Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development
Aim: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors in the development of gastroint...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development / A. Sultanova, M. Chistjakovs, S. Chapenko, S. Donina, M. Murovska // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 93-96. — Бібліогр.: 18 назв. — англ. |
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irk-123456789-1452112019-01-20T01:23:38Z Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development Sultanova A. Chistjakovs M. Chapenko S. Donina S. Murovska M. Original contributions Aim: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors in the development of gastrointestinal cancer. Methods: Sixty five patients with gastrointestinal cancer before surgery and without any treatment were enrolled in this study and divided into two groups depending on lymphocytes’ count: I group (n = 35) — lymphocytes > 1400x10⁶ /L and II group (n = 30) — lymphocytes < 1400x10⁶ /L. Nested polymerase chain reaction was used to detect latent and active stage of persistent human herpesvirus-6 and -7 infection, laser flow cytometry with monoclonal antibodies — to determine immunological parameters. Results: Activation of herpesvirus-6 and -7 was more frequently observed in the patients’ group with lymphopenia (HHV-6 1/1 (100%), HHV-7 4/8 (50%) and HHV-6 + HHV-7 6/9 (66%); p < 0.05). Cellular immune parameters were analysed in immunocompromised II group’s patients dependently on beta-herpevirus infection. Although number of leukocytes was higher in patients with active HHV-6/-7 infection (p = 0.01), number of lymphocytes CD3⁺, CD4⁺, CD8⁺ and CD38⁺ in patients with active HHV-6/-7 infection tended to decrease (p < 0.0001, P = 0.0002, p = 0.0001 and p < 0.0001, respectively). However, number of CD19+ had tendency to increase (p = 0.03). Conclusion: Activation of herpesvirus-6 and -7 may lead to decrease of lymphocytes total count and develop immunosuppression in patients with gastrointestinal cancer. Key Words: beta-herpesvirus-6, beta-herpesvirus-7, gastrointestinal cancer. 2013 Article Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development / A. Sultanova, M. Chistjakovs, S. Chapenko, S. Donina, M. Murovska // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 93-96. — Бібліогр.: 18 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145211 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Sultanova A. Chistjakovs M. Chapenko S. Donina S. Murovska M. Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development Experimental Oncology |
| description |
Aim: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors in the development of gastrointestinal cancer. Methods: Sixty five patients with gastrointestinal cancer before surgery and without any treatment were enrolled in this study and divided into two groups depending on lymphocytes’ count: I group (n = 35) — lymphocytes > 1400x10⁶ /L and II group (n = 30) — lymphocytes < 1400x10⁶ /L. Nested polymerase chain reaction was used to detect latent and active stage of persistent human herpesvirus-6 and -7 infection, laser flow cytometry with monoclonal antibodies — to determine immunological parameters. Results: Activation of herpesvirus-6 and -7 was more frequently observed in the patients’ group with lymphopenia (HHV-6 1/1 (100%), HHV-7 4/8 (50%) and HHV-6 + HHV-7 6/9 (66%); p < 0.05). Cellular immune parameters were analysed in immunocompromised II group’s patients dependently on beta-herpevirus infection. Although number of leukocytes was higher in patients with active HHV-6/-7 infection (p = 0.01), number of lymphocytes CD3⁺, CD4⁺, CD8⁺ and CD38⁺ in patients with active HHV-6/-7 infection tended to decrease (p < 0.0001, P = 0.0002, p = 0.0001 and p < 0.0001, respectively). However, number of CD19+ had tendency to increase (p = 0.03). Conclusion: Activation of herpesvirus-6 and -7 may lead to decrease of lymphocytes total count and develop immunosuppression in patients with gastrointestinal cancer. Key Words: beta-herpesvirus-6, beta-herpesvirus-7, gastrointestinal cancer. |
| format |
Article |
| author |
Sultanova A. Chistjakovs M. Chapenko S. Donina S. Murovska M. |
| author_facet |
Sultanova A. Chistjakovs M. Chapenko S. Donina S. Murovska M. |
