JOURNAL OF VIROLOGY, Apr. 2008, p. 3713–3724
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Vol. 82, No. 7
Simian Immunodeficiency Virus SIVagm Dynamics in African
Ivona Pandrea,1,2* Ruy M. Ribeiro,3Rajeev Gautam,4Thaidra Gaufin,4Melissa Pattison,4
Mary Barnes,4Christopher Monjure,4Crystal Stoulig,1Jason Dufour,5Wayne Cyprian,5
Guido Silvestri,6Michael D. Miller,7Alan S. Perelson,3and Cristian Apetrei4,8
Divisions of Comparative Pathology,1Microbiology,4and Veterinary Medicine,5Tulane National Primate Research Center,
Covington, Louisiana 70433; Department of Pathology, School of Medicine, Tulane University, New Orleans,
Louisiana 701122; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos,
New Mexico 875453; Department of Pathology, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 191076; Gilead Sciences, Inc., Foster City, California 944047; and
Department of Tropical Medicine, School of Public Health,
Tulane University, New Orleans, Louisiana 701128
Received 7 November 2007/Accepted 15 January 2008
The mechanisms underlying the lack of disease progression in natural simian immunodeficiency virus (SIV)
hosts are still poorly understood. To test the hypothesis that SIV-infected African green monkeys (AGMs)
avoid AIDS due to virus replication occurring in long-lived infected cells, we infected six animals with SIVagm
and treated them with potent antiretroviral therapy [ART; 9-R-(2-phosphonomethoxypropyl) adenine (teno-
fovir) and beta-2,3-dideoxy-3-thia-5-fluorocytidine (emtricitabine)]. All AGMs showed a rapid decay of plasma
viremia that became undetectable 36 h after ART initiation. A significant decrease of viral load was observed
in peripheral blood mononuclear cells and intestine. Mathematical modeling of viremia decay post-ART
indicates a half-life of productively infected cells ranging from 4 to 9.5 h, i.e., faster than previously reported
for human immunodeficiency virus and SIV. ART induced a slight but significant increase in peripheral CD4?
T-cell counts but no significant changes in CD4?T-cell levels in lymph nodes and intestine. Similarly, ART did
not significantly change the levels of cell proliferation, activation, and apoptosis, already low in AGMs
chronically infected with SIVagm. Collectively, these results indicate that, in SIVagm-infected AGMs, the bulk
of virus replication is sustained by short-lived cells; therefore, differences in disease outcome between SIVmac
infection of macaques and SIVagm infection of AGMs are unlikely due to intrinsic differences in the in vivo
cytopathicities between the two viruses.
One of the most intriguing pathogenic features of simian
immunodeficiency virus (SIV) infection is that African nonhu-
man primate (NHP) natural hosts, such as African green mon-
keys (AGMs), sooty mangabeys (SMs), mandrills, and chim-
panzees, naturally or experimentally infected with their
species-specific SIV generally do not progress to AIDS (3, 5,
16, 43, 50, 59, 65, 66). This feature is in striking contrast to
pathogenic lentiviral infections of humans and macaques, for
which the outcome of infection is disease progression (32). It is
now widely acknowledged that a better understanding of the
mechanisms of the lack of disease progression in natural SIV
infections may be needed for understanding the pathogenesis
of AIDS in human immunodeficiency virus (HIV)-infected
individuals (70, 71).
Both HIV type 1 (HIV-1) and HIV-2 originated from cross-
species transmission events of SIVs naturally infecting chim-
panzees/gorillas and SMs, respectively (73). SIVsmm/SIVmac
strains that are pathogenic in rhesus macaques (RMs) also
originated from naturally infected SMs (2). Infection of SMs or
RMs and AGMs or pigtailed macaques with the same strains
of SIVsmm/SIVmac or SIVagm, respectively, results in differ-
ent outcomes, with disease progression in macaques and per-
sistent nonprogressive infection in natural African NHP hosts
(17, 25, 29, 65). Therefore, the differences in pathogenic po-
tentials do not appear to be virus related. Importantly, some of
the immunological consequences of SIV infection shared by
pathogenic and natural SIV infections are very similar, most
notably the early and massive CD4?T-cell depletion at the
mucosal sites (19, 33, 38, 48). Hence, the current view is that
the main reason behind the lack of disease progression in
natural African hosts lies in a better adaptation of the host in
response to the highly replicating virus rather than it reflecting
an infection with less pathogenic viral strains. This improved
adaptation of the host immune system does not mean stronger
or broader immune responses to viral antigens (10, 24, 76; I.
