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Keywords:

  • AIDS;
  • disease association;
  • HIV-1;
  • HLA profile

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

HIV/AIDS is currently the leading cause of infectious disease mortality around the world. Since many alleles and/or haplotypes of HLA have been reported to be associated with progressive HIV infection, more detailed information on the HLA profile in HIV-1 infected individuals in Chongqing, southwest China would facilitate further understanding of HIV-1 infection, help AIDS vaccine design and the planning of effective preventive strategies. In this study, we performed 4-digit resolution HLA-A, B, DRB1 genotyping of 759 HIV-1 seropositive individuals using PCR-SSO methods. Six alleles were found at more than 10% high frequency: A*1101, A*0201, A*2402, B*4601, B*4001 and DRB1*0901. The most common 2- and 3-locus haplotypes were A*0201-B*4601, A*1101-B*4001, A*1101-B*4601, A*3303/1-B*5801, A*0201-B*4601-DRB1*0901, A*1101-B*4601-DRB1*0901 and A*3303/1-B*5801-DRB1*0301.

690 HIV-1 seropositive individuals with records of CD4 counts were divided into two groups: an AIDS patient group comprising 216 subjects with AIDS-defining symptoms and CD4 counts below 200 cells/mm3 and an asymptomatic, HIV seropositive group of 474 subjects with a stable CD4 count of no less than 200 individuals. In the AIDS patient group, A*3303/1 and B*5801 alleles and the A*3303/1-B*5801 haplotype were significantly underrepresented as compared to the HIV-infected group, whereas A*1101-B*4001, A*1101-B*1502, A*2402-B*4801 haplotypes and five common haplotypes from two groups were significantly overrepresented. HLA-A or B and HLA-Bw6-Bw6 homozygotes were also overrepresented in the AIDS patients group. Our observations suggest that the presence of the B*3501 allele, A*2402-B*4801, common 2-locus and 3-locus haplotypes, HLA-A or B and Bw6-Bw6 homozygosity may predict a poor disease outcome in HIV-1 infection. However, HIV-1 infected individuals who have B*5801 alleles, A*3303/1-B*5801 haplotype and are heterozygous for Bw4-Bw6 are more likely to be resistant to progression of AIDS in this Chinese population.

List of Abbreviations: 
CI

confidence interval

CTL

cytotoxic T-lymphocyte

EM

expectation maximization

HLA

human leukocyte antigen

NK

natural killer

OR

odds ratio

SSO

sequence-specific oligonucleotide(s)

Since the beginning of the AIDS epidemic in the 1980s, 25 million people have died of HIV-related causes worldwide (1). Globally, the annual number of new HIV infections has declined from 3.0 million (2.6–3.5 million) in 2001 to 2.7 million (2.2 –3.2 million) in 2007 (1). However developing countries such as China have been facing many challenges in attempting to prevent a nation-wide AIDS epidemic. Chongqing, located in southwest China, has a population of more than 31 million and is confronting the threat of AIDS with more than 1000 newly confirmed HIV-1 positive cases in each of the last three years, accounting for 84% of its accumulated cases. Two hundred and seventy-seven of these have been diagnosed as AIDS patients. The prevalent HIV-1 subtype in Chongqing has been classified as CRF07_BC.

HLA class I and II loci are the most polymorphic genes known in humans. HLA class I genes, located at the HLA-A, -B, and -C loci, initiate specific CTL responses. HLA class II loci, HLA-DR, -DQ, and -DP, account for cytokine production and T cell assistance with antibody production. It has been demonstrated that HLA class I, with a dominant HIV-1 subtype B, has associations with AIDS survival and HIV-1 viremia in Caucasian populations in North America, Europe and Australia (2). Studies from Caucasoids and Africans have indicated that HLA-B27 and HLA-B57 are associated with a slow progression to AIDS, while HLA-B35 is associated with rapid disease progression (3–7). Recently, it was reported that in south India HLA-A11 is associated with resistance, and B40 and DR2 with susceptibility, to HIV-1 infection (8). For HLA class II antigens, DRB1 is the most polymorphic locus among class II genes and forms haplotypes with DRB3, DRB4 and DRB5. The role of DRB alleles/haplotypes on resistance/susceptibility to HIV-1 infection remains elusive. In a study of 1090 Pumwani sex workers, it was demonstrated that three DRB1 alleles were associated with resistance, another seven alleles with susceptibility, and that certain haplotypes were associated with resistance/susceptibility to HIV-1 infection (9). These findings provide additional support for the contention that HLA-DRB-specific CD4+ T-cell responses are important in resistance to HIV-1 infection.

In this study, in order to explore potential host genetic factors involved in the pathogenesis of HIV-1 infection, the distribution of HLA-A, B, DRB1 genes in HIV-1 seropositive individuals was investigated, and the frequencies of various HLA alleles and haplotypes between an AIDS patient group and an HIV-1 infected group from Chongqing, China were compared. These data contribute to the database of HLA alleles/haplotypes from different ethnic populations, and their association with disease outcomes of HIV-1 infection.

MATERIALS AND METHODS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Study subjects

Study subjects comprised HIV-1 infected individuals enrolled at the Chongqing Center for Disease Control and Prevention in Chongqing, China from 2002 to 2007. Their serostatuses were tested with commercial ELISA kits (BioMerieux, Boxtel, the Netherlands) and confirmed by Western blot assay (HIV BLOT 2.2, MP Diagnostics, Singapore Science Park, Singapore). A total of 690 HIV-1 seropositive individuals were classified into two groups for an observational study on the correlation of HLA and HIV/AIDS with the outcome of HIV-1 infection. Two hundred and sixteen HIV-1 seropositive individuals with AIDS-defining symptoms and CD4 T-cell counts below 200 cells/mm3 were defined as AIDS patients, according to the 1993 Centers for Disease Control and Prevention (CDC) guidelines. Four hundred and seventy-four individuals who were HIV-1 seropositive, with a stable CD4+ count of no less than 200 on two to three separate tests during one year of follow-up, and who were free of clinical symptoms in the absence of any antiretroviral therapy, were defined as HIV-1 infected. Individuals whose CD4+ T-cell counts had not been checked were excluded from the comparisons between AIDS patients and the HIV-1 infected individuals. This study was approved by the Institutional Review board of Chongqing Center for Disease Control and Prevention and informed consent was obtained from all subjects.