| author_sort |
Sultanova A. |
| title |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| title_short |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| title_full |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| title_fullStr |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| title_full_unstemmed |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| title_sort |
possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2013 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/145211 |
| citation_txt |
Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development / A. Sultanova, M. Chistjakovs, S. Chapenko, S. Donina, M. Murovska // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 93-96. — Бібліогр.: 18 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT sultanovaa possibleinterferenceofhumanbetaherpesviruses6and7ingastrointestinalcancerdevelopment AT chistjakovsm possibleinterferenceofhumanbetaherpesviruses6and7ingastrointestinalcancerdevelopment AT chapenkos possibleinterferenceofhumanbetaherpesviruses6and7ingastrointestinalcancerdevelopment AT doninas possibleinterferenceofhumanbetaherpesviruses6and7ingastrointestinalcancerdevelopment AT murovskam possibleinterferenceofhumanbetaherpesviruses6and7ingastrointestinalcancerdevelopment |
| first_indexed |
2025-07-10T21:06:46Z |
| last_indexed |
2025-07-10T21:06:46Z |
| _version_ |
1837295581412720640 |
| fulltext |
Experimental Oncology ��� ������ ���� ���ne���� ������ ���� ���ne� ���ne� ��
POSSIBLE INTERFERENCE OF HUMAN BETA-
HERPESVIRUSES-6 AND -7 IN GASTROINTESTINAL CANCER
DEVELOPMENT
A. Sultanova1,*, M. Chistjakovs1, S. Chapenko1, S. Donina1,2, M. Murovska1
1Riga Stradins University, August Kirchenstein Institute of Microbiology and Virology, Riga LV-1067, Latvia
2Riga Eastern Clinical University Hospital, Latvian Oncology Centre, Riga, LV-1079, Latvia
Aim: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies
the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors
in the development of gastrointestinal cancer. Methods: Sixty five patients with gastrointestinal cancer before surgery and without any
treatment were enrolled in this study and divided into two groups depending on lymphocytes’ count: I group (n = 35) — lymphocytes
> 1400x106/L and II group (n = 30) — lymphocytes < 1400x106/L. Nested polymerase chain reaction was used to detect latent and
active stage of persistent human herpesvirus-6 and -7 infection, laser flow cytometry with monoclonal antibodies — to determine
immunological parameters. Results: Activation of herpesvirus-6 and -7 was more frequently observed in the patients’ group with lym-
phopenia (HHV-6 1/1 (100%), HHV-7 4/8 (50%) and HHV-6 + HHV-7 6/9 (66%); p < 0.05). Cellular immune parameters were
analysed in immunocompromised II group’s patients dependently on beta-herpevirus infection. Although number of leukocytes was
higher in patients with active HHV-6/-7 infection (p = 0.01), number of lymphocytes CD3+, CD4+, CD8+ and CD38+ in patients
with active HHV-6/-7 infection tended to decrease (p < 0.0001, P = 0.0002, p = 0.0001 and p < 0.0001, respectively). However,
number of CD19+ had tendency to increase (p = 0.03). Conclusion: Activation of herpesvirus-6 and -7 may lead to decrease of lym-
phocytes total count and develop immunosuppression in patients with gastrointestinal cancer.
Key Words: beta-herpesvirus-6, beta-herpesvirus-7, gastrointestinal cancer.
Gastrointestinal cancer �GIC� �s�ally develops
from a benign polyp thro�gh an adenoma with dys-
plasia into a carcinoma with metastatic potential.
The late diagnosis of this disease often leads to the
high incidence of patients’ death. This signifies the
need for better diagnostic� prognostic and predictive
tools. The emergence of knowledge on the molec�lar
level has gained insight in ca�ses for initiation and
progression of t�mo�r development. This knowledge
has also revealed the complexity and heterogeneity
of the disease� explaining why only few biomarkers are
in ro�tine clinical �se. GIC is the second and third most
commonly diagnosed cancer in the world for women
and men� respectively. Approximately half of GIC pa-
tients develop metastatic disease [�].
H�man herpesvir�s-� �HHV-�� and h�man herpes-
vir�s-7 �HHV-7� are �biq�ito�s beta-herpesvir�ses [�].
