Cannabinoid administration attenuates the progression of simian immunodeficiency virus.

Abstract

Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic Δ(9)-THC use may impact HIV disease progression. We examined the impact of chronic Δ(9)-THC administration (0.32 mg/kg im, 2 × daily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV(mac251); 100 TCID(50)/ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV(mac251) inoculation resulted in measurable viral load, decreased lymphocyte CD4(+)/CD8(+) ratio, and increased CD8(+) proliferation. Δ(9)-THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic Δ(9)-THC administration decreased early mortality from SIV infection (p = 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass (p = NS). In vitro, Δ(9)-THC (10 μm) decreased SIV (10 TCID(50)) viral replication in MT4-R5 cells. These results indicate that chronic Δ(9)-THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for Δ(9)-THC-mediated modulation of disease progression that warrant further study.

Full text

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Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus

1Patricia E. Molina, MD, PhD, 2Peter Winsauer, PhD, 5Ping Zhang, MD, PhD,1Edith Walker,
1Leslie Birke, DVM, 3Angela Amedee, PhD, 1Curtis Vande Stouwe, 4Dana Troxclair, MD, 4Robin
McGoey, MD, 2Kurt Varner, PhD, 1Lauri Byerley, PhD, 6Lynn LaMotte, PhD

1Departments of Physiology, 2Pharmacology, 3Microbiology, 4Pathology, and 5Medicine, 6School
of Public Health, Alcohol Research Center, and Alcohol and Drug Abuse Center of Excellence,
LSUHSC, New Orleans, LA