HLA genotyping

DNA was extracted from whole blood using the TIANamp Blood DNA Kit (Tiangen Biotech, Beijing, China). All DNA samples were dissolved in hydration solution and stored at −20°C before HLA typing. HLA class I and class II genotyping was performed using the LABType SSO Typing Test (Lambda Array Beads Multi-Analyte System, One Lambda, Canoga Park, CA, USA) and Lifematch HLA-SSO Typing Kits (Tepnel lifecodes, Tepnal Lifecodes Corporation, Stamford, CT, USA). Genotyping of mediate-resolution HLA (A, B, DRB1) was performed using SSO to identify which HLA alleles were present in a PCR amplified sample. Four-digit resolution genotyping of HLA-A, B and DRB1 alleles was obtained according to the manufacturer's instructions.

Statistical analysis

Allele and haplotype frequencies were analyzed and estimated by means of the EM algorithm using Arlequin ver.2.000 software (10). The configuration and frequencies of multilocus haplotypes under an unknown gametic phase were estimated. Exact tests of the Hardy-Weinberg equilibrium locus by locus and linkage disequilibrium between all pairs of loci were performed. To compare allele and haplotype distribution between AIDS patients and HIV-1 infected group with Epi Info 2002, the P value was obtained by the χ2 test with Yates correction or by Fisher's exact test (2-tailed) if the expected value of the 2 × 2 table was <5. The strength of an association, calculated with Epi Info, was indicated by an OR with a 95% CI, and P < 0.05 was accepted as a significant difference. To identify their independent and potential association with susceptibility or resistance to HIV-1 infection, a binary logistic regression analysis with multivariate comparisons was applied to all alleles and other host factors using SPSS14.0.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Basic information for HIV-1 seropositive individuals from Chongqing, China

The basic data for all participants- HIV-1 seropositive individuals (n= 759), AIDS patients (n= 216) and HIV-1 infected individuals (n= 474) are shown and compared in Table 1. A total of 759 individuals were screened for entry into the study, including 595 male (78.4%) and 164 female subjects (21.6%). Most of them were 18–49 years old (89.2%), nearly half of them were 30–39 years old (43.2%). Among the 759 HIV-1 seropositive individuals, 48.5% had been infected via heterosexual transmission, 31.2% were users of injection drug, 14.0% had been infected via homosexual transmission and 2.2% via blood transfusion; the transmission route for the rest remains unknown. After excluding individuals without CD4 T-cell counts, 216 subjects were classified as AIDS patients, and another 474 as HIV-1 infected individuals. Basic information such as gender, age and transmission routes was compared between the AIDS patient and HIV-1 infected groups. Significant differences between the two groups were observed with respect to age and gender. However, within stratified age groups, significant differences between AIDS patients and HIV-1 infected individuals were observed only in the 18–29 and 50–59 age groups. There were fewer AIDS patients in the 18–29 age group (12.5% vs. 25.7%, P= 0.0001), while there were more from the HIV-1 infected group in the 50–59 age group (11.6% vs. 5.1%, P= 0.0034). When stratified by transmission routes, there were no significant differences between the two groups. CD4+ T cell counts differed significantly between AIDS patients and HIV-1 infected individuals (108.25 ± 59.97 vs. 409.40 ± 165.95 cells/mm3, P < 0.0001).

Table 1.  Baseline characteristics of the research subjects
 HIV-1 seropositive (n= 759)AIDS patients (n= 216)HIV-1 infected individuals (n= 474)
  1. n” indicates the number of people. The percentage is indicated in parentheses.

  2. *: indicates P < 0.05

  3. **: indicates P < 0.01

  4. ***: indicates P < 0.001

Sex
 Male*595 (78.4)154 (71.3)373 (78.7)
 Female*164 (21.6)62 (28.7)101 (21.3)
Age (years)
 Age: 18–29***162 (21.3)27 (12.5)122 (25.7)
 Age: 30–39328 (43.2)97 (44.9)203 (42.8)
 Age: 40–49187 (24.6)57 (26.4)111 (23.4)
 Age: 50–59**55 (7.2)25 (11.6)24 (5.1)
 Age: >6027 (3.6)10 (4.6)14 (3.0)
Transmission route
 Heterosexual contact368 (48.5)126 (58.3)236 (49.8)
 Injection drug user237 (31.2)60 (27.8)164 (34.6)
 Homosexual contact106 (14.0)14 (6.5)43 (9.1)
 Blood transfusion17 (2.2)6 (2.8)10 (2.1)
 Unknown31 (4.1)10 (4.6)21 (4.4)
 CD4+ T cells (mm3)*** 108.25 ± 59.97409.40 ± 165.95

Distribution of HLA-A, B and DRB1 alleles, 2-locus and 3-locus haplotypes in HIV-1 seropositive individuals from Chongqing, China

From the 759 HIV-1 seropositive individuals of Chongqing, China, a total of 22 HLA-A, 61 HLA-B and 38 HLA-DRB alleles (Table 2) were identified. Of the 22 HLA-A alleles detected, limited allelic diversity was demonstrated, since three alleles, A*1101, A*0201 and A*2402 (at overall frequencies of 32.61%, 24.70% and 17.06%, respectively) accounted for over 74% of all HLA-A alleles among these HIV-1 seropositive individuals. As in many other ethnic groups, HLA-B was extremely diverse, a total of 61 alleles being identified in these subjects. Six B alleles (in order of frequency, B*4601, B*4001, B*1301, B*5801, B*1502 and B*1501) were detected at a frequency of greater than 4%, comprising nearly 60% of the total. Meanwhile, 17 different alleles were identified for the B*15 locus, accounting for 14% of the total alleles in these subjects. Of the 38 HLA-DRB1 alleles detected in this population, 6 were detected at a frequency of greater than 6%, the most frequently observed allele was DRB1*0901 (20.03%), followed by DRB1*1501 (9.88%), DRB1*1202 (9.42%), DRB1*0803 (8.24%), DRB1*1101 (6.72%), DRB1*1401 (6.52%), resulting in over 60% of the total for HLA-DRB1 in these subjects. However, the HLA-A, B and DRB1 allele frequencies observed in this cohort did not deviate significantly from the Hardy-Weinberg equilibrium.

