Toll-like receptor 4 polymorphism influence on the development of opportunistic diseases
description
Transcript of Toll-like receptor 4 polymorphism influence on the development of opportunistic diseases
Institutes:Ukrainian Medical and Dental Academy,
Regional HIV/AIDS Prevention and Control Center, Poltava Ukraine
Toll-like receptor 4 polymorphism influence on the development of opportunistic diseases
in HIV-infected patients
The presenting author is Tetiana Kyrychenko
Authors: G. Dubynska, T.Koval, I.Kaidashev, V.Korshenko
Ukraine
11,0 12,514,8
17,3 18,0
28,3
34,237,8
40,943,2 44,7 46,6
0,0
5,0
10,0
15,0
20,0
25,0
30,0
35,0
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2000. 2001. 2002. 2003. 2004. 2005. 2006. 2007. 2008. 2009. 2010. 2011.
Ukraine has one of the fastest growing HIV/AIDS
epidemics in the world and the
highest in all of Europe. Late 2011 Ukraine
numbered 210,000 HIV-positive persons.
Dynamics of officially registered new cases of HIV-infection in Ukraine (on 100 thousand population)
Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these
receptors have been associated with increased or decreased susceptibility to infections.
Objectives:
to study the prevalence of TLR4 Asp299Gly SNP among the healthy and HIV-positive persons in Ukraine;
to find out HIV clinical manifestations depending on TLR4 genotype variants.
Asp299Gly, A>G
chromosome 9q32–33
Methods Patients. The study included 180
antiretroviral treatment-naive HIV-1 infected patients.
The stage of the disease was recorded in accordance with the expanded European AIDS case definition.
Laboratory procedures. Routine CD-4 cell count was determined
using conventional flow cytometry with fresh blood samples from all patients.
Plasma HIV-RNA was also routinely measured by the polymerase chain reaction (PCR) (Real time HIV-1, Abbout).
TLR4 genotyping was performed by real-time PCR using oligonucleotide primers (Tercik PCR system, DNA-technology, Moscow)
Characteristic of a Cohort of 180 patients infected with HIV-1 and studied in Relation to
SNP of TLR4 Characteristic Wild type
(AA, n=165)
Asp299Gly heterozygous
(AG, n=15)Male-to-female ratio 98:67 10:5
Ageª, mean years± standard deviation
35,21±0,51 35,13±1,33
Nadir CD-4 cell countª, mean cell/mm³± standard deviation
259,52±16,2 233,6±30,38
Maximum viral loadª, median copies/mL
249826 152671
Clinical stage(%)ABC
11 (6,6)72 (43,7)82 (49,7)
2(13,3)2(13,3)11(73,4)
History of opportunistic infections in 180 HIV-infected patients
1%1%1%
4%
14%18%
20%25%
27%28%
33%
51%
48%
9%
0% 10% 20% 30% 40% 50% 60%
Progressive multifocal leukoencephalopathy
Kaposi sarcoma
Pneumocystis jiroveci
Cytomegalovirus disease
Toxoplasmosis of brain
TB extra pulmonary
Herpes simplex: chronic ulcers
Herpes zoster
Tuberculosis pulmonary
Wasting syndrome caused by HIV
Bacterial pneumonia
Hairy leukoplakia, oral
Candidiasis
Chronic hepatitis C
History of opportunistic infections in 180 HIV-infected patients in relation to SNP of the Toll-like receptor 4 gene
(No. (%) of patients)
Variable Wild type (AA,n=165)
Asp299Gly heterozygous
(AG, n=15)
p
Mycobacterium tuberculosis, pulmonary or extrapulm.
59 (35.7) 11 (73.3) 0.007*
Bacterial pneumonia, recurrent
42 (25.5) 8 (53.3) 0.021*
Hairy leukoplakia, oral
51 (30.9) 9 (60) 0.022*
Herpes zoster (shingles), involving two or more episodes or at least one dermatome
29 (17.6) 7 (46.7) 0.007*
*AG compared to AA, Mann-Whitney U-test
History of opportunistic infections in 180 HIV-infected patients in relation to SNP of the Toll-like receptor 4 gene
(No. (%) of patients)
Variable Wild type (AA,n=165)
Asp299Gly heterozygous
(AG, n=15)
p
Chronic hepatitis C 80 (48.5) 12 (80) 0.018*Candidiasis, oropharyngeal or esophageal
78 (47.3) 8 (53.3) >0.05
Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) associated with either chronic diarrhea or chronic weakness and documented fever for ≥1 month)
42 (25.5) 6 (40) >0.05
Herpes simplex: chronic ulcers (>1 month in duration)
28 (17) 5 (33.3) >0.05
Any 19 (11.5) 3 (20) >0.05
*AG compared to AA, Mann-Whitney U-test
Distribution of the 299 alleles of the patients when they were grouped by CD-4 T-cell counts equal to or above and below
350, 200 100
cells/mm³, respectively
*Only patients with CD4 T-cell counts above 200cells/mm³ had the prevalence of the Asp299Gly polymorphism (12%) significantly higher than patients with CD4 T-cell counts below than 200 cells/mm³ (3.7%), p<0.05
133
1232
30
20
40
60
80
100
120
140N
umbe
r of i
ndiv
idua
ls
≤350 >350
CD4 T cell/mm
AAAG
77
3
88
12*
0102030405060708090
Num
ber o
f ind
ivid
uals
≤200 >200
CD4 T cells/mm
AAAG
312
134
13
020406080
100120140
Num
ber o
f in
divi
dual
s
≤100 >100CD-4 T cells/mm
AAAG
Detection of opportunistic infections in HIV-infected patients with different levels of CD4
(No. (%) of patients)CD-4 T-cell counts /mm³
<100 101-349 >350
TLR-4 genotype
AA,n=31
AG, n=3
AA,n=102
AG, n=9
AA,n=32
AG, n=3
Tuberculosis 20(64.5) 3(100) 34(33.3) 6(66.7)* 5(15.6) 2(66.7)*
Toxoplasmosis 12(38.8) 3(100)* 0(0) 1(11.1)* 0 0
Herpes zoster 2(6.5) 1(33.3) 24(23.6) 5(55.6)* 3(9.3) 1(33.3)
Pneumonia 10(32.3) 1(33.3) 22(21.6) 5(55.6)* 10(31) 2(66.7)
*AG compared to AA, X²-test, p<0.05
Conclusions This study suggests a grater risk for
development of active tuberculosis, bacterial pneumonia, herpes zoster, hairy leukoplakia, toxoplasmosis of brain, chronic hepatitis C in patients with the Asp299Gly TLR4 polymorphism
our results demonstrate the impact of a TLR4 genetic polymorphism on development of opportunistic infections for CD4 levels more than 100.
Acknowledgments G.Dubynska, prof., department of
infectious diseases, Ukrainian Medical and Dental Academy, Poltava, Ukraine
T.Koval, prof., department of infectious diseases, Ukrainian Medical and Dental Academy, Poltava, Ukraine
I. Kajdashev, prof., chair of research department, Ukrainian Medical and Dental Academy, Poltava, Ukraine
V.Korshenko, chief doctor of Regional centre of HIV/AIDS Poltava, Ukraine