JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Role of HLA Class I (HLA-A, B) and HLA Class II (HLA-DRB, DQB) in HIV-1 Patients With and Without Pulmonary Tuberculosis
Shankarkumar, U Phd; Pawar, A Phd; Prabu, G Msc; Ghosh, K MD
Department of HLA, National Institute of Immunohaematology, ICMR, KEM Hospital,, Parel, Mumbai,, Maharashtra, India
AIDS caused by HIV infection is endemic all over the globe and it is on the rise especially in resource-limited countries. Over 33 million people are living with HIV, 2.5 million are newly infected, and 2.1 million people are died of AIDS.1 Individuals with impaired cell-mediated immunity due to AIDS have a greatly increased risk of coinfection with Mycobacterium tuberculosis (MTB).2 The coinfection of HIV-1 and MTB causes 2 infectious diseases endangering human health significantly. The pathogenesis of HIV-1 and PTB coinfection is available. The factors influencing the greater interindividual variability to susceptibility to PTB coinfection and progression of AIDS are not known. This may be due to considerable varied immune responses of HIV-1 and MTB exposed individuals may result from the different genetic background. Major histocompatibility complex class I-restricted CD8+ T cells are important for the generation of protective immune response in MTB infection. CD8+ CTL (cytotoxic T lymphocytes)-derived IFN-γ may be especially important both for cells lacking major histocompatibility complex class II molecules.
Both HLA class I and class II genes have been shown to be associated with susceptibility or resistance to HIV infection.3 Among the HLA class II alleles, HLA-DQB1 and HLA-DBP1 alleles have been shown to be associated with HIV infection.4,5 But, we have much less information about the HLA-linked genetic control of susceptibility to HIV-1 and MTB coinfection. We have attempted to study the role of HLA class I (HLA-A, B) and HLA class II (HLA-DRB, DQB) in HIV-1 patients with or without pulmonary tuberculosis (PTB). A total of 390 individuals comprising 102 HIV-1+ patients coinfected with PTB, 88 HIV-1+ patients without PTB, and 200 healthy controls were included in HLA class I analysis. And a total of 184 individuals comprising 30 HIV-1+ patients coinfected with PTB, 25 HIV-1+ patients without PTB, and 129 healthy controls were included in HLA class II analysis. The clinically confirmed cases of HIV-1 with or without PTB were included in our study. Class I antigens (HLA-A, B) were typed serologically by microlymphocytotoxicity assay. HLA class II (HLA-DRB, DQB) typing was done molecularly by PCR-SSOP (polymerase chain reaction-sequence specific oligonucleotide probing) method using kit (Dynal Kit; Invitrogen, Carlsbad, CA). The frequencies of the HLA class I (HLA-A, B) and HLA class II (HLA-DRB, DQB) alleles were determined by direct allelic count and expressed as percent frequency using standard software.
The HLA class I and HLA class II alleles identified among HIV+/PTB+ coinfected patients compared with HIV+ PTB− patients and healthy controls are given in Table 1. Significantly increased frequency of HLA-B8 was observed in HIV+/PTB+ coinfected patients when compared with healthy controls [P = 0.011, odds ratio (OR): 3.335, 95% confidence interval (CI): 1.35 to 8.18] but decreased significantly in HIV+ PTB− patients (P = 0.086, OR: 0.502, 95% CI: 0.24 to 1.03). Likewise, HLA-DQB1*030103 was significantly increased in HIV+/PTB+ coinfected patients as against healthy controls (P < 0.0001, OR: 107.5, 95% CI: 6.195 to 1865.3). Similarly, HLA-DQB*060102 allele frequency was observed in HIV+/PTB+ coinfected patients as against healthy controls (P = 0.003, OR: 4.808, 95% CI: 1.72 to 13.39) and also when compared with HIV+ PTB− patients (P = 0.0207, OR: 16.352, 95% CI: 0.91 to 290.99). A significantly increased frequency of HLA-A2 (P = 0.015, OR: 1.762, 95% CI: 1.13 to 2.73), HLA-B17 (P = 0.017, OR: 1.973, 95% CI: 1.15 to 3.37), HLA-B22 (P = 0.029, OR: 2.606, 95% CI: 1.16 to 5.85), HLA-DRB1*040301 (P = 0.006, OR: 7.727, 95% CI: 1.79 to 33.3), HLA-DRB1*090102 (P = 0.012, OR: 9.143, 95% CI: 1.63 to 51.174), HLA-DRB1*140103 (P = 0.024, OR: 13.526, 95% CI: 1.381 to 132.49), and HLA-DQB1*050201 (P < 0.0001, OR: 28.556, 95% CI: 8.36 to 242.16) and a significantly decreased frequency was observed in HLA-B5 (P = 0.009, OR: 0.434, 95% CI: 0.236 to 0.799), HLA-DQB1*030101 (P = 0.045, OR: 0.219, 95% CI: 0.051 to 0.940), HLA-DQB1*060101 (P = 0.012, OR: 0.334, 95% CI: 0.145 to 0.770), alleles in HIV+/PTB+ coinfected patients when compared with healthy controls. Significantly increased frequency of HLA-A10 (P = 0.086, OR: 0.502, 95% CI: 0.24 to 1.03), was observed in HIV+/PTB+ coinfected patients when compared with HIV+ PTB− patients.