Table 2.  Frequencies of HLA-A, B and DRB1 alleles in HIV-1 seropositive individuals from Chongqing, China
HLA-AFrequency (2n= 1518)HLA-BFrequency (2n= 1518)HLA-BFrequency (2n= 1518)HLA-DRB1Frequency (2n= 1518)
  1. “2n” indicates the number of chromosomes as each person has two chromosomes containing each gene.

  2. †Methods used in this study do not allow differentiation between A*3303 and A*3301.

A*01010.0237B*07020.0066B*37010.0158DRB1*01010.0119
A*02010.2470B*07050.0033B*38010.0020DRB1*01020.0007
A*02030.0455B*08010.0020B*38020.0277DRB1*03010.0455
A*02050.0007B*13010.0758B*39010.0178DRB1*04010.0073
A*02060.0204B*13020.0145B*39050.0026DRB1*04030.0296
A*03010.0086B*14020.0007B*39150.0007DRB1*04040.0026
A*11010.3261B*15010.0435B*40010.1397DRB1*04050.0448
A*11020.0007B*15020.0474B*40020.0165DRB1*04060.0132
A*11030.0007B*15050.0020B*40030.0033DRB1*04070.0026
A*24020.1706B*15070.0026B*40060.0198DRB1*04110.0007
A*24030.0033B*15080.0007B*44020.0033DRB1*07010.0329
A*24040.0007B*15100.0007B*44030.0132DRB1*08020.0020
A*24070.0020B*15110.0132B*46010.2088DRB1*08030.0824
A*26010.0270B*15120.0059B*48010.0079DRB1*08090.0020
A*26030.0007B*15150.0007B*48030.0033DRB1*09010.2003
A*29010.0059B*15170.0020B*50010.0020DRB1*10010.0178
A*30010.0171B*15180.0033B*51010.0395DRB1*11010.0672
A*31010.0204B*15250.0073B*51020.0086DRB1*11030.0007
A*32010.0046B*15270.0059B*51080.0007DRB1*11040.0013
A*3303/1†0.0698B*15320.0046B*52010.0211DRB1*11060.0007
A*68010.0040B*15460.0007B*54010.0343DRB1*12010.0224
A*74010.0007B*15530.0007B*55010.0020DRB1*12020.0942
 B*15580.0020B*55020.0376DRB1*13010.0086
 B*18010.0020B*55040.0007DRB1*13020.0185
 B*27020.0007B*55070.0007DRB1*13120.0237
 B*27030.0013B*56010.0079DRB1*14010.0652
 B*27040.0066B*56020.0007DRB1*14020.0026
 B*27070.0026B*57010.0046DRB1*14030.0033
 B*35010.0257B*58010.0606DRB1*14040.0033
 B*35030.0046B*67010.0059DRB1*14050.0198
 B*35050.0020  DRB1*14100.0007
     DRB1*14180.0059
     DRB1*14250.0007
     DRB1*15010.0988
     DRB1*15020.0165
     DRB1*15040.0040
     DRB1*16010.0033
     DRB1*16020.0428

The top 20 haplotypes in the 759 subjects, including 2-locus HLA-A-B haplotypes and 3-locus HLA-A-B-DRB1 haplotypes, are shown in Table 3. The listed HLA-A-B haplotypes accounted for 60% of the total, with the most common 2-locus haplotypes; A*0201-B*4601 (13.66%), A*1101-B*4001 (6.08%), A*1101-B*4601 (4.77%), A*3303/1-B*5801 (4.77%); accounting for almost 30% of the total 2-locus haplotypes in these subjects. For the HLA-A, B and DRB1 3-locus haplotypes, A*0201-B*4601-DRB1*0901 (6.53%) was the greatest in frequency, followed by A*1101-B*4601-DRB1*0901 (2.94%), A*3303/1-B*5801-DRB1*0301 (2.70%), A*0201-B*4601-DRB1*0803 (2.39%) and A*0201-B*4601-DRB1*1401 (2.31%).

Table 3.  Frequencies of HLA-A-B and HLA-A-B-DRB1 haplotypes in HIV-1 seropositive individuals from Chongqing, China
HLA-A-B HaplotypeFrequency (2n= 1518)HLA-A-B-DRB1 HaplotypeFrequency (2n= 1518)
  1. Only the top 20 most common haplotypes are listed individually. “2n” indicates the number of chromosomes as each person has two chromosomes containing each gene.

  2. †Methods used in this study do not allow differentiation between A*3303 and A*3301.