Running title: chronic THC decreases early mortality from SIV


Address correspondence to:
Patricia E. Molina, MD, Ph.D.
LSUHSC Physiology
Medical Education Building
1901 Perdido Street
New Orleans, LA 70112
Phone (504) 568-6187
Fax (504) 568-6158
e-mail: pmolin@lsuhsc.edu
Sources of support: DA020419-01
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Abstract
Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive component in marijuana, is FDA-
approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are
expressed on cells of the immune system, chronic Δ9-THC use may impact HIV disease
progression. We examined the impact of chronic Δ9-THC administration (0.32mg/kg i.m., 2 X
daily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIVmac251; 100
TCID50/ml, i.v.), on immune and metabolic indicators of disease during the initial 6 month
asymptomatic phase of infection in rhesus macaques. SIVmac251. Inoculation resulted in
measurable viral load, decreased lymphocyte CD4+/CD8+ ratio, and increased CD8+
proliferation. Δ9-THC treatment of SIV-infected animals produced minor to no effects in these
parameters. However, chronic Δ9-THC administration decreased early mortality from SIV
infection (p=0.039), and this was associated with attenuation of plasma and CSF viral load and
retention of body mass (p=NS). In vitro, Δ9-THC (3.2μg/ml) decreased SIV (10 TCID50) viral
replication in MT4-R5 cells. These results indicate that chronic Δ9-THC does not increase viral
load or aggravate morbidity and may actually ameliorate SIV disease progression. We
speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation
are likely mechanisms for Δ9-THC-mediated modulation of disease progression that warrant
further study.
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The cannabinoids including cannabidiol, cannabinol, and Δ9-tetrahydrocannabinol (Δ9-THC)
exert their effects by binding to two major subtypes of cannabinoid receptor, CB1 and CB2.1
The CB1 receptor is preferentially expressed in the brain where it mediates neurobehavioral
effects. The CB2 receptor is expressed primarily in peripheral tissues, particularly in immune
cells where they have been shown to affect cytokine production, lymphocyte phenotype, function
and survival, cell-mediated immunity, and balance of Th1/Th2 cells.2 With the advent of highly
active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has
become a chronic disease frequently co-existing with chronic use of drugs of abuse, including
marijuana.3 In addition, Dronabinol (Δ9-THC; Marinol), is approved by the Food and Drug
Administration for treatment of HIV-associated anorexia.4 Although this approval has gained
strong support from the lay public, little scientific evidence exists to support the efficacy of such
an intervention. To date, no clinical studies have rigorously addressed the impact of chronic Δ9-
THC use on the course and progression of HIV infection. Only one study has examined the
impact of short-term (21 day) Δ9-THC administration (3 daily 0.9 g marijuana cigarettes; 3.95%
Δ9-THC) on HIV viral load. The results from that study did not show substantial elevation in viral
load in HIV-infected individuals receiving stable antiretroviral regimens containing nelfinavir or
indinavir,5 and thus, were considered to reflect the relative safety of short-term Δ9-THC use in
this patient population. The long-term effects of cannabinoid administration on progression of
HIV infection had not been previously examined.
Using a well established nonhuman primate model of HIV disease, we examined the impact
of chronic intramuscular Δ9-THC (provided by National Institute on Drug Abuse; Research
Technical Branch, Rockville, MD) administration on the early phase of simian immunodeficiency
virus (SIV) infection in age (4-6 year old) - and body weight-matched healthy male Indian-
derived rhesus macaques. Chronic administration of Δ9-THC (or 0.05 ml/kg vehicle (VEH)) was
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initiated prior to SIV with 0.18 mg/kg, a dose that eliminated responding in a complex operant
behavioral task in almost all of the subjects. The dose was subsequently increased for each
subject to 0.32 mg/kg, over a period of approximately 2 weeks, and maintained for the duration
of the study. Almost all of the animals demonstrated tolerance to the behavioral effects of this
dose prior to SIV inoculation, reported elsewhere.6 Approximately one month after initiating
chronic Δ9-THC administration, eight animals were inoculated intravenously with 100 times the
TCID50 (50% tissue culture infective dose) of SIVMAC251. Pathogenicity of this SIV isolate is
similar to HIV.7 The progression of SIV disease was monitored through clinical and biochemical
parameters, and viral load in plasma and CSF.
Contrary to what we expected, chronic cannabinoid administration did not significantly
increase viral load or exacerbate immune dysfunction. Mean viral load in VEH/SIV+ animals was
6.56±0.16 log copies at 7 days, and 6.04±0.6 log copies/ml at 2 months post infection (Figure
1A). Viral load remained elevated (6.35±0.76 and 5.8±0.06 log copies/ml at 3 and 6 months,
respectively) throughout the duration of the study. Viral load in THC/SIV+ was lower (4.83±0.56
log copies/ml) as compared to VEH/SIV+ beginning at 2 months post SIV infection (p=NS). Viral
mRNA in CSF peaked at day 14 post-infection, and remained elevated up until 2 months post
infection in the VEH/SIV+ and THC/SIV+ animals (Figure 1B). Thereafter, CSF viral load
fluctuated between levels below the limit of detection and low counts in both SIV-infected
groups. Across all time points, 60% of VEH/SIV+ CSF samples were above the limit of detection
for the assay. In contrast, only 40% of CSF samples from THC/SIV+ animals had viral loads
above the limit of detection.
Complete and differential blood counts were performed using a Beckman Coulter LH755
for total leukocyte counts and Wright-Giemsa staining of blood smears for leukocyte differentials.
Blood lymphocyte subsets were determined by flow cytometry as previously described.8 The
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CD4+ to CD8+ ratio decreased significantly from pre-infection values (p=0.0001) in both VEH-
and THC-treated animals (Figure 2B). The marked decrease in CD4+ lymphocyte counts,
reached statistical significance (p=0.023) at 0.5 and 1 months post SIV infection in VEH/SIV+