Pandrea, unpublished data). Moreover, studies by us and oth-
ers have shown that normal levels of immune activation, T-cell
proliferation, and apoptosis are characteristic for the chronic
phase of SIV infection in natural hosts (7, 29, 43, 44, 46, 50, 65,
66) and, at least in the case of SIVagm infection of AGMs, may
be due to an anti-inflammatory response very rapidly estab-
lished upon SIVagm infection (30). These responses are dif-
ferent from pathogenic infections in humans and macaques,
which are characterized by significant increases in immune
activation, the levels of which have been reported to be pre-
dictive for disease progression (13, 68). Furthermore, in patho-
* Corresponding author. Mailing address: Division of Comparative
Pathology, Tulane National Primate Research Center, 18703 Three
Rivers Road, Covington, LA 70433. Phone: (985) 871-6408. Fax: (985)
871-6510. E-mail: email@example.com.
?Published ahead of print on 23 January 2008.
genic infections, immune cell proliferation and apoptosis are
severely compromised (42, 56).
One of the hypotheses proposed to explain the lack of dis-
ease progression in natural African NHP hosts is that the
better preservation of peripheral CD4?T cells and the partial
immune restoration of mucosal CD4?T cells in the presence
of high levels of viral replication may be due to a different in
vivo viral cythopathicity (64), the corollary of this being a
significantly longer average life span of infected cells. The in
vivo life span of infected cells has been previously measured in
pathogenic HIV/SIV infections using potent antiretroviral
therapy (ART) (27, 37, 54, 55, 77, 79). These studies reported
a two-phase decline in plasma viral load (VL) after the admin-
istration of ART: an initial rapid decline of viremia, due to loss
of short-lived virus-producing cells (activated CD4?T cells),
followed by a slower decline, occurring as a consequence of
loss of longer-lived virus-producing cells (resting T cells or
macrophages) (53, 55). Mathematical modeling showed that
the bulk of HIV replication (93 to 99%) occurs in recently
infected cells that die soon after infection, with an average life
span calculated on the order of 1 day after the start of viral
production, and only 1 to 7% of virus production derives from
long-lived cells, which have an average life span on the order of
1 to 4 weeks (53).
In this study, we followed a similar approach and estimated,
from the kinetics of viral decline in vivo, the life span of
virus-producing cells in SIVagm-infected AGMs receiving
ART during chronic infection. We report that the bulk of
SIVagm replication in vivo is sustained by short-lived infected
cells. The decay of viremia following ART was more rapid in
SIVagm.sab-infected AGMs than in HIV-infected individuals
and SIV-infected RMs. These data suggest that the lack of
disease progression in SIVagm-infected AGMs is unlikely to
be related to reduced intrinsic virus cytopathicity, and the data
suggest a key role for species-specific host factors in determin-
ing the outcome of a primate lentiviral infection.
MATERIALS AND METHODS
Animals. Six Caribbean AGMs (Chlorocebus sabaeus), originating from St.
Kitts Island, were included in this study. The animals were adults (mean age, 7
years). All animals were negative for simian T-cell lymphotropic virus (Vironos-
tika human T-cell lymphotropic virus types I and II enzyme-linked immunosor-
bent assay; BioMerieux, Durham, NC) and SIV by an in-house SIVagm.sab-
specific enzyme-linked immunosorbent assay and were housed at the Tulane
National Primate Research Center, an AAALAC International-accredited facil-
ity. Housing and handling of animals were in accordance with the Guide for the
Care and Use of Laboratory Animals (40) and the Animal Welfare Act. All
protocols and procedures for the animal studies were reviewed and approved by
the Tulane University Institutional Animal Care and Use Committee.
SIVagm.sab infection. To avoid selection of viral variants in vitro, inocula used
inthis study consistedof plasma
SIVagm.sab92018-infected AGM. Plasma titers were determined on SupT1 as
described elsewhere (9), and all six AGMs were inoculated with plasma contain-
ing the equivalent of 300 50% tissue culture infective doses of SIVagm.sab92018.
Antiretroviral therapy. All AGMs included in this study were treated with
nucleotide reverse transcriptase inhibitors (NRTIs) 9-R-(2-phosphonome-
thoxypropyl) adenine (PMPA; tenofovir) and beta-2,3-dideoxy-3-thia-5-fluoro-
cytidine (FTC; emtricitabine) for 21 days. Antiretroviral (ARV) drugs were
administered starting from day 254 post-SIV inoculation, when levels of plasma
viremia had reached the set point and were remarkably stable. Subcutaneous
injections of both drugs were given at doses of 30 mg/kg of body weight/day. Prior
to treatment, monkeys were trained for subcutaneous injections, which allowed
drugs to be administered without repeatedly undergoing anesthesia. PMPA and
FTC were kindly provided by Gilead (Foster City, CA).
Blood and tissue collection. In order to model the dynamics of virus replica-
tion, thorough sampling schedules during the primary SIVagm.sab infection and
antiretroviral treatment were designed. Blood (4.9 ml, EDTA anticoagulated)
was collected from the femoral vein at days ?7 and 0, 3, 6, 8, 10, 13, 15, 18, 20,
28, 30, 42, 56, 72, 100, 132, 185 post-SIVagm.sab inoculation. Moreover, every 7
days between day 100 and day 132, 4.9 ml of blood was collected (with EDTA)
to determine the weekly variation of VLs in SIVagm.sab-infected AGMs. Then,
the animals were not sampled for 4 months to minimize stress prior to treatment.
