viremia.
plasma viremia did not, however, correlate with markers
of immune activation including C-reactive protein, D-dimer,
interleukin 6, soluble TNF receptor I, and CD38 expression
on CD4 and CD8 T-cells.
findings, the study authors wrote, suggest that "reactivation
of the latent viral reservoir may not be the sole source of
residual plasma viremia."
Residual viremia "may also originate from productively
infected CD4+ T-cells in various lymphoid tissues," they
proposed, noting that "it is possible to have low levels
of viral replication and cell-to-cell spread of virus, particularly
in lymphoid organs, without such replication being reflected
in the levels of plasma viremia, even as measured by the most
If this is the case, they concluded, activating resting T-cells
may not be enough to get rid of the virus, and "[n]ovel
therapeutic strategies aimed at targeting the source of residual
viremia may be necessary to achieve viral eradication."
"Achieving eradication of HIV in infected individuals
receiving ART remains a daunting challenge for the scientific
community," they continued in their discussion. "To
achieve a functional cure, as defined by the absence of detectable
HIV for extended periods of time in the absence of ART, therapeutic
strategies aimed at eliminating cellular reservoirs in various
tissue compartments must be accompanied by comprehensive virological
assays that monitor infected CD4+ T-cells that may or may
not contribute to residual plasma viremia."
affiliations: Laboratory of Immunoregulation, and Biostatistics
Research Branch, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD; Department
of Medicine, University of Toronto, Ontario, Canada.
Chun, D Murray, JS Justement, et al. Relationship Between
Residual Plasma Viremia and the Size of HIV Proviral DNA Reservoirs
in Infected Individuals Receiving Effective Antiretroviral
Therapy. Journal of Infectious Diseases 204(1):135-138
July 1, 2011.