Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts
Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts
Wei Cao 1 2 3
Vikram Mehraj 1 3
Benoit Trottier 7
Jean-Guy Baril 6
Roger Leblanc 1 5
Bertrand Lebouche 1
Joseph Cox 1
Cecile Tremblay 4 9
Wei Lu 2
Joel Singer 8
Taisheng Li 2
Jean-Pierre Routy 0 1 3
0 Division of Hematology, McGill University Health Centre
1 Chronic Viral Illness Service
2 Department of Infectious Diseases, Peking Union Medical College Hospital , Beijing , China
3 Research Institute of the McGill University Health Centre
4 CHUM Research Centre
5 Clinique Médicale OPUS
6 Clinique Médicale Quartier Latin
7 Clinique Médicale l'Actuel
8 School of Population and Public Health, University of British Columbia , Vancouver , Canada
9 Department of Microbiology and Immunology, University of Montreal , Quebec , Canada
Background. CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. Methods. Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. Results. At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. Conclusions. ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.
Human immunodeficiency virus (HIV) infection is featured by
profound immune dysfunction and a skewed T-cell homeostasis
]. In addition to the gradual loss of CD4 T cells in most
untreated HIV-infected individuals, elevation of CD8 T-cell
counts (hereinafter CD8 counts) persists until the very late
phase when T cells are depleted [
]. Robust expansion of
both HIV-specific and nonspecific CD8 T cells occurs soon
after HIV acquisition. Broader bystander activation has been
observed in CD8 than in CD4 T cells, probably through
antigen-independent mechanisms, and it persists throughout the
course of infection [
]. It is also reported that circulating
CD8 T cells exhibit more features of exhaustion and
immunosenecence than CD4 T cells over the disease progression,
including increased expression of PD-1, CD160, Tim-3, and
Although antiretroviral therapy (ART) achieves a progressive
recovery of CD4 T cells in the majority of treated HIV-infected
individuals, quantitative and functional defects in CD8 T cells
continue to exist even after a decade of effective treatment [
]. The CD8 counts exhibit a modest change with ART
initiated in chronic HIV infection but remain consistently elevated
with prolonged duration of treatment [
underlying CD8 persistence remain unclear and may include
immune activation due to residual viral replication, alteration of
lymph node architecture, gut mucosal dysfunction, microbial
translocation, and T-cell trafficking or redistribution [
Nevertheless, the unremitting elevation of CD8 counts and the
resulting low CD4/CD8 ratio after long-term ART have been
associated with an increased non–AIDS-related morbidity and
mortality risk independent of CD4 T-cell recovery [
12, 13, 17
Considered a window of opportunity, early ART initiated in
primary HIV infection (PHI) especially before 6 months of
infection has been associated with decreased seeding in latent
reservoirs and an almost back-to-normal level of immune
]. However, damage of gut mucosal integrity and
elevation of microbial product due to microbial translocation
are expected to persist despite early or extremely early ART
]. It remains unknown whether this early
approach could alleviate the ongoing elevation of CD8 counts.
In the present study, we examined factors associated with
trajectories of CD8 counts in early HIV infection. By comparing
individuals receiving early versus delayed ART, we also assessed
the impact of timing and duration of ART on elevated CD8
T-cell counts over time.
The Montreal Primary HIV Infection Study is a prospective
cohort study established in 1996 and implemented in 6 university
medical centers and 5 private medical centers in Montreal,
Quebec, Canada. HIV-1–infected individuals aged ≥18 years with an
estimated date of HIV acquisition <180 days were recruited and
followed for an intended 24 months. Diagnosis of HIV infection
was established based on positivity for p24 antigen and/or
detectable HIV RNA, subsequently confirmed by Western blot. In the
present study, all participants enrolled in the Montreal PHI study
from 1 May 1996 to 31 December 2012 were retrospectively
assessed. Participants were evaluated at a maximum interval of 3
months, when clinical and laboratory assessments were
conducted including testing for plasma viral load (VL) and CD4 and CD8
counts. The initiation of ART during follow-up was based on
CD4 counts and the decision of physicians and participants.
To better understand the effects of ART on T-cell dynamics,
we also assessed HIV-1–infected adults receiving care during a
similar period (1996–2010) at McGill University Health Centre
(MUHC), Montreal, including 182 age-matched individuals
who started ART during chronic infection and maintained
undetectable VLs for ≥5 years. We used 5 years as an inclusive
criterion to allow enough time for CD8 T-cell homeostasis after
viral control, because most studies suggest an average of 2–3
years after ART initiation for stabilization of CD8 counts [
]. We examined the CD4 and CD8 counts measured each
calendar year after VLs became undetectable. Another 40
agematched uninfected healthy volunteers enrolled at MUHC
were included as uninfected controls. This study was approved
by the MUHC Ethics Review Board, and all study subjects
provided written informed consent for participation in the study.