Both are widely distrib�ted in the general pop�lation
and primary infection �s�ally occ�rs in the early years
of life and remains latent in the host for the lifelong
period [�]. These vir�ses can be reactivated in im-
m�nos�ppressed conditions and can lead to severe
complications in patients with solid organ transplan-
tation [4]. Malignancy also is associated with imm�-
nos�ppression in hematological t�mors and in solid
organ cancers as well.
HHV-� and HHV-7 share a high degree of genomic
homology and have some similar biological proper-
ties. Th�s� these herpesvir�ses might share a similar
oncogenic potential [�]. For both� HHV-� and HHV-7�
main target cells appeared to be CD4+ lymphocytes�
b�t nat�ral killer cells� CD8+ T cells� macrophages�
epithelial� endothelial� ne�ral cells and fibroblasts may
also be infected [�� 7].
HHV-� has imm�nomod�lating properties and
is a powerf�l ind�cer of cytokines. One important mecha-
nism of HHV-� pathogenesis is the engagement of the
primary viral receptor� CD4�� a complement-reg�latory
cell s�rface molec�le that provides a key link between
innate and adaptive imm�ne responses [8]. Recently
it was shown that expos�re to HHV-� res�lts in a dramatic
inhibition of IL-�� p7� prod�ction by differentiated h�man
macrophages in the absence of a prod�ctive viral infec-
tion� a phenomenon that is likely mediated by CD4� en-
gagement [�]. Other mechanisms of imm�ne dereg�la-
tion by HHV-� incl�de defective antigen presentation
by dendritic cells and aberrant cytokine prod�ction by pe-
ripheral blood monon�clear cells� s�ch as an increased
secretion of IL-�β� t�mor necrosis factor alpha �TNF-α��
and IL-�� and a decreased secretion of IL-� associated
with diminished cell�lar proliferation [�����]. Persistent�
IL-� reg�lated� HHV-� infection of ad�lt T-cell le�kemia
cells ca�ses T cell le�kemia to progress more rapidly� b�t
in vivo st�dies a pathogenic role for HHV-� in this disease
has not been yet confirmed [��]. Vir�s-ind�ced changes
in cytokines secretion can lead to changes in t�mor mi-
croenvironment and deviation of anti-t�mo�r imm�ne re-
sponse. HHV-� may also contrib�te to cancer circ�ito�sly
thro�gh imm�ne s�ppression. HHV-� can directly infect
CD4+ T-cells and ind�ce apoptosis� as an effective CD4+
T cells response is believed to prevent tolerance ind�ction
by t�mor antigen [�4���].
Received: October 16, 2012.
*Correspondence: E-mail: a.sultanova@inbox.lv
Abbreviations used: GIC — gastrointestinal cancer; HHV-6 — beta-
herpesvirus-6; HHV-7 — beta-herpesvirus-7; IL — interleukin;
nPCR — nested polymerase chain reaction; TNF-α — tumor necro-
sis factor alpha.
Exp Oncol ����
��� �� �����
�4 Experimental Oncology ��� ������ ���� ���ne�
Despite of HHV-7 and HHV-� similarities� important
differences between these vir�ses exist� incl�ding the
fact that HHV-7 binds to the cell�lar CD4+ molec�le
and �ses this protein as a necessary component of its
receptor� while HHV-� binds to a different receptor. F�r-
thermore� the pathogenesis and seq�elae of HHV-7 in-
fection remains very poorly �nderstood [�7].
MATERIALS AND METHODS
Patients �n = ��� with histologically confirmed
vario�s stages of gastrointestinal cancer �GIC� were
aged from �� to 8� years. The cohort was established
with the approval of the Ethics Committee of the Riga
Stradins University and all participants gave their in-
formed consent prior to the examination. Blood was
drawn before s�rgery and any antit�mor treatment�
patients were divided into two gro�ps depending
on lymphocyte co�nt: I gro�p �n = ��� — lymphocytes
> �4�� x���/L and II gro�p �n = ��� — lymphocytes <
�4�� x���/L. Imm�nological parameters were deter-
mined by Becton Dickinson �USA� laser flow cytofl�o-
rimeter �sing corresponding monoclonal antibodies
to lymphocyte s�bpop�lations: CD�+� CD4+� CD8+�
CD�8+� CD��+� CD��+� CD��+ and CD��+.