A*0201 B*46010.1366A*0201B*4601DRB1*09010.0653
A*1101 B*40010.0608A*1101B*4601DRB1*09010.0294
A*1101 B*46010.0477A*3303/1†B*5801DRB1*03010.0270
A*3303/1† B*58010.0477A*0201B*4601DRB1*08030.0239
A*1101 B*13010.0410A*0201B*4601DRB1*14010.0231
A*2402 B*40010.0358A*1101B*1502DRB1*12020.0188
A*1101 B*15020.0337A*1101B*1301DRB1*15010.0152
A*0201 B*40010.0326A*1101B*4001DRB1*11010.0149
A*2402 B*54010.0207A*1101B*4001DRB1*09010.0133
A*1101 B*15010.0179A*0101B*3701DRB1*10010.0105
A*2402 B*13010.0163A*3001B*1302DRB1*07010.0105
A*2402 B*46010.0144A*1101B*4001DRB1*15010.0105
A*0203 B*38020.0142A*2402B*4001DRB1*09010.0101
A*1101 B*51010.0127A*2402B*4001DRB1*15010.0085
A*0101 B*37010.0125A*1101B*4601DRB1*08030.0077
A*3001 B*13020.0125A*2402B*4001DRB1*08030.0074
A*1101 B*55020.0122A*1101B*1502DRB1*15010.0074
A*0201 B*51010.0114A*3303/1†B*5801DRB1*13020.0073
A*1101 B*39010.0111A*2402B*5401DRB1*09010.0071
A*3303/1† B*44030.0108A*1101B*1301DRB1*12020.0068

Comparison of HLA-A, B and DRB1 alleles in the AIDS patient and HIV-1 infected groups

HLA-A, B and DRB1 allele frequencies were detected and compared between the AIDS patient and HIV-1 infected groups (Table 4). A*1101, A*0201, A*2402, B*4601, B*4001, B*1301 for HLA class-I, and DRB1*0901, DRB1*1501, DRB1*1202 for HLA class-II, were the most common alleles in these two groups. For all loci, several alleles were unevenly distributed between the two groups. In the AIDS patient group, the A*3303/1 and B*5801 alleles had lower frequencies and were significantly underrepresented. In contrast, the B*3501 allele was overrepresented, (although the difference was not significant), in comparison to the HIV-1 infected group. In addition, increased frequencies in alleles of A*1101 (35.34% vs. 30.38%), A*0206 (3.01% vs. 1.69%), B*4001 (15.97% vs. 13.29%), and DRB1*0403 (3.94% vs. 2.32%), DRB1*0803 (9.95% vs. 7.38%) were observed, while other alleles such as B*5101 (2.55% vs. 3.90%) and DRB1*0901 (17.82% vs. 20.78%) had smaller frequencies in the AIDS patient group. However, none of these inequalities proved to be statistically significant. In order to identify HLA alleles which were associated with either favorable or unfavorable disease outcomes, an OR with a 95% CI on possible differences in the expression of HLA alleles and haplotypes between AIDS patients and HIV-1 infected individuals was calculated with Epi Info. As expected, alleles with a statistically significant difference between the two groups were A*3303/1 and B*5801, these were significantly associated with a decreased risk of disease progression.

Table 4.  Comparison of HLA-A, B and DRB1 alleles in the AIDS patient and HIV-1 infected groups
AllelesAIDS patients (n= 216)HIV-1 infected (n= 474)P valueOdds ratio95%CI‡
FrequencyN (%)FrequencyN (%)
  1. Only alleles with frequencies of more than 1% in either group of subjects are listed.

  2. n” indicates the number of people (whether a person has the genotype or not). The percentage is indicated in parentheses.

  3. †Methods used in this study do not allow differentiation between A*3303 and A*3301; ‡CI, confidence interval.

  4. Bold type denotes alleles where the difference is statistically significant.

A*11010.3634124 (57.4)0.3038252 (53.2)   
A*02010.231587 (40.3)0.2574209 (44.1)   
A*24020.171369 (31.9)0.1730146 (30.8)   
A*3303/1†0.048621 (9.7)0.081276 (16.0)0.0360.560.33–0.97
A*02030.039417 (7.9)0.047545 (9.5)   
A*02060.030112 (5.6)0.016916 (3.4)   
A*26010.027812 (5.6)0.026424 (5.1)   
A*01010.025511 (5.1)0.023222 (4.6)   
A*31010.01396 (2.8)0.020019 (4.0)   
A*30010.01165 (2.3)0.020019 (4.0)   
B*46010.210782 (38.0)0.2110179 (37.8)   
B*40010.159765 (30.1)0.1329121 (25.5)   
B*13010.071829 (13.4)0.076071 (15.0)   
B*15010.053223 (10.6)0.041139 (8.2)   
B*15020.053223 (10.6)0.045440 (8.4)   
B*58010.044017 (7.9)0.073867 (14.1)0.0270.520.29–0.93
B*55020.037016 (7.4)0.039037 (7.8)   
B*35010.034715 (6.9)0.017917 (3.6)0.0802.010.93–4.32
B*54010.032414 (6.5)0.032731 (6.5)   
B*51010.025510 (4.6)0.039036 (7.6)   
B*38020.02329 (4.2)0.029528 (5.9)   
B*39010.023210 (4.6)0.015815 (3.2)   
B*37010.01858 (3.7)0.015815 (3.2)   
B*52010.01858 (3.7)0.022221 (4.4)   
B*51020.01627 (3.2)0.00636 (1.3)   
B*15110.01396 (2.8)0.014814 (3.0)   
B*40060.01396 (2.8)0.024323 (4.9)   
B*48010.01396 (2.8)0.00535 (1.1)   
B*56010.01165 (2.3)0.00746 (1.3)   
DRB1*09010.178272 (33.3)0.2078176 (37.1)   
DRB1*15010.106544 (20.4)0.092882 (17.3)   
DRB1*08030.099539 (18.1)0.073868 (14.3)   
DRB1*12020.092635 (16.2)0.092883 (17.5)   
DRB1*11010.074131 (14.4)0.067563 (13.3)   
DRB1*14010.071830 (13.9)0.064458 (12.2)   
DRB1*03010.039416 (7.4)0.051748 (10.1)   
DRB1*04030.039416 (7.4)0.023222 (4.6)   
DRB1*04050.039417 (7.9)0.050648 (10.1)   
DRB1*16020.037016 (7.4)0.045442 (8.9)   
DRB1*12010.025511 (5.1)0.020019 (4.0)   
DRB1*13120.025511 (5.1)0.023221 (4.4)   
DRB1*14050.025511 (5.1)0.020018 (3.8)   
DRB1*07010.023210 (4.6)0.036933 (7.0)   
DRB1*10010.01858 (3.7)0.019017 (3.6)   
DRB1*04060.01396 (2.8)0.012712 (2.5)   
DRB1*15020.01396 (2.8)0.017917 (3.6)   
DRB1*01010.01165 (2.3)0.010610 (2.1)   
DRB1*13020.01165 (2.3)0.021120 (4.2)   