We have studied, HLA-A, B, DRB, and DQB loci to find out the role of these HLA alleles in HIV+/PTB+ coinfection. Significantly increased frequency of HLA-B8 and HLA-DQB*030103 in HIV+/PTB+ coinfected patients against controls may suggest that these alleles play an associative role in HIV infection and PTB development. But on the contrary, a significantly decreased frequency of HLA-B8 and HLA-DQB*030103 observed in HIV+/PTB+ coinfected patients when compared with HIV+ PTB− patients may be suggestive of their protective role in PTB development. Our study reveals that HLA-B8 and HLA-DQB*030103 are associative to enhance HIV infection but play a protective role in development of PTB coinfection. The decreased frequency of HLA-DQB1*0301 has been reported in PTB patients from China.6 In our study, HLA-DQB1*030101 is decreased in HIV+/PTB+ coinfected patients compared with controls suggesting that it may play a protective role in HIV+/PTB+ coinfection, whereas HLA-DQB*030103 is associative in HIV infection but plays a protective role in development of PTB in HIV infected patients.
Recently among south Indians, an increased frequency of HLA-DQB1*0601 has been reported in HIV− PTB+ and HIV+ PTB+ patients, suggesting that HLA-DQB1*0601 is associated with susceptibility to PTB as well as development of PTB in HIV patients.7 Further earlier association of HLA-DQB1*0601 with susceptibility to PTB has also been reported in south India.8 In contrast to the above 2 studies on south Indian population, it is reported that HLA-DQB1*0601 plays a protective role against HIV disease progression in Europeans.9 In our study, a significantly increased frequency of HLA-DQB*060102 in HIV+/PTB+ coinfected patients when compared with controls and HIV+ PTB− patients may suggest its strong association with both HIV infection and PTB coinfection. But on the contrary, HLA-DRB1*060101 frequency was significantly decreased in HIV+/PTB+ coinfected patients compared with controls, thereby may protect from HIV infection and PTB development. HLA-DQB1*0502 allele is reportedly related to high risk of developing TB in population from Asia and Latin America.10 In the present study, frequency of HLA-DQB1*050201 is increased in HIV+/PTB+ coinfected patients compared with healthy subjects to show that HLA-DQB1*050201 may be associated with HIV+/PTB+ coinfection. There was no considerable change in frequency of HLA-A10 in HIV+/PTB+ coinfected patients when compared with controls and also decreased frequency was observed when compared with HIV+ PTB− patients. This suggests that HLA-A10 may not be associated with HIV infection and also may play a protective role in PTB development. HLA-A31 and HLA-B41 antigens and the HLA-DRB1*10 and HLA-DQB1*05 were overrepresented in Brazilian patients with AIDS and tuberculosis (TB), suggesting association to TB with AIDS.11 As reported earlier, HLA-DRB1*13 is associated with susceptibility to HIV-1 infection, whereas HLA-DQB1*0203 and DRB1*01 are resistant to HIV-1 infection, which may vary in different ethnic groups.4 HLA-DRB1*15 is susceptible in PTB development and DRB1*11 may be protective allele in Chinese population.6 In the present study, HLA-DRB alleles HLA-DRB1*040301, DRB1*090102, DRB1*140103 and also HLA-DQB1*050201 allele are significantly increased in HIV+/PTB+ coinfected patients compared with healthy controls. Thus, these alleles may be associated to susceptibility of HIV+/PTB+ coinfection among Indians.
In conclusion, different HLA alleles may render susceptibility or protection to an infection in different ethnic population. Both HLA class I and class II alleles may influence immunopathogenesis of either HIV and/or PTB infection. Further study on the HIV progression and resistant TB would enlighten the mechanism of action of the HLA in HIV and/or PTB infection.
U. Shankarkumar, PhD
A. Pawar, PhD
G. Prabu, MSc
K. Ghosh, MD
Department of HLA,
National Institute of Immunohaematology, ICMR,
1. National AIDS Control Organization (NACO) report 2008. April-June 2008. Ministry of Health and Family Welfare, Government of India News letter October 2008.
2. Vijayalakshmi V, Shilpa SR, Anuradha B, et al. Role of HLA-B51 and HLA-B52 in susceptibility to pulmonary tuberculosis. Infect Genet Evol. 2006;6:436-439.
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8. Ravikumar M, Dheenadhayalan V, Rajaram K, et al. Associations of HLA-DRB1, DQB1 and DPB1 alleles with pulmonary tuberculosis in South India. Tuber Lung Dis. 1999;79:309-317.
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11. Fernando de castro JF, Maria de Lourdes VR, Neifi Hassam SD, et al. HLA Profile in patients with AIDS and Tuberculosis. Braz J Infect Dis. 2008;12:278-280.
12. Patricia M, Karina M, Adrian S, et al. Association of HLA-DQ and HLA-DR alleles with susceptibility or resistance to HIV-1 infection among population of Chaco province, Argentina. Medicina. 2002;62:245-248.
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