Nested polymerase chain reaction �nPCR� was �sed
for the detection of persistent infection �viral genomic
seq�ences in whole blood DNA� and active phase �viral
genomic seq�ences in cell free plasma DNA� of persis-
tent HHV-� and HHV-7 infection. Total DNA was isolated
from �.� ml of fresh whole blood by phenol-chloroform
extraction. For DNA p�rification from ��� µl of cell free
blood plasma QIAamp Blood Kit �QIAGEN� Germany� was
�sed. The plasma samples were treated with Deoxyribo-
n�clease I before DNA p�rification. To ass�re the q�ality
of the whole blood DNA as well as to excl�de contami-
nation of plasma DNA by cell�lar DNA� globin PCR was
performed. PCR amplification for the vir�ses was car-
ried o�t in the presence of � µg of whole blood DNA and
�� µl of plasma DNA �corresponding to ��� µl of plasma�.
The detection of HHV-� and HHV-7 DNA was performed
according to Secchiero et al. ������ and Berneman et al.
������� respectively. Positive �vir�ses genomic DNA�
ABI� USA� and negative �DNA witho�t vir�s-specific se-
q�ences� as well as water controls were incl�ded in each
experiment.
HHV-� variants were identified �sing restriction
endon�clease analysis. The restriction enzyme HindIII
�Fermentas� Lith�ania�� which c�ts the ���-bp HHV-�B
amplimer into two fragments of �� and �7 bp� b�t does
not c�t the HHV-�A amplimer was �sed for this p�rpose.
HHV-� specific antibody testing in the plasma
samples was carried o�t �sing HHV-� IgG ELISA
kit �Panbio� A�stralia� according to the man�fac-
t�rer’s recommendations.
H�man TNF-α� IL-�β� sIL �R: Solid-phase� two-site
chemil�miniscent imm�nometric assay �Imm�lite� SIE-
MENS� USA�. IL-�: solid-phase� enzyme-labeled chemi-
l�miniscent seq�ential imm�nometric assay �Imm�lite
SIEMENS� USA� according to the man�fact�rer’s rec-
ommendations. All samples were tested in d�plicates.
Statistical difference in the prevalence of latent
and active HHV-� and HHV-7 infection was as-
sessed by Fisher’s exact test. St�dent’s t-test was
�sed to compare significance in changes of plasma
cytokines’ levels and cell co�nts. For the prediction
of lymphopenia regression analysis was �sed.
RESULTS
Comparative analysis of cell�lar imm�ne pa-
rameters in both imm�nocompetent �lymphocytes
> �4��x���/L� and imm�nocompromised �lympho-
cytes < �4��x���/L� GIC patients gro�ps showed sig-
nificant differences in almost all rates independently
of beta-herpesvir�ses infection. The mean absol�te
n�mber of lymphocytes in the I gro�p was two times
���%� higher than in the II gro�p ���7� ± 7��x���/L;
��4� ± ��� x ���/L� respectively; p = �.����� �Table ��.
However� the mean n�mber of le�kocytes in the II gro�p
�7��� ± ���� ���/L� was significantly �p = �.���� higher
��7%� than in the I gro�p ��8�� ± ����x���/L�. Com-
parative analyses of the lymphocyte s�bsets between
the I and II gro�p �CD�+� CD4+� CD8+� CD�8+� CD��+�
CD��+� CD��+ and CD��+� showed significant de-
crease of imm�nological parameters in the II gro�p —
approximately two times decrease in comparison with
the I gro�p �Table ��.