animals, and beginning at 2 months in THC/SIV+ (p=0.037). In contrast, CD8+ counts showed a
short-lived increase at 2 weeks post infection, which reached statistical significance only in
THC/SIV+ animals (p=0.029) (Figure 2D). CD4+ and CD8+ lymphocyte expression of Ki67 and
Caspase 3 (Cas3) were measured as indices of proliferation and apoptosis. No significant
changes were noted in the percent of neither Ki67+ nor Cas3+ on CD4+ lymphocytes in either
of the experimental groups (data not shown). In contrast, both markers were increased
significantly in CD8+ lymphocytes at 2 weeks post infection, suggesting increased activation of
these cells during the acute response to infection (Figure 3A). The CD8+ Ki67 expression was
increased 10-fold at this time point, and was significantly higher in THC/SIV+ animals when
compared to the VEH/SIV+ infected animals (p=0.049). This rise in CD8+ lymphocyte
proliferation was transient in both groups with only values for THC/SIV+ animals remaining
higher (p=0.05) than controls at 1 month post SIV infection. Values for VEH/SIV+ and THC/SIV+
groups were not different from control beyond one month post-infection. The changes in the
number of Ki67+ CD8+ lymphocytes were paralleled by those in number of Cas3+ CD8+
lymphocytes. Cas3+ CD8+ lymphocytes showed a transient and significant (p=0.001) 7-8-fold
increase that peaked at 2 weeks post-SIV infection in both VEH/SIV+ and THC/SIV+ animals
(Figure 3B). Although a similar pattern of higher levels of Cas3+ CD8+ lymphocytes was
observed in the THC/SIV+ animals, this difference failed to reach statistical significance in
comparison to the VEH/SIV+ animals (p=0.06). This rise in CD8+ lymphocyte apoptosis was
short-lived, and values after 1 month post-SIV infection were not different from uninfected
control values.
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No deaths were noted during the first 5 months post SIV infection in VEH/SIV+ or
THC/SIV+ animals (Figure 4). Two of the VEH/SIV+ animals succumbed to SIV infection shortly
after 5 months, and a third reached end-stage at 7 months. Among the THC/SIV+ animals, the
first animal did not reach end stage until 11 months post-SIV inoculation. A summary of the
clinical indications for euthanasia and the most salient necropsy findings is presented in Table 1.
Notably different patterns in weight gain were observed between the initial 3 month post
SIV-infection period and the subsequent 3-6 month post-SIV period (Figure 5). This was
particularly true for the VEH/SIV+ animals, which showed a tendency for greater (p=NS) weight
loss than the THC/SIV+ animals. Echocardiography (Toshiba Aplio at 8.5 MHz) performed prior
to (baseline), and 3 and/or 6 months after SIV infection in the two SIV-infected groups (VEH and
THC) failed to show significant alterations in cardiac systolic or diastolic function (data not
shown).
Cannabinoids, including Δ9-THC, have been shown to have immunomodulatory
effects9,10 on cytokine production and lymphocyte phenotype, function and survival11,12,13 as well
as cell-mediated immunity.14 Similar immunosuppressant effects on lymphocyte15 and alveolar
macrophage16 function have been reported in nonhuman primates. Furthermore, the potential of
cannabinoids to regulate the activation and balance of human Th1/Th2 cells by a CB2 receptor-
dependent pathway has been supported by findings from several studies.17,18 More recent
studies have provided evidence that the synthetic cannabinoid WIN 55,212-2 can potently
inhibit HIV-1 expression in CD4+ lymphocytes and microglial cell cultures in a time- and
concentration-dependent manner.19 Moreover, Rock et al.20 demonstrated the involvement of
CB2 receptors in cannabinoid antiviral activity in microglial cells. To examine the possibility that
the improved survival of SIV-infected rhesus could have been due to direct suppression of viral
replication, we examined the in vitro effects of 1 and 10 μM Δ9-THC on viral replication in MT4-
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R5 cells (human T-cell line)21 infected with SIVMAC251 (10 TCID50). Pretreatment with 10 μM of
Δ9-THC (3.2 µg/ml) resulted in a significant decrease in cell-associated viral load in cells
collected at 3 and 6 days post-SIV inoculation (Figure 6). Several possible mechanisms could
be involved in this suppression of viral replication, including effects on cell cycle, interaction of
cannabinoids with viral co-receptor, and viral integration into the host genome. Moreover, the
contribution of the specific cannabinoid receptor subtypes to the overall effects also remains to
be examined.
In summary, this study is the first to report in vivo experimental data demonstrating that
chronic Δ9-THC initiated prior to, and continued throughout the asymptomatic phase of SIV
infection, does not impair the host’s ability to control viral load, and does not increase morbidity
and mortality from the infection. While the small groups and natural variation in SIV disease is a
limitation of the study, the vehicle-treated group is representative of typical rhesus infections
with SIVmac251. Δ9-THC treatment clearly did not increase disease progression, and indeed
resulted in generalized attenuation of the classic markers of SIV disease (set point viral load/
viral level in general). The mechanisms underlying the decreased mortality in cannabinoid-
treated SIV-infected animals remain to be elucidated. However, based on our results and
reports in the literature, we speculate that retention of body mass, attenuation of viral replication,
and an overall immunosuppressant effect of cannabinoids may contribute to the amelioration of
SIV disease progression seen in our study. The cellular mechanisms, including the potential
role of the recently identified interaction between the HIV coreceptor CXCR4 and the
cannabinoid system22 as potential sites of pharmaco-immuno-modulation remain to be
determined.
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Acknowledgements:
The authors would like to thank Joseph Moerschbaecher, PhD, for his helpful
discussions on chronic THC administration and dosing and Dr. Catalin Filipeanu for cannabinoid
receptor expression measurements. Additionally, the authors would like to acknowledge the
technical expertise of Connie Porretta, Jean Carnal, Nedra Lacour, Peter Lewis, Merlin Johnson,
Jessica Howard, and Jaime Hubbell. Supported by NIDA-020419-01.

