Role of HLA-A , HLA-B , HLA-DRB 1 and HLADQB 1 Alleles in HIV-1 Patients with Pulmonary Tuberculosis Co-Infection from Western India

We attempted to study the role of HLA HLA-A, B, DRB1 and DQB1 in HIV-1 patient’s co infected with pulmonary tuberculosis (PTB). A total of 102 HIV-1+ patients co-infected with pulmonary tuberculosis and 200 healthy controls were included in HLA analysis. HLA-A*, HLA-B* HLA-DRB1* and DQB1* typing was done molecularly by PCRSSOP (Polymerase Chain reaction-Sequence Specific Oligonucleotide Probing) method using kit (Dynal Kit-Invitrogen). The frequencies of the HLA-A, B HLA-DRB, 1 and DQB1 alleles were determined using standard software. The HLA alleles identified among HIV+ve/PTB+ve co-infected patients as compared with healthy controls showed a significantly increased frequency of HLA-B*08:01:01 in HIV+ve/PTB+ve co-infected patients when compared with healthy controls (p = 0.011, OR 3.335, 95% CI 1.35 8.18), Likewise HLA-DQB1*03:01:03 was significantly increased in HIV+ ve/PTB+ve co-infected patients as against healthy controls (p < 0.0001, OR 107.5, 95% CI 6.195 1865.3). Similarly HLA-DQB*06:01:02 allele frequency was observed in HIV + ve/PTB + ve co-infected patients as against healthy controls (p = 0.003, OR 4.808, 95% CI 1.72 13.39), HLA-DQB1*03:01:01 (p = 0.045, OR 0.219, 95% CI 0.051 0.940), HLA-DQB1*06:01:01:01 (p = 0.012, OR 0.334, 95% CI 0.145 0.770), alleles in HIV+ve/PTB+ve co-infected patients when compared with healthy controls. We can be concluded that different HLA alleles may render susceptibility or protection to in different ethnic population.


Introduction
Acquired immunodeficiency syndrome (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 have died of AIDS [1].Individuals with impaired cell mediated immunity due to AIDS have a greatly increased risk of co-infection with Mycobacterium tuberculosis [1][2].The co-infection of HIV-1 and Mycobacterium tuberculosis causes two infectious diseases endangering human health significantly.The pathogenesis of HIV-1 and PTB co-infection is unavailable.The factors influencing the greater inter individual variability to susceptibility to PTB co-infection and progression of AIDS is yet to be identified.This may be due to considerable varied immune re-sponses of HIV-1 and MTB exposed individuals may result from the different genetic background.MHC class-I restricted CD8+ T cells are important for the generation of protective immune response in Mycobacterium tuberculosis infection.CD8+ CTL (Cytotoxic T lymphocytes)-derived IFN- may be especially important both for cells lacking MHC class-II molecules.

Materials and Methods
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 shown to be associated with HIV infection [4,5].However, we have much less information about the HLA linked genetic control of susceptibility to HIV-1 and MTB co-infection.We have Tuberculosis Co-Infection from Western India attempted to study the role of HLA-A, B,DRB1 and DQB1 in HIV-1 patients with pulmonary tuberculosis (PTB).A total of 102