Table 1. Immunological parameters in the I and II patients groups
Parametrs
Group I Ly > 1400 (n=35) Group II Ly < 1400 (n=30)
p ≤ 0.05Absolute
count ± SD Count, % Absolute
count ± SD Count, %
Leu 7910 ± 1960 5830 ± 2210 0.002
Mo 650 ± 170 8.44 440 ± 220 7.87 0.0005
Ly 2270 ± 700 28.83 1140 ± 210 19.88 0.0001
CD3+ 1600 ± 580 70.77 780 ± 180 70.77 0.0001
CD4+ 880 ± 330 39.29 450 ± 130 39.0 0.0001
CD8+ 680 ± 370 29.11 330 ± 120 31.08 0.0001
CD38+ 660 ± 300 29.03 320 ± 90 28.4 0.0001
CD16+ 460 ± 310 19.69 220 ± 130 19.4 0.0015
CD19+ 190 ± 110 8.03 110 ± 60 7.0 0.0018
CD95+ 1130 ± 370 50.89 520 ± 130 48.8 0.0001
CD25+ 180 ± 150 8.63 80 ± 50 7.5 0.047
CD4+/
CD8+
1.58 ± 0.85 1.18 ± 0.57 0.03
Virological st�dies showed that 44 o�t of �� ��8%�
GIC patients had persistent beta-herpesvir�ses
infection. HHV-� genomic seq�ence was detected
in ��/�� ���%�� when presence of anti-HHV-� specific
IgG class antibodies was detected in ��/�� ���%�
patients. HHV-7 genomic seq�ence was fo�nd
in 4�/�� ���%� patients DNA. Freq�ency of single
HHV-7 persistent infection was significantly higher
�p = �.���� in the I gro�p ��/�� ��7%� than in the
II gro�p 8/�� ��7%�� when do�ble �HHV-� + HHV-
7� persistent infection was significantly �p = �.�4��
higher in the II gro�p �/�� ���%� than in the I gro�p
4/�� ���%�. However� single HHV-� persistent infec-
tion was detected only in one I gro�p’s patient and
in two patients of the II gro�p �Table ��. Nonetheless�
HHV-7 genomic seq�ence was fo�nd only in � o�t
of �� ���%� plasma DNA samples of CIG patients of the
I gro�p. In contrast� activation of HHV-7 was fo�nd
in 4 o�t of 8 ���%� patients of the II gro�p. F�rther-
more� sim�ltaneo�s activation of both vir�ses �HHV-� +
HHV-7� was significantly more often detected in the
Experimental Oncology ��� ������ ���� ���ne���� ������ ���� ���ne� ���ne� ��
II gro�p’s patients ��/� ���%�; p < �.��� �Table ��.
In all HHV-� positive DNA samples isolated from GIC
patients’ white blood cells and plasma HHV-�B variant
was identified.
Table 2. Distribution of latent and active beta-herpesviruses (HHV-6 and
HHV-7) infection
HHV-6 la-
tent/active
infection
HHV-7 la-
tent/active
infection
HHV-6 +
HHV-7 la-
tent/active
infection
Without
HHV-6 or
HHV-7 in-
fection
I patients group (n = 35) 1/0 17/3 4/0 10
II patients group (n = 30) 1/1 4/4 3/6 11
Comparative analysis of cell�lar imm�ne parame-
ters in the I and II gro�p was performed dependently
of beta-herpevir�ses infection. Each gro�p was s�b-
divided into three s�bgro�ps: GIC patients witho�t�
with latent and with active HHV-� and/or HHV-7 infec-
tion. In the I gro�p patients with active viral infection
had tendency to increase all cell�lar imm�nological
parameters �le�kocytes� monocytes� lymphocytes
and CD�+� CD4+� CD8+� CD�8+� CD��+� CD��+� CD��+�
CD��+� comparing with the s�bgro�ps with latent and
witho�t HHV-� and HHV-7 infection. Altho�gh n�mber
of le�kocytes in the II gro�p with active HHV-�/-7 in-
fection was higher than in other s�bgro�ps� n�mber
of lymphocytes� CD�+� CD4+� CD8+ and CD�8+ cells
had tendency to decrease. However� n�mber of CD��+
cells had tendency to increase �Table ��. The logistic
regression analysis showed that patients with active
viral infection have higher risk of lymphopenia �OR �.���
��% CI �.7����.��; p = �.����� than patients with latent
viral infection �OR �.��� ��% CI �.����.�7; p = �.�����.
