Background: Recent
thymic emigrants are identifiable by measuring TCR excision circles (TRECs)
which are diluted during T-cell division and have been shown to be lower in
individuals with chronically stimulated immune systems. TREC content declines
with age and is lower in some but not all HIV infected patients (pts).
Persistent immune activation is thought to play an important role in HIV
pathogenesis and may explain the loss of TRECs during HIV infection rather than
thymic dysfunction alone. As a history of immune activation prior to HIV
infection might predict disease progression after infection with HIV, we
investigated the impact of pre-seroconversion TREC content on the CD4
trajectory in HIV-infected injecting drug users (IDU) who are at high risk of having
a history of infections prior to HIV infection due to their lifestyle.
Methods: From the Amsterdam
Cohort Study, 51 IDU with known date of HIV seroconversion (SC) were selected,
for whom cryopreserved peripheral blood samples were available, taken before HIV infection (at least 3 months
before the last negative HIV test). Signal joint TRECs in purified CD4 cells
were measured using quantitative real-time PCR. The decline of CD4 cells during
HIV infection was modeled using regression analysis for repeated measurements,
in a piecewise manner as CD4 cell counts are known to show a steeper decline in
the first 6 months (mos) of HIV infection. Analyses were censored at HAART
initiation. We also
modeled the CD4 trajectory after the initiation of HAART. Categories of TREC
content were defined by the 67th percentile.
Results: Mean age of the 51 IDU was 32 yrs, 33% was female,
and median follow up since SC was 6.6 yrs. By September 2002, 15 IDU had
initiated HAART 1.4–9.7 yrs after SC and 15 IDU had died. Subjects who had a
TREC content below 4,325/μg DNA before HIV infection show a significantly steeper
decline in CD4 cell counts from 6 mos after SC onwards than those with higher
pre-SC TREC content (p = 0.01; see Figure 1). Correcting for age and gender did
not change results. After HAART initiation, a less steep CD4 increase was
observed in those with low pre-SC TREC content. However the difference was not
significant, but numbers are small (n = 15).
Conclusions: Low TREC content prior to HIV infection is associated with a
significantly faster decline of CD4 T-cell numbers during HIV infection. Thus a
history of recurrent immune activation before HIV infection may have an adverse
effect on HIV-1 disease progression.