Comparison of HLA-A-B and HLA-A-B-DRB1 haplotypes and HLA genotype in the AIDS patient and HIV-1 infected groups

Next 2-locus of HLA-A-B and 3-locus of HLA-A-B-DR haplotypes with frequencies of more than 1% were analyzed and compared between these two groups (Table 5). For HLA-A-B the most common haplotypes were A*0201-B*4601, A*1101-B*4001 and A*1101-B*4601 in the AIDS patient group, in contrast to A*0201-B*4601, A*3303/1-B*5801 and A*1101-B*4001 in the HIV-1 infected group. The highest frequency HLA-A-B-DR haplotypes were A*0201-B*4601-DRB1*0901, A*1101-B*1502-DRB1*1202 and A*0201-B*4601-DRB1*0803 in the AIDS patient group and A*0201-B*4601-DRB1*0901, A*1101-B*4601-DRB1*0901 and A*3303/1-B*5801-DRB1*0301 in the HIV-1 infected group. For HLA-A-B haplotypes, A*3303/1-B*5801 was significantly underrepresented, while A*1101-B*4001, A*1101-B*1502 and A*2402-B*4801 were significantly overrepresented in AIDS patients. Statistical analysis of the haplotypes of HLA-A-B-DR showed that A*1101-B*4601-DRB1*0803, A*0201-B*4001-DRB1*0901, A*1101-B*4001-DRB1*1501, A*2402-B*4601-DRB1*0901 and A*1101-B*4001-DRB1*1405 were significantly overrepresented in AIDS patients.

Table 5.  Comparison of HLA-A, B and DRB1 haplotypes and genotypes in the AIDS patient and HIV-1 infected groups
Haplotype/genotypeAIDS patients (n= 216)HIV-1 infected (n= 474)P valueOdds ratio95%CI‡
Frequencyn (%)Frequencyn (%)
  1. Only haplotypes with frequencies of more than 1% in either group of subjects are listed.

  2. “n” indicates the number of people (whether a person has the genotype or not). The percentage is indicated in parentheses.

  3. †Methods used in this study do not allow differentiation between A*3303 and A*3301; ‡CI, confidence interval; §“N/A” indicates not available.

  4. Bold type denotes haplotypes/genotypes where the difference is statistically significant.

HLA-A-B haplotype
A*0201 B*46010.121449 (22.7)0.1494130 (27.4)   
A*1101 B*40010.083235 (16.2)0.047642 (8.9)0.0071.991.20–3.30
A*1101 B*46010.056624 (11.1)0.040537 (7.8)   
A*1101 B*15020.048221 (9.7)0.027225 (5.3)0.0451.931.01–3.68
A*0201 B*40010.043618 (8.3)0.027226 (5.5)   
A*1101 B*13010.037415 (6.9)0.041439 (8.2)   
A*3303/1† B*58010.030113 (6.0)0.059555 (11.6)0.0320.490.25–0.95
A*2402 B*40010.025911 (5.1)0.041239 (8.2)   
A*2402 B*46010.024811 (5.1)0.011811 (2.3)   
A*1101 B*15010.02149 (4.2)0.013713 (2.7)   
A*2402 B*54010.02069 (4.2)0.016215 (3.2)   
A*2402 B*13010.01788 (3.7)0.016516 (3.4)   
A*0101 B*37010.01627 (3.2)0.011611 (2.3)   
A*1101 B*55020.01426 (2.8)0.013813 (2.7)   
A*0203 B*38020.01366 (2.8)0.013313 (2.7)   
A*2402 B*15010.01296 (2.8)0.00787 (1.5)   
A*0201 B*15010.01165 (2.3)0.00858 (1.7)   
A*1101 B*39010.01165 (2.3)0.011911 (2.3)   
A*0203 B*55020.01095 (2.3)0.00495 (1.1)   
A*2402 B*48010.01075 (2.3)0.00161 (0.2)0.01311.211.27–255.09
A*3001 B*13020.00693 (1.4)0.015815 (3.2)   
A*1101 B*54010.00723 (1.4)0.014614 (3.0)   
A*0201 B*51010.00884 (1.9)0.013213 (2.7)   
A*3303/1† B*44030.00462 (0.9)0.012111 (2.3)   
A*1101 B*51010.00392 (0.9)0.011911 (2.3)   
A*2402 B*55020.00452 (0.9)0.011711 (2.3)   
A*0201 B*13010.00904 (1.9)0.011211 (2.3)   
A*1101 B*38020.00713 (1.4)0.011211 (2.3)   
HLA-A-B-DRB1 haplotype
A*0201 B*4601 DRB1*09010.064526 (12.0)0.070564 (13.5)   
A*1101 B*1502 DRB1*12020.025411 (5.1)0.016314 (3.0)   
A*0201 B*4601 DRB1*08030.02109 (4.2)0.026825 (5.3)   
A*1101 B*4001 DRB1*11010.01928 (3.8)0.012011 (2.3)   
A*1101 B*1301 DRB1*15010.01908 (3.8)0.014013 (2.7)   
A*0201 B*4601 DRB1*14010.01868 (3.7)0.026924 (5.1)   
A*3303/1† B*5801 DRB1*03010.01858 (3.7)0.032731 (6.5)   
A*1101 B*4601 DRB1*08030.01848 (3.7)0.00192 (0.4)0.0039.081.77–62.38
A*1101 B*4601 DRB1*09010.01798 (3.6)0.033131 (6.5)   
A*0201 B*4001 DRB1*09010.01557 (3.1)0.00424 (0.8)0.0403.941.02–16.16
A*1101 B*4001 DRB1*15010.01446 (2.9)0.00273 (0.6)0.0304.490.99–22.83
A*0101 B*3701 DRB1*10010.01396 (2.8)0.00959 (1.9)   
A*2402 B*4601 DRB1*09010.01326 (2.6)0.00343 (0.7)0.0304.490.99–22.83
A*1101 B*4001 DRB1*14050.01255 (2.5)0.00000 (0.0)0.003N/A§N/A§
A*1101 B*1301 DRB1*12020.01034 (2.1)0.00646 (1.3)   
A*1101 B*4001 DRB1*09010.00362 (0.7)0.018618 (3.7)   
A*3001 B*1302 DRB1*07010.00693 (1.4)0.012612 (2.5)   
A*2402 B*4001 DRB1*15010.00251 (0.5)0.011911 (2.4)   
A*2402 B*4001 DRB1*09010.00080 (0.0)0.01009 (2.0)   
Homogeneous HLA-A or B
A allele homozygous0.240752 (24.1)0.192091 (19.2)   
B allele homozygous0.088019 (8.8)0.073835 (7.4)   
A or B allele homozygous0.300965 (30.1)0.2236106 (22.4)0.0371.491.02–2.18
HLA-Bw4-Bw6 genotype
Bw6-Bw6 homozygous0.5787125 (57.9)0.4726224 (47.3)0.0121.531.09–2.15
Bw4-Bw6 heterozygous0.333372 (33.3)0.4156197 (41.6)0.0490.700.49–1.00
Bw4-Bw4 homozygous0.088019 (8.8)0.111853 (11.2)   