There were no significant changes in the ser�m
levels of IL-�� IL-�β� sIL-�R and TNF-α between GIC
patients of the I and II gro�p. However� in the I and
II gro�p of patients with active viral infection the levels
of IL-� and sIL-�R had tendency to increase� none-
theless� level of TNF-α in the II gro�p was lower than
in patients with latent and witho�t viral infection� and
also lower in comparison to the I gro�p’s patients with
active viral infection �Table 4�.
DISCUSSION
At the moment there is little information abo�t in-
fl�ence of beta-herpesvir�ses infection on the co�rse
of disease in patients with GIC. Gastrointestinal malig-
nancies are associated with a compromised imm�ne
system and vir�ses� s�ch as imm�notropic and imm�-
nomod�lating HHV-� and HHV-7 may be able to �tilize
cell�lar mechanisms responsible for the imm�ne
response inhibition. Mod�lation of f�nctional proper-
ties of host imm�ne factors is an important mechanism
of evading the imm�ne response or creating an envi-
ronment in which the vir�s can s�rvive. O�r res�lts have
shown that in GIC patients gro�p with lymphopenia the
activation of HHV-� and HHV-7 infection is significantly
more freq�ent �p = �.����. In all HHV-� positive pa-
tients HHV-�B variant was detected. This corresponds
with the data demonstrated by Lempinen et al. [�8].
Proportionally balance of lymphocytes s�bpop�lations
in both gro�ps was identical� however� lymphopenia
was observed in the II gro�p’s patients� which co�ld
be closely related with the higher rate of activation
of beta-herpesvir�s infection. S�ch interaction co�ld
lead to the worst o�tcomes. However� absol�te co�nt
of le�kocytes in the II gro�p patients with active viral
infection increases� preferable beta-herpesvir�s
cell target pop�lations are decreased �lymphocytes
absol�te co�nt and CD�+� CD8+ and CD�8+ s�bpop�-
lations�. S�ch difference in cell pop�lations co�ld
be another evidence of HHV-� and HHV-7 involve-
ment in this disease progression. Another interesting
observation is noticed in nat�ral killers’ pop�lation
�CD��+�� which do not increase even in patients with
active viral infection. This abnormal anti-viral response
co�ld lead to worse progression of co-infections and
worst o�tcomes in GIC patients.
There are no significant changes observed in ser�m
levels of IL-�� IL-�β� sIL-�R and TNF-α between GIC
patients of the I and II gro�ps with latent and witho�t
HHV-�/-7 infection� b�t in the II gro�p’s patients
with active viral infection level of TNF-α is decreased
comparing to the other gro�ps. However� it was hard
Table 3. Average count of immunocompetent cells in the I group and II group patients
Para metrs Without HHV-6/-7 p HHV-6/-7 latent p HHV-6/-7 active pGroup I (n = 10) Group II (n = 11) Group I (n = 22) Group II (n = 8) Group I (n = 3) Group II (n = 11)
Leu 7670 ± 1610 5420 ± 2480 0.02 7720 ± 2050 5800 ± 2090 0.03 10030 ± 1420 6310 ± 2110 0.01
Mo 650 ± 130 490 ± 290 0.0007 610 ± 140 320 ± 50 < 0.0001 930 ± 280 420 ± 190 0.003
Ly 2260 ± 870 1130 ± 230 0.0005 2110 ± 490 1230 ± 60 < 0.0001 3400 ± 420 1070 ± 250 < 0.0001
CD3+ 1580 ± 790 770 ± 140 0.003 1490 ± 360 870 ± 110 0.0001 2500 ± 270 730 ± 240 < 0.0001
CD4+ 890 ± 450 420 ± 120 0.003 850 ± 280 500 ± 50 0.002 1110 ± 240 440 ± 180 0.0002
CD8+ 670 ± 520 340 ± 90 0.052 600 ± 180 370 ± 120 0.002 1190 ± 470 290 ± 130 0.0001
CD38+ 680 ± 320 330 ± 140 0.004 630 ± 300 310 ± 40 0.006 780 ± 160 300 ± 50 < 0.0001
CD16+ 490 ± 330 250 ± 180 0.04 410 ± 320 210 ± 70 0.1 650 ± 190 210 ± 90 0.0001
CD19+ 180 ± 90 80 ± 50 0.004 170 ± 70 110 ± 50 0.04 350 ± 280 130 ± 80 0.03
CD95+ 1170 ± 460 500 ± 100 0.0001 1040 ± 230 570 ± 160 0.0002 1620 ± 230 510 ± 150 < 0.0001
CD25+ 170 ± 100 110 ± 60 0.11 180 ± 180 50 ± 30 0.05 220 ± 90 80 ± 40 0.001
CD4+/CD8+ 1.68 ± 0.85 1.24 ± 0.49 0.16 1.55 ± 0.9 1.31 ± 0.49 0.5 1.37 ± 0.56 1.29 ± 0.65 0.8
Table 4. Levels of IL-1β, IL-6, sIL2R and TNF-α in the I and II group patients*
Patients groups IL-1β (pg/ml); N < 5.0 IL-6 (U/ml); N = 3.4 sIL2R (U/ml); N = 223–710 TNF-α (pg/ml); N = 8.1
Group I (n = 10) Without HHV-6/-7 < 5.0 4.08 ± 1.23 527 ± 159.58 15.13 ± 5.15
Group II (n = 11) Without HHV-6/-7 < 5.0 5.15 ± 2.76 559.80 ± 379.10 15.58 ± 5.66
Group I (n = 22) HHV-6/-7 latent < 5.0 5.44 ± 2.99 604.78 ± 242.33 11.62 ± 1.08
Group II (n = 8) HHV-6/-7 latent < 5.0 5.55 ± 1.91 617.00 ± 173.20 13.83 ± 3.06
Group I (n = 3) HHV-6/-7 active infection < 5.0 7.20 ± 11.88 851 ± 528.55 14.40 ± 5.31
Group II (n = 11) HHV-6/-7 active infection < 5.0 6.18 ± 2.91 733.67 ± 388.76 9.78 ± 4.23
*p > 0.05 for all groups.
�� Experimental Oncology ��� ������ ���� ���ne�
to compare GIC patients with active viral infection
beca�se of higher HHV-� and HHV-7 distrib�tion
in the II gro�p and low presence of active infection
in the I gro�p. Despite of this observation� it is pos-
sible to s�ppose important role of beta-herpesvir�ses
in GIC development and decreased level of TNF-α and
increased levels of IL-� and sIL�R in patients with
active and persistent vir�s infection co�ld confirm
HHV-� and HHV-7 imm�nomod�lating properties.
Both facts� decrease in lymphocytes’ s�bpop�lations
and changes in levels of interle�kins� co�ld show
possible mechanisms of how HHV-� and HHV-7 in-
fl�ence the co�rse of the disease. First mechanism
is direct infl�ence on lymphocytes by infecting them
and ind�cing cell lyses� and second — infl�ence
thro�gh changes in interle�kins expression. Com-
bining st�dies of both vir�s and cancer mediated
imm�ne s�ppressive mechanisms will help �s to �n-
derstand the complicated host-t�mo�r interactions.
The f�rther investigation is important to eval�ate not
only changes in pro-inflammatory cytokines b�t also
in anti-inflammatory cytokines expression in patients
with GIC. It co�ld explain ways of vir�s infl�ence on the
co�rse of disease and wo�ld help to choose the most
efficient treatment tactic.
In concl�sion� activation of HHV-� and HHV-7 may
lead to decrease of lymphocytes’ total co�nt and wors-
ening of imm�ns�ppresion in patients with GIC. High
freq�ency of beta-herpesvir�ses infection in patients
with GIC is contrib�ting into increase of IL-�� sIL-�R
and decrease of TNF-α expression levels what co�ld
lead to the worse clinical o�tcomes. Estimation of the
vir�ses-associated impairment of imm�nological f�nc-
tions may be �sef�l for clinical application to monitor-
ing of GIC patients.
ACKNOWLEDGEMENTS
This work was s�pported partly by the National
Research Program in Medicine� “M�lti-Disciplinary
Research Consorti�m on Major Pathologies Threaten-
ing the Life Expectancy and Q�ality of life of Latvian
Pop�lation” project № ��.
CONFLICT OF INTEREST
None of the a�thors of the above man�script has
declared any conflict of interest.
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