ART was initiated at 254 days post-SIV inoculation. During the ART, the
sampling schedule was every 2 hours during the first 6 hours, every 6 hours during
the first 2 days, and then every 2 days during the first 2 weeks and every 3 days
during the third week. After the treatment interruption, samples were collected
every day for 4 days, then every 3 days for 2 weeks, and weekly for another 2
weeks. A final sample was collected 7 weeks after treatment ceased.
Whole blood was used for flow cytometry within 1 h of collection. Plasma was
separated within 2 h of collection and stored in aliquots at ?80°C until used for
Endoscopically guided pinch biopsies from the proximal jejunum, intestinal
resections of the small intestine, and excisional biopsies of axillary and inguinal
lymph nodes (LNs) were collected from all the animals as previously described
(46, 48). LNs and intestine were sampled before infection (day ?14) and at
different time points during the acute (days 10, 21, and 28 postinfection [p.i.])
and chronic (days 42, 72, 100, 132, 200, and 230 p.i.) phases of SIVagm infection.
Intestinal biopsies and LN biopsies were also performed at the initiation, at the
end, and at 72 days post-antiretroviral treatment.
Isolation of lymphocytes. Mononuclear cells were separated from the blood
through Ficoll density gradient centrifugation. Lymphocytes from the intestine
and LNs were isolated and stained for flow cytometry as previously described (46,
48). Briefly, lymphocytes were isolated from intestinal biopsies using EDTA
followed by collagenase digestion and Percoll density gradient centrifugation
(48). Lymphocytes were isolated from the axillary LNs by gently mincing and
pressing tissues through nylon mesh screens.
Antibody detection. Anti-SIVagm.sab92018 antibody dynamics were moni-
tored by using a SIVagm.sab-specific enzyme immunoassay (PIV-EIA) based on
peptides mapping the conserved Gp41 immunodominant region and the highly
variable V3 loop of SIVagm.sab2 (67). Serological reactivity was confirmed by
Western blotting for all the monkeys included in this study (Zeptometrix Corp.,
Viral RNA quantification. Viral RNA was extracted from 540 ?l of plasma
using the QIAamp viral RNA extraction kit (Qiagen, Valencia, CA). During the
ART, in order to improve the efficacy of testing, viral RNA was extracted from
the maximum amount of plasma available (840 to 1,000 ?l). RNA was also
extracted from 3 ? 106mononuclear cells isolated from blood, LNs, and intes-
tinal biopsies using an RNeasy kit (Qiagen, Valencia, CA). A DNase digestion
step was applied to the tissue extractions. Viral RNA was extracted from pe-
ripheral blood mononuclear cells (PBMCs), LNs, and intestine prior to, at the
end of, and at 72 days post-antiretroviral treatment.
VL quantification was done by real-time PCR as previously described (30, 49).
Briefly, total RNA was retrotranscribed into cDNA using the TaqMan Gold
reverse transcription-PCR kit and random hexamers (PE, Applied Biosystems,
Foster City, CA). PCRs were carried out in a spectrofluorometric thermal cycler
(ABI Prism 7700; PE). Quantification was based on the amplification of 180 bp
located in the long terminal repeat (LTR) region. This region is very conserved
within different SIVagm strains. The SIVagm.sab primers and probe were the
following: J15S (5?-CTG GGT GTT CTC TGG TAA G-3?), 5? J15S (5?-CAA
GAC TTT ATT GAG GCA AT-3?), and J15P (6-carboxyfluorescein–CGA ACA
CCC AGG CTC AAG CTG G–6-carboxytetramethylrhodamine) as previously
described (9). SIVagm.sab cDNA was added to the universal master mix (PE,
Applied Biosystems) containing a 10 ?M concentration of each primer and 10
?M concentration of the probe. All PCRs were carried out in duplicate in
parallel with a negative non-RT control reaction. The PCR cycling conditions
were as follows: a first cycle of denaturation (95°C, 10 min), followed by 45 cycles
of denaturation (95°C, 10 s), annealing (50°C, 30 s), and extension (72°C, 30 s).
Absolute viral RNA copy numbers were deduced by comparing the relative
signal strength to corresponding values obtained for seven 10-fold dilutions of
standard RNA, which were reverse transcribed and amplified in parallel. The
RNA standard consisted of a larger LTR region of SIVagm.sab92018 that was
PCR amplified with primers LTR2A (5?-AAC TAA GGC AAG ACT TTA TTG
AGG-3?) and LTR4S (5?-ACT GGG CGG TAC TGG GAG TGG CTT-3?). The
PCR product was cloned into the pCR 2.1 vector (Invitrogen, Carlsbad, CA). In
vitro transcription was then performed using the MEGAscript kit (Ambion,
Austin, TX). Known amounts of the SIVagm LTR standard RNA were used to
3714PANDREA ET AL. J. VIROL.
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