Individuals with identical alleles at a given locus were considered to be homozygotes. The term homozygote is used here to describe an individual with identical 4-digit resolution genotyping results at HLA-A and B. HLA-A allele homozygotes (24.1%) and HLA-B allele homozygotes (8.8%) occurred more frequently in the AIDS patient group than in the HIV-1 infected group, although the difference was not significant. However, combined HLA-A or HLA-B homozygotes were significantly different between the AIDS patient and HIV-1 infected groups.

In addition, HLA-B alleles can be grouped as HLA-Bw4 or HLA-Bw6 on the basis of the amino acid residues at position 79–83. According to their HLA-B genotypes, all subjects can be classified into three groups: Bw4-Bw4 homozygotes, Bw6-Bw6 homozygotes and Bw4-Bw6 heterozygotes. The distribution of HLA-Bw4 and Bw6 genotypes in the two experimental groups revealed that significantly more AIDS patients were homozygous for HLA-Bw6-Bw6, while significantly fewer were heterozygous for HLA-Bw4-Bw6 than in the HIV-1 infected group.

Analysis of the association of HLA haplotypes and genotypes with AIDS outcomes revealed that A*1101-B*4001, A*1101-B*1502 and A*2402B*4801 of the 2-locus haplotypes, and A*1101-B*4601-DRB1*0803, A*0201-B*4001-DRB1*0901, A*1101-B*4001-DRB1*1501, A*2402-B*4601-DRB1*0901 and A*1101-B*4001-DRB1*1405 of the 3-locus haplotypes, and A or B allele homozygosity and Bw6-Bw6 homozygosity were associated with accelerated progression of AIDS, while A*3303/1-B*5801 was identified as a protective haplotype with respect to disease progression.

Multivariate analysis

A binary logistic regression analysis for observed HLA-A, HLA-B and HLA-DRB1 alleles, the homozygosity of HLA alleles and the serotype group of Bw4/Bw6 was conducted using the forward stepwise (Wald) method with multivariate comparisons. As shown in Table 6, the A*3303/1, B*5801 and B*3501 alleles, A or B allele homozygotes and Bw6-Bw6 homozygotes all demonstrated a significant difference in distribution between AIDS patients and HIV-1 infected individuals. To determine if the association of the alleles identified in this study were independent of each other, other logistic regression analyses were conducted. A multivariate analysis of A*3303/1 and B*5801 alleles revealed that A*3303/1 was not significantly associated with resistance in the absence of the B*5801 allele. In addition, the associations of the B*5801 and B*3501 alleles, A or B allele homozygosity and Bw6-Bw6 homozygosity with progression of AIDS were independent of the other two host factors: age and gender.

Table 6.  Binary logistic regression analysis
Logistic regression analysis  Sig. Exp(B) §95.0% C.I .for EXP(B)
LowerUpper
  1. Binary logistic regression analysis: Method: Forward Wald; Probability for stepwise: Entry (0.05), Remove (0.1).

  2. 1. Covariates: all HLA-A alleles in Table 4;

  3. 2. Covariates: all HLA-B alleles in Table 4;

  4. 3. Covariates: A allele homozygous, B allele homozygous, A or B allele homozygous;

  5. 4. Covariates: HLA-Bw4-Bw4, HLA-Bw4-Bw6, HLA-Bw6-Bw6;

  6. 5. Covariates: A*3303/1, B*5801;

  7. 6. Covariates: B*5801, B*3501, Age, Gender, Transmission route;

  8. 7. Covariates: A homozygous, B homozygous, A or B homozygous, Age, Gender, Transmission route;

  9. 8. Covariates: HLA-Bw4-Bw4, HLA-Bw4-Bw6, HLA-Bw6-Bw6, Age, Gender, Transmission route;

  10. †Variables entered on this step, no more variables can be deleted from or added to the current model;

  11. ‡Sig, Significance;

  12. §Exp(B), Exponent of B, odds ratio;

  13. CI, Confidence interval

1Step 1A*3303/10.0310.5690.3400.950
 Constant0.0000.492  
2Step 2B*58010.0170.5070.2890.888
 B*35010.0502.0541.0004.217
 Constant0.0170.5070.2890.888
3Step 1A/B homozygous0.0461.4451.0072.074
 Constant0.0000.416  
4Step 1Bw6-Bw60.0101.5341.1082.123
 Constant0.0000.365  
5Step 1B*58010.0200.5150.2950.900
 Constant0.0000.493  
6Step 4B*58010.0260.5260.2980.927
 B*35010.0222.3611.1334.917
 Age0.0001.4331.2161.689
 Gender0.0140.6220.4260.908
 Constant0.0000.203  
7Step 3A/B homozygous0.0331.4951.0342.162
 Age0.0001.4331.2171.687
 Gender0.0160.6280.4310.916
 Constant0.0000.177  
8Step 3Bw6-Bw60.0141.5121.0872.104
 Age0.0001.4201.2061.673
 Gender0.0250.6490.4460.946
 Constant0.0000.158  