Testing for HIV-1 p24 antigen and testing for HIV-1 antibodies
with enzyme immunoassay were performed in laboratories of
the involved university medical centers. Confirmatory Western
blot testing was performed at the Laboratoire de Santé Publique
du Québec. The Architect HIV Ag/Ab Combo assay was used
for concurrent testing of p24 antigen and HIV-1 antibodies
after 2011 (Abbott Laboratories). Plasma VL was measured
using the Roche Amplicor HIV Monitor assay (Roche
Diagnostics) or the Abbott RealTime HIV-1 assay (Abbott Laboratories),
depending on the time of testing. Virological suppression was
defined as undetectable if plasma VL was <50 copies/mL with the
Roche or <40 copies/mL with the Abbott assay. Absolute CD4
and CD8 counts were determined using 4-color flow cytometry
performed with a FACSCalibur cytometer (Becton-Dickinson
Immunocytometry Systems) as reported elsewhere [
Statistical analyses were performed using SPSS 22.0 (SPSS) and
GraphPad Prism 6.0 (GraphPad Software). Summary statistics
were used to describe the study samples. Univariate linear
regression analysis was conducted to examine factors potentially
associated with CD8 counts at baseline. All variables from
univariate analyses were included in a multivariate linear regression
For follow-up analyses, time was calculated from the date of
ART initiation or study entry until the date of measurement
(±15 days). Correlations between CD8 counts and VLs were
assessed with Spearman rank correlation. All tests were 2 sided,
and differences were considered statistically significant at
P < .05. For further comparisons between N groups, differences
were considered significant at P < .05/N(N − 1).
A total of 280 individuals were enrolled in the Montreal PHI
study from May 1996 to December 2012 (Figure 1); 266 were
included in the baseline analysis, because the other 14 had
started ART before study entry. Of those in the baseline analysis, 246
(92.5%) were white, 254 (95.5%) were men, and 207 (77.8%)
were men who have sex with men; the mean (standard deviation
[SD]) age was 36.1 (9.4) years. Participants were recruited at a
median (interquartile range [IQR]) of 82 (56–121) days after
the estimated date of infection (EDI), including 40 patients
(15%) in Fiebig stage II–III, 81 (30.5%) in stage IV, and 145
(54.5%) in stage V–VI [
]. The mean (SD) VL at baseline
was 4.59 (1.07) log copies/mL, and the median (IQR) CD4
count was 500 (380–658) cells/µL.
For follow-up analysis, 251 participants with PHI were
included; 84 (33.5%) had started ART within 6 months after
EDI (eART) and 49 (19.5%) between 6 and 24 months
(dART), and the other 118 (47.0%) remained untreated over
the follow-up (no ART [nART]) (Figure 1 and Table 1).
Twenty-nine individuals were excluded from this analysis owing to
lack of CD8 data (n = 25) or premature termination of
treatment followed by a viral rebound (n = 4). The median time of
ART initiation was day 81 after EDI in the eART group, and
day 436 in the dART group. A total of 2648 CD8 counts were
measured for these participants over a median (IQR) follow-up
of 24 (15.6–24) months. Age, sex, VLs, and CD8 counts at entry
were comparable between the 3 groups. However, the eART
group had lower CD4 counts (P < .001) and lower CD4/CD8
ratios (P < .01) than the other 2 groups, partly accounting for early
ART initiation in this group.
We also assessed 182 age-matched individuals receiving
long-term ART initiated during chronic HIV infection. These
individuals have been treated for a median (IQR) of 8 (6–11)
years, and maintained undetectable VLs for ≥5 years (median,
6 years; range, 5–8 years). Their demographic characteristics
and T-cell measurements at the fifth year with undetectable
VLs are shown in Table 1.
The uninfected control group included 27 men and 13
women with a mean (standard deviation) age of 45.4 (7.4)
years. Compared with the HIV-infected individuals, they had
higher CD4 counts, lower CD8 counts, and higher CD4/CD8
ratios, as expected (Table 1).
Baseline CD8 Counts in PHI Group
The distribution of CD8 counts in 266 participants with PHI at
baseline is summarized in Table 2. Overall, the median CD8
count at baseline was 800 cells/µL, remarkably higher than
that in the uninfected controls (376 cells/µL; P < .001). In the
univariate analysis, white ethnicity, higher plasma VLs, and
Abbreviations: HIV, human immunodeficiency virus; IDU, injection drug use; IQR, interquartile range; MSM, men who have sex with men.
a CD8 T-cell counts did not differ significantly by coinfection status—including cytomegalovirus seropositivity (P = .35), hepatitis C virus coinfection (P = .43), and hepatitis B virus coinfection
(P = .13)—or by time of enrollment (P = .33).
higher CD4 counts were associated with higher CD8 counts before
the start of ART. However, in multivariate analysis with all factors
in Table 1 included, CD8 counts were much higher with more
acute and recent infection (Fiebig stage II/III; P = .02). Higher
CD8 counts were also associated with higher VLs (P < .001) and
higher CD4 counts (P < .001) in multivariate analysis. Otherwise,
CD8 counts were comparable in the adjusted analysis despite
differences in ethnicity, age, sex, route of infection, coinfection with
hepatitis B or C virus, or cytomegalovirus seropositivity.
Trajectories of CD4 and CD8 Counts and CD4/CD8 Ratios in Early-Treated
Individuals With PHI
After 24 months of ART, mean (SD) VLs in the eART group
decreased from 4.67 (1.30) to 1.89 (0.61) log copies/mL. Sixty-eight
of the 84 individuals had their VLs tested at 24 months, with
undetectable VLs achieved in 54. Changes in T-cell counts and ratio
in the eART group over time are depicted in Figure 2A–C.
CD8 counts underwent a median (IQR) change of 1 (−156 to
121) cells/µL during the month before treatment. The median
(IQR) CD8 count before ART was 797 (533–1338) cells/µL,
which decreased to 588 (450–877) cells/µL (P = .01) by 24 months
of treatment, with a median change of −170 (−560 to −29) cells/
µL). The decline in CD8 counts was most prominent during the
first month after ART initiation (median [IQR] change, −73
[−347 to 22] cells/µL). After the first 3 months, CD8 counts
became relatively stable, with the median fluctuating within 600 and
700 cells/µL. At 24 months, CD8 counts in the eART group were
lower than those of the long-term–treated individuals with
chronic infection (743 cells/µL at the fifth year with undetectable VLs;
P = .01), although they still remained elevated compared with the
uninfected controls (median, 376 cells/µL; P < .001).
Meanwhile, the median CD4 count in the eART group
increased from a median (IQR) of 410 (325–607) cells/µL to
594 (471–702) cells/µL (P = .002) over 24 months, with a
median change of 87 (I−21 to 257) cells/µL. At 24 months, CD4
counts in this group were similar to those in the chronic
infection, long-term ART group at the fifth year with undetectable
VLs (median, 534 cells/µL; P = .63), but were still lower than in
the uninfected group (median, 858 cells/µL; P = .003). The
median [IQR] CD4/CD8 ratio increased from 0.47 (0.22–0.75)
before ART to 0.95 (0.62–1.22; P < .001) at 24 months, which was
slightly higher than that of the chronic infection, long-term
. . .
ART group at the fifth year with undetectable VLs (median,
0.75; P = .08), but remained lower than in the uninfected
group (median, 2.1; P < .001).
Changes in CD4 and CD8 Counts and CD4/CD8 Ratios in Long-term–
Treated Individuals With Chronic Infection
Dynamics of CD4 and CD8 counts and CD4/CD8 ratios in the
context of undetectable VLs after long-term ART are also
depicted in Figure 2D–F. The median CD4 count in these
individuals increased from 397 to 578 cells/µL over the 8 years with
undetectable VLs (P < .001). Specifically, since the fourth year,
CD4 counts in the chronic infection, long-term ART group had
become comparable to those of early-treated individuals.
Meanwhile, due to the recovery in CD4 T cells, the CD4/CD8 ratio
increased from 0.67 to 0.77 over 8 years (P < .001), to a level
slightly lower than that in the eART group at 24 months
(P = .08). In contrast, CD8 counts in these individuals remained
rather stable over as long as 8 years of successful viral control
and were constantly higher than those of the uninfected
controls (P < .001) or the eART group at 24 months (P = .047).
Trajectories of CD4 and CD8 Counts and CD4/CD8 Ratio in Individuals
Trajectories of CD4 and CD8 counts in the eART, dART, and
nART groups over time are shown in Figure 3. CD8 counts
remained relatively stable in untreated individuals, in contrast to
the decline in both eART and dART groups. Interestingly,
although ART was started at different time points in the eART
and dART groups, only a modest difference in CD8 counts
was observed between the 2 at 24 months (median, 627 and
668 cells/µL, respectively). In both treated PHI groups, CD8
counts were lower than those in the chronic infection,
longterm ART group and fell within the limits of normal for the
Compared with the other 2 PHI groups, the eART group
achieved the most prominent CD4 increase at 24 months
(median, from 403 to 570 cells/µL; P < .001). In contrast, the dART
and nART groups underwent a gradual loss in CD4 T cells over
time. Of note, the decrease was so prominent in the dART
group (lowest point at 6 months, 361 cells/µL) that even the
eventual initiation of ART for approximately 1 year did not
reconstitute its baseline level.
Regarding the CD4/CD8 ratio, increases were observed in
both eART and dART groups; the medians (IQRs) at 24 months
were 0.76 (0.58–1.22) and 0.75 (0.53–0.91), respectively. The
eART group exhibited a more significant increase as a result
of concurrent CD4 T-cell recovery and CD8 T-cell reduction
(P < .001). However, all the infected individuals, even the
early-treated ones, continued to display a decreased ratio
compared with the uninfected controls.
We also assessed CD8 counts by VLs at baseline and at 12
and 24 months in individuals with PHI. At baseline, CD8
counts were strongly correlated to VL in all PHI groups.
However, at the end of 24 months, no significant correlation was
observed between CD8 counts and VLs for all 3 groups
(Supplementary Table 1).
The dynamic of CD8 counts during PHI remains poorly
studied, especially in the context of early ART initiation. In this
study, we examined trajectories of CD8 counts in individuals
with acute and early HIV infection, with or without early
ART initiation. We found that CD8 counts were markedly
increased in untreated PHI. Early ART initiated in PHI was
associated with a significant decrease in CD8 counts coupled with
VL reduction and CD4 T-cell recovery, which was even more
prominent when ART was initiated within 6 months of
infection. In contrast, although prolonged ART initiated in chronic
HIV infection was associated with progressive recovery in CD4
counts and CD4/CD8 ratio, CD8 counts in these individuals
remained persistently elevated and were higher than those
observed with ART initiation in PHI.
Elevation and expansion of CD8 T cells occurs from the very
early days of HIV infection, as a general situation in viral
infections such as Epstein-Barr virus and cytomegalovirus
infections. During the acute phase, the robust expansion of CD8 T
cells, particularly in the viral-specific subsets, almost always
indicates a strong immune reaction followed by a rapid control of
viremia, as suggested by our cohort, in which higher CD8
counts were also associated with higher CD4 counts in acute
infection. However, the HIV-specific CD8 T cells rapidly undergo
exhaustion and senescence during the course of HIV infection,
while the circulating bystander CD8 T cells remain elevated,
representing the major part of CD8 persistence. Although
long-term ART can induce a contraction in the CD8
compartment, normalization of CD8 counts is achieved in only a small
proportion of individuals, as observed in our long-term–treated
patients with chronic HIV infection and in other studies [
Unlike the situation in chronic HIV infection, when ART was
initiated early in PHI, we observed a rapid decrease in CD8
counts to a level within the upper limit of normal for uninfected
persons. In addition to this quantitative improvement, previous
studies indicated that some of the CD8 functional defects could
also be partially reversed by early treatment [
early initiation of ART is probably more promising than
prolonged duration for the normalization of CD8 counts, which
may further contribute to reducing future risks of
non–AIDSrelated events. Our result is consistent with previous reported
association between CD4/CD8 ratio and ART timing .
However, we further demonstrated that CD8 persistence
might be more responsible for the long-term dynamics of
the CD4/CD8 ratio, given that optimal CD4 count recovery
has been achieved in the majority of treated HIV-infected
Although the decline of CD8 counts occurred soon after ART
initiation in individuals with PHI, it gradually slowed down,
leading to relatively stable CD8 counts for the rest of
followup. Similar findings have been reported when ART is started
during chronic HIV infection [
]. Although our study
design does not allow further assessment of CD8 T-cell trends
with prolonged early ART, some early-treated participants
with PHI continue to be followed up in our center. Available
data based on a median (IQR) follow-up of 5 (3–6) years
showed no further significant changes in CD8 counts compared
with levels documented at 2 years. Based on these observations,
we propose that before the very late stage of infection, elevation
of circulating CD8 T cells in HIV infection may contain 2 major
compartments: a fast-responsive compartment, which responds
and decays rapidly on initiation of effective ART, and a
persistent compartment, which may endure even with prolonged
ART. Progression of HIV infection may lead to accumulation
in the persistent compartment over time, and ART initiated
at different time points may result in different levels of CD8
persistence. Furthermore, it is possible that expansion of the
persistent compartment is limited in early infection, because similar
levels of post-ART CD8 counts were observed in our study even
when treatment was initiated 1 year apart in PHI.
Most probably, the fast-responsive compartment mainly
includes activated CD8 T cells such as the CD38+/HLA-DR+
subsets, which are associated with viral antigenic stimulation. In
one of our recent studies, CD8 T-cell activation (CD38+/
HLA-DR+) was examined longitudinally in selected
participants from the eART and nART groups [
]. Compared with
the elevated level of CD8 activation in the untreated individuals,
the frequencies of activated CD8 T cells rapidly normalized
after ART initiation, which corresponds to the partial recovery
of CD8 counts on treatment. In contrast, the persistent
compartment may have a more profound origin, including gut
mucosal damage, T-cell exhaustion, or acquired “immunoaging,”
which persist even after early initiated ART [
impaired distribution and homing capacity of T cells may also
contribute to the CD8 persistence . However, the situation
would be quite different in late stage of infection with
overwhelming destruction of T cells, in which ART induced viral
suppression will first lead to reconstitution of both CD4 and
CD8 T cells, as reported by us and others [
Although a definite improvement in CD8 counts was
observed in early-treated individuals with PHI, our study has
several limitations as a nonrandomized retrospective study. With
growing evidence showing the benefit of early ART, it will be
increasingly difficult to observe and follow up persons with
early infection as per randomization. Nevertheless, the similar
shapes of T-cell curves after ART initiation indicated the impact
of ART on CD8 counts. Our PHI cohort was composed mainly
of young men who have sex with men, and outcomes described
here may be different for groups with older or female subjects.
However, as also indicated by other studies, the effects of age
and sex may be minimal in terms of longitudinal assessment.
In summary, timing rather than duration of ART seems be
more critical for normalization of CD8 counts in HIV infection.
In addition to the recovery of CD4 T cells and delay in disease
progression, ART initiation during PHI may further contribute
to reducing future non–AIDS-related morbidity and mortality
risk by alleviating CD8 elevation. Our findings bring more
insights into the underlying mechanisms for CD8 T-cell
dynamics in HIV infection. More research should be conducted on
CD8 T-cell persistence in the context of treated infection,
assessing in-time contributions of viral persistence, T-cell
homing, trafficking, and turnover in circulating blood and, more
importantly in tissues such as lymph nodes and gut mucosa.
Supplementary materials are available at http://cid.oxfordjournals.org.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Acknowledgments. We thank the following physicians for collaboration
in screening, recruiting, and following up participants with primary or
chronic HIV infection: Drs S. Vézina, L. Charest, M. Milne, E. Huchet,
S. Lavoie, J. Friedman, M. Duchastel, and F. Villielm, at l’Actuel Medical
Clinic; P. Côté, M. Potter, B. Lessard, M. A. Charron, S. Dufresne, and
M. E. Turgeon, at Quartier Latin Medical Clinic; Drs D. Rouleau,
L. Labrecque, C. Fortin, A de Pokomandy, V. Hal-Gagné, M. Munoz,
B. Deligne, and V. Martel-Laferrière, at UHRESS CHUM Hôtel-Dieu and
Notre-Dame; and N. Gilmore, M. Fletcher, and J. Szabo, at MUHC Chest
Institute. We thank Mario Legault and Costas Pexos for database
management; Angie Massicotte for coordination and assistance in manuscript
writing; Jacquie Sas and Jim Pankovich, from the Canadian Institutes of
Health Research (CIHR) Canadian HIV Trials Network (CTN), for
coordinating the international research collaboration between MUHC and Peking
Union Medical College Hospital with the support of CIHR/CTN.
Financial support. This work was supported by the Fonds de la
Recherche Québec-Santé (FRQ-S): Thérapie Cellulaire and Réseau SIDA/Maladies
Infectieuses, the Canadian Institutes of Health Research (grants MOP
103230 and CTN 257), the Canadian Foundation for AIDS Research
(CANFAR; grant 023–512), and the Canadian HIV Cure Enterprise Team (grant
HIG-133050 from the CIHR in partnership with CANFAR). W. C. is
supported by a CTN postdoctoral fellowship award, V. M. is supported by an
FRQ-S postdoctoral fellowship award, and J. P. R. holds the Louis
Lowenstein Chair in Hematology & Oncology at McGill University.
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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