Address correspondence to:
Patricia Molina, M.D. PhD
Department of Physiology
Louisiana State University, Health Sciences Center
1901 Perdido St
New Orleans LA 70112
Email: pmolin@lsuhsc.edu

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Table 1. Clinical indications for euthanasia and necropsy findings.
Animals were studied during the pre-treatment period (prior to initiating the Δ9-THC
administration) and following SIV infection during the “asymptomatic phase of infection” prior to
any of them reaching criteria for euthanasia. This period was defined as the period of time
following SIV infection during which none of the animals showed clinical signs of disease
including weight loss greater than 5% of basal, secondary infections that required antibiotic
treatment, neurological manifestations of disease, severe diarrhea and dehydration. Animals
were sacrificed and necropsy performed when they met pre-defined clinical indications including
presence of three or more of the following: weight loss greater than 15%, hypoalbuminemia (<3
mg/dl) in the presence of edema, anemia and thrombocytopenia, three days of complete
anorexia, major organ failure or medical conditions unresponsive to treatment (including
respiratory distress, intractable diarrhea, or persistent vomiting, secondary infections that
required antibiotic treatment), neurological manifestations of disease, severe diarrhea and
dehydration. Survival was tracked throughout the first year post infection, at which time all
animals still on study were euthanized and necropsy performed.
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FIGURE LEGEND
Figure 1. Viral load detected in (A) plasma and (B) CSF (log SIV RNA copies/ml) over time in
relation to SIV infection. Shown are individual viral counts for each infected animal in the
vehicle-treated (VEH/SIV+; solid triangles) and THC-treated (THC/SIV+; empty squares) groups
as well as geometric means (lines). SIV copy number in plasma and CSF was measured by a
real-time RT-PCR assay using gag primers and probe as previously described. Virus was
isolated from 500 µl of plasma or 100 µl of CSF by high-speed centrifugation (20,000 g for 60
min.) at 4°C. The limit of detection for this assay (50 copies/ml plasma and 100 copies/ml CSF)
is shown in the dotted lines. The contribution of the values below the limit of detection in the
CSF assay was assessed as limit of detection divided by the square root of two.23
Figure 2. (A) Lymphocyte count (cells X 103/µl), CD4+/CD8+ lymphocyte ratio, CD4+ and CD8+
counts determined by flow cytometry in vehicle-treated uninfected (VEH/SIV-), THC-treated
uninfected (THC/SIV-), vehicle-treated infected (VEH/SIV+), THC-treated infected (THC/SIV+)
rhesus macaques expressed as means over time post SIV infection. Change from baseline was
analyzed by a model that included baseline value, as a covariate, and factor effects for Study
Period (SPno), THC (+/-), SIV (+/-), and all SPno, THC, and SIV interaction effects. The PROC
MIXED procedure in SAS (version 9.1) was selected to perform the analyses. As these are
repeated measures on the same subjects over the eight study periods, the within-subjects
covariance structure was modeled as compound symmetry; the Kenward-Roger approximation
was used to compute p-values for tests of significance. Values for experimental groups N=3 in
VEH/SIV- and N=4 in all others. *p<0.05 vs. time- and treatment-matched uninfected controls.
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Figure 3. Numbers of (A) Ki67+, and (B) Caspase 3+ CD8+ lymphocytes as determined by flow
cytometry in vehicle-treated uninfected (VEH/SIV-), THC-treated uninfected (THC/SIV-), vehicle-
treated infected (VEH/SIV+), THC-treated infected (THC/SIV+) rhesus macaques expressed as
means over time post SIV infection. Values for experimental groups N=3 in VEH/SIV- and N=4
in all others. *p<0.05 vs. time- and treatment-matched uninfected control. + vs. time-matched
VEH/SIV+ values.
Figure 4. Percent survival of vehicle-treated infected (VEH/SIV+) and THC-treated infected
(THC/SIV+) rhesus macaques over the initial 11 months post SIV infection, the timepoint when