In summary, our investigation suggests that the presence of the B*3501 allele, A*2402-B*4801, common 2-locus of A*1101-B*4001, A*1101-B*1502 and 3-locus of A*1101-B*4601-DRB1*0803, A*0201-B*4001-DRB1*0901, A*1101-B*4001-DRB1*1501, A*2402-B*4601-DRB1*0901, A*1101-B*4001-DRB1*1405 haplotypes, HLA-A or B and Bw6-Bw6 homozygosity may predict a poor disease outcome in HIV-1 infection. However individuals who have the B*5801 alleles, A*3303/1-B*5801 haplotype and are heterozygous for Bw4-Bw6 are more likely to be resistant to progression of AIDS in this Chinese population (Table 7).

Table 7.  Associations of HLA alleles, haplotypes and genotypes with progression of AIDS in Chongqing, China
 HLA association with AIDS
Rapid progressionSlow progression
AllelesB*3501B*5801
HaplotypesA*1101-B*4001A*3303/1-B*5801
A*1101-B*1502 
A*2402-B*4801 
A*1101-B*4601-DRB1*0803 
A*0201-B*4001-DRB1*0901 
A*1101-B*4001-DRB1*1501 
A*2402-B*4601-DRB1*0901 
A*1101-B*4001-DRB1*1405 
GenotypesA or B homozygoteBw4-Bw6 heterozygote
Bw6-Bw6 homozygote 

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Since the early days of the AIDS epidemic, many studies have been conducted focusing on the association of HLA class I and II antigens with HIV-1 infection and disease outcomes in different ethnic populations (2–8). In the subjects selected for this study, the gene frequencies for A*1101, A*0201, A*2402, B*4601, B*4001, B*1301, DRB1*0901, DRB1*1501, DRB1*1202 appear to be relatively high. However the A*01, A*23, A*68, B*08, B*27, B*57 genes, which have been reported to have a consistent association with HIV/AIDS (2, 11), occurred with a low frequency in HIV-1 seropositive individuals. Notably, B*4601 (20.88%) was the most frequently observed B allele in this group of Chinese subjects, although it rarely occurs in Caucasians and Africans, suggesting the importance of investigating ethnicity-dependent HLA polymorphisms on progression of AIDS among various ethnic populations.

The HLA haplotypes with high frequency included A*0201-B*4601, A*1101-B*4001, A*1101-B*4601 and A*3303/1-B*5801 of 2-locus and A*0201-B*4601-DRB1*0901, A*1101-B*4601-DRB1*0901 and A*3303/1-B*5801-DRB1*0301 of 3-locus. The top 20 most common HLA-A-B and HLA-A-B-DR haplotypes in this study accounted for 60% and 32% of the haplotypes, respectively. The HLA profile of the subjects in this study was similar to that of previous reports on the HLA gene distribution amongst the Han nationality of south China (12–15). In our study, it was shown that HIV-1 infected individuals who have the B*5801 and B*3501 alleles are more likely to develop progression of AIDS. Moreover, homozygosity for HLA-A or B and HLA-Bw6-Bw6 was significantly different between the two groups, suggesting an association with increased susceptibility to progression of AIDS. In addition, the presence of the common 2-locus haplotypes and 3-locus haplotypes may predict a poor disease outcome of HIV-1 infection in this Chinese population from Chongqing, China.

The B58 supertype has been the most reproducibly observed HLA association with HIV-1 viremia and prolonged AIDS survival in Caucasians and Africans who have been infected with either B or C subtype (2, 16). Previous research has confirmed that mutations occur uniquely and frequently at specific positions of certain HIV-1 gag-encoded peptides in HLA-B*58 patients, as does adaptive plasticity of T-cell receptor recognition of HIV-1 motifs, both of which could result in deficient HIV-1 replication (2, 4, 11, 17). The protective role of the B*5801 allele in regard to progression of AIDS was confirmed in this study. However, the A*3303/1 allele and A*3303/1-B*5801 haplotype were less frequently observed in the AIDS patients than in HIV-1 infected individuals. In fact, binary logistic regression analysis showed that resistance conferred by A*3303/1 may due to the presence of the B*5801 allele. Meanwhile, A*3303/1-B*5801 is in a strong linkage disequilibrium in the southwest of China (12, 13, 15).

The HLA-B*35 allele has a highly significant association with disease progression in Caucasians but not in African-Americans (11, 18, 19). Differences have been observed in a single amino acid at position 116, dividing the allele into two groups according to peptide- binding specificity: the B35-PY group and the more broadly reactive B35-Px group. Generally, possession of the B35-PY allele has no effect on AIDS progression in African-Americans (11, 20). However, the present data indicate that the B*3501 subtype allele, which belongs to the B35-PY group, may be associated with more rapid AIDS progression in the study group. B*3503 (0.7% vs. 0.4%, P= 0.68) and B*3505 (0.5% vs. 0.1%, P= 0.23) also express more in the AIDS patient group than in the HIV-1 infected group. However, our data does not support a different effect on AIDS progression between the B35-PY group and B35-Px group.

The B*4801 allele (1.39% vs. 0.53%, P= 0.10), which is not quite as common in the Chinese population, seems to be linked to accelerated progression of AIDS in this study. This allele is in linkage disequilibrium with A*2402 in the population of Chongqing, consequently, the A*2402-B*4801 haplotype was significantly different between the two groups, suggesting its association with increased susceptibility to progression of AIDS. To our knowledge, the B*4801 allele and A*2402-B*4801 haplotype have not thus far been reported to be disadvantageous factors in HIV-1 infection, the underlying mechanisms for such associations remains elusive.

