In HIV research, there is a persistent and vigorous debate around
the question of whether or not viral replication persists in the face of successful
antiretroviral therapy. During a plenary session at the International AIDS Conference in Mexico City back in
August, Bob Siliciano made a compelling argument that, in most cases,
antiretroviral therapy completely shuts down virus production. Now, a new paper
in PNAS provides additional support for this view. Beda Joos and colleagues
evaluated a staggering 1,753 genetic sequences from the envelope region of HIV,
sampled over the course of a treatment interruption trial known as SSITT
(Swiss-Spanish Intermittent Treatment Trial). The study design involved a
series of two-week treatment breaks followed by a prolonged interruption
(therapy was subsequently reinitiated according to the CD4 and viral load thresholds used in
current treatment guidelines).
The researchers used the sequence data to plot the
relationships between the different viruses, using a technique called
phylogenetic analyses. For each study participant analyzed, the sequences were
used to define “the most recent common ancestor” (MRCA), which is an approximation of the ancestral virus
sequence from which all the others derived. Viruses that appeared during treatment
interruptions (TIs) were then compared to the MRCA, to see if the sequences
suggested that there had been ongoing replication and evolution while the study
participants were on ART. The results showed that the rebounding viruses during
TI were actually more distant from the MRCA than the viruses detected when the
participants first entered the study. The researchers conclude: “the striking
lack of a temporal relationship between rebounding virus and pretreatment
viruses strongly suggests that rebounding virus originates from reactivated,
latently infected cells rather than from a cellular pool or compartment engaged
in low-level replication.”
PNAS October 28, 2008 vol. 105 no. 43 16725-16730
Published online before print October 20, 2008, doi:
10.1073/pnas.0804192105
HIV rebounds from latently infected cells, rather than from
continuing low-level replication
Beda Joosa,1, Marek Fischera, Herbert Kustera, Satish K.
Pillaib, Joseph K. Wongb, Jürg Bönic, Bernard Hirscheld, Rainer Webera,
Alexandra Trkolaa, Huldrych F. Güntharda,1, and The Swiss HIV Cohort Study2
aDepartment of Medicine, Division of Infectious Diseases and
Hospital Epidemiology, University Hospital Zürich, CH-8091 Zurich, Switzerland;
bSan Francisco Veterans Affairs Medical Center, University
of California, San Francisco, CA 94121;
cNational Center for Retroviruses, University of Zurich,
CH-8028 Zurich, Switzerland; and
dDivision of Infectious Disease, University Hospital Geneva,
1211 Geneva, Switzerland
Rapid rebound of plasma viremia in patients after
interruption of long-term combination antiretroviral therapy (cART) suggests
persistence of low-level replicating cells or rapid reactivation of latently
infected cells. To further characterize rebounding virus, we performed
extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions
and exploited the temporal relationships of rebounding plasma viruses with
regard to pretreatment sequences in 20 chronically HIV-1-infected patients
having undergone multiple 2-week structured treatment interruptions (STI).
Rebounding virus during the short STI was homogeneous, suggesting mono- or
oligoclonal origin during reactivation. No evidence for a temporal structure of
rebounding virus in regard to pretreatment sequences was found. Furthermore,
expansion of distinct lineages at different STI cycles emerged. Together, these
findings imply stochastic reactivation of different clones from long-lived latently
infected cells rather than expansion of viral populations replicating at low
levels. After treatment was stopped, diversity increased steadily, but
pretreatment diversity was, on average, achieved only >2.5 years after the
start of STI when marked divergence from preexisting quasispecies also emerged.
In summary, our results argue against persistence of ongoing low-level
replication in patients on suppressive cART. Furthermore, a prolonged delay in
restoration of pretreatment viral diversity after treatment interruption
demonstrates a surprisingly sustained evolutionary bottleneck induced by
punctuated antiretroviral therapy.
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