the first THC/SIV+ animal reached end-stage criteria. Log rank statistic for the survival curve
(Kaplan Meier Survival Analysis) is greater than would be expected by chance (p=0.037).
Figure 5. Body weight change (kg) during the initial 3 months post SIV infection (left panels) and
during the subsequent 3-6 month period of infection. Top panels depict change in body weight
in vehicle-treated uninfected (VEH/SIV-), THC-treated uninfected (THC/SIV-), vehicle-treated
infected (VEH/SIV+), THC-treated infected (THC/SIV+) rhesus macaques expressed as means ±
SEM over time post SIV infection. Because of the individual variability, data are shown for each
animal during the initial 3 months post SIV infection and during the later 3-6 month post SIV
infection in the lower panels, showing the trends in body-weight changes. The symbols in the
line graphs represent individual animals in the specified treatment group and carry over across
time.
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Figure 6. MT4-R5 cells (human T-cell line) were seeded at a cell density of 5 X 105/ml in RPMI
1640 containing 10% heat – inactivated fetal calf serum, 2mM glutamine, 100 U/ml penicillin,
100 µg/ml streptomycin, and 1 µg/ml puromycin in T25 flasks and maintained at 37o C with 5 %
CO2 in the presence of Δ9-THC (1 or 10μM) or vehicle for 11 days. Culture media was replaced
at 3-4 day intervals. After 11 days, 1.5 X106 MT4-R5 cells from each treatment group were
inoculated with 10 TCID50 SIVmac in fresh media containing Δ9-THC or vehicle, plated in 96 well
dishes at a density of 1 X 105 cells/well, and maintained at 37o C with 5% CO2. Uninfected
cultures of Δ9-THC- and vehicle-treated cells were maintained identically for use as controls.
One-half of the replicate cultures were harvested 3 days post-SIV-infection, with the remainder
harvested 6 days after infection. Supernatant and cell pellets were fractionated by
centrifugation at 700 x g for 5 minute at room temperature. Cell viability was monitored through
cell counts using trypan blue. DNA was prepared and the quantity of proviral SIV DNA in the cell
pellets was determined by real-time PCR. DNA viral load (log SIV DNA copies/well) was
quantified in cells harvested at 3 and 6 days post inoculation. Expression of CB1 and CB2
receptors was confirmed in these cells prior to using them in the study. Values are mean ± SEM
of 8 replicate wells. Results were analyzed with two-way ANOVA followed by pair-wise multiple
comparison procedures (Holm-Sidak method) *p≤0.008.
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References
Table 1. Clinical indications for euthanasia and necropsy findings
Subject
ID
Time
days
post-
SIV
Clinical findings
Necropsy findings
VEH/SIV+
A2L046
148
Head pressing, ataxia, inactivity, lack of a
palpebral reflex and decreased papillary light
reflex in the right eye, serum albumin < 3 mg/dl,
and dehydration, unresponsive to treatment.
Cytomegalovirus
meningitis with
cerebral edema and
uncal herniation
Acute bilateral
bronchopneumonia
and pulmonary edema
Giant cell pneumonia
with mycobacterium sp.
Pneumocystis jiroveci,
Meningoencephalitis
and cerebral vasculitis

Pulmonary
thromboembolism
A1R047
166
Unilateral right facial nerve paralysis, lethargic,
ventral recumbence, dyspnea
A1R058
220
Decreased platelet count, hematuria,
hematochezia, pyuria.
Collapsed and did not respond to CPR
none
A2R065
503
Pulmonary congestion,
hepatic steatosis
THC/SIV+
A1R044
343
Chronic progressive intermittent diarrhea,
nonresponsive to treatment, chronic intermittent
rectal prolapse, gradual body weight loss (>
25%), serum albumin < 3 mg/dl.
Mycobacterium sp.
Involving lungs, liver,
spleen, kidneys,
gastrointestinal tract
and mesenteric lymph
nodes with
granulomatous
inflammation
Pulmonary edema,
congestion, mild
hepatic microsteatosis
Steatohepatitis,
pulmonary
granulomatous
inflammation, chronic
pancreatitis
Mild cerebral edema,
mild acute
A1R022
351
none
A1R005
461
none
A2L094
503
none
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steatohepatitis


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