In our study, most of the common HLA-A-B and HLA-A-B-DR haplotypes were overrepresented in the AIDS patients group, such as A*1101-B*4001, A*1101-B*4601, A*1101-B*1502, A*0201-B*4001, A*2402-B*4601 and A*1101-B*1501 for 2-locus haplotypes and A*1101-B*1502-DRB1*1202, A*1101-B*4001-DRB1*1101, A*1101-B*4601-DRB1*0803, A*0201-B*4001-DRB1*0901, A*1101-B*4001-DRB1*1501 and A*2402-B*4601-DRB1*0901 for 3-locus haplotypes. These common haplotypes consisted of common alleles such as A*1101, B*4001, B*1501, DRB1*1501, DRB1*1202 and DRB1*0803. Most of them were observed with higher frequencies in the AIDS patient group, although the differences were not significant. It has been reported that possession of certain common HLA alleles confers a disadvantage in regard to progression of AIDS (21–23). A possible reason for the association of these common HLA alleles with a more rapid onset of AIDS in HIV-1 infected individuals is frequency-dependent selection, in which a pathogen has evolved to escape an efficient immune response mediated by common alleles in the population, but remains susceptible to responses mediated by low-frequency alleles (11, 21). Therefore, HIV is more likely to adapt to the most common HLA types in a given population. However, we also observed that common alleles such as A*0201, B*4601, DRB1*0901 and the most common, A*0201-B*4601-DRB1*0901, haplotype of this population did not occur at greater frequencies. Even the most common HLA-A-B haplotype, A*0201-B*4601, occurred slightly less frequently in the AIDS patient group, the difference not being significant. Moreover, the frequency of common A*0201-B*4601-DRB1*1401 (1.86% vs. 2.69%) and A*1101-B*4601-DRB1*0901 (1.79% vs. 3.31%) haplotypes was less in AIDS patients. These observations suggest that common alleles of A*0201, B*4601, DRB1*0901 are not risk factors for the development of AIDS.

It has been reported that HLA class I homogeneity accelerates disease progression in HIV-1 infection (18, 25). Accordingly, homozygosity at class I loci can reduce the repertoire for such HLA-dependent interactions, leading to accelerated disease progression. The high population diversity in HLA alleles implies low frequencies of homozygosity in individuals. Complete absence of class I homozygosity would maximize the likelihood of receiving at least one of the less frequent, but more effective, alleles mediating a favorable CTL response. On the other hand, higher frequencies of class I homozygosity may reduce the CTL repertoire, and the effectiveness of the CTL response to the constantly evolving HIV-1 antigen profiles (11, 24). Our data suggest a significant association of HLA class I homozygosity with rapid progression to AIDS in the Chinese population of Chongqing.

The Bw4 and Bw6 serotype differ in their antigen recognition properties, resulting in differences in association with different viral epitopes presented, and in intensity of the cytotoxic T lymphocyte response. It had been reported that HLA-Bw4 homozygosity is associated with slow progression to AIDS and less likelihood of HIV-1 transmission in heterosexual couples (26, 27). Some HLA-Bw4 molecules serve as ligands for NK cell receptors. The interaction between the HLA-Bw4 epitope and the NK cell receptors induces elimination of HIV-1 infected cells by NK-mediated lysis (28, 29). In this study, homogeneous Bw6-Bw6 occurred significantly more often in the AIDS patient group than in the HIV-1 infected group. This association with accelerated disease progression had been confirmed in Chinese HIV-1 infected patients (30). In contrast, heterogeneous Bw4-Bw6 was underrepresented in the AIDS patients, implying that HLA-Bw4-Bw6 heterozygosity may be a protective factor in regard to progression of HIV-1 infection.

Differences were observed between AIDS patients and HIV-1 infected individuals in other host factors such as gender and age. There were more AIDS patients in the 50–59 age group and more female patients in the AIDS patient group than that in the HIV-1 infected group. Previous reports have shown that older age is associated with lower CD4+ counts at a similar time from seroconversion, which may explain the relationship between age and disease progression (31). In this study, older or female patients were subject to poorer disease outcomes of HIV-1 infection. However, binary logistic regression analyses also demonstrated the associations of the alleles and genotypes identified in this study were independent of these two host factors.

Our results not only revealed consistent HLA associations with AIDS progression, including increased susceptibility with B*3501 and some common haplotypes, HLA A or B and Bw6-Bw6 homozygosity, and a protective effect of the B*5801 allele and A*3303/1-B*5801 haplotype, but also suggested that the B*4801 allele and A*2402-B*4801 haplotype are unique disadvantageous factors. However, since the time since infection had occurred was unknown, it was difficult to estimate the duration of infection in each individual. Meanwhile, virus loads in the plasma were not determined in this study. Therefore, these two aspects restrict the application to other populations of conclusions from this study.

In summary, we observed the HLA profile of HIV-1 seropositive subjects from Chongqing, China, and identified differences between AIDS patients and HIV-1 infected individuals. Our study also suggests that HLA alleles and haplotypes may be associated with progression of HIV-1 infection to AIDS for the predominant HIV-1 CRF07_BC clade in China. These data are consistent with evidence that the progression of infectious disease is associated with host genetic factors, indicating that the HLA-mediated immune response determines the course of AIDS. Thus, our investigation of polymorphism in HLA alleles and haplotype analysis in HIV-1 seropositive individuals from Chongqing, China may provide further insight into other potential associations and linkages between protective/susceptible alleles, as well as the effect of whole haplotypes on anti-HIV-1 immunity, and finally, contribute to predicting rates of disease progression, the development of therapeutics, and future vaccine design for this Chinese population.

ACKNOWLEDGMENTS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

This study was supported by the Chongqing Science Technology Commission (Grant No CSTC-2008AC5019) in China. The authors are very grateful to Rongfang Zhang for help with data analysis. We would like to thank staff from the Chongqing Center for Disease Control and Prevention for their assistance with sample/data collection. We also thank all participants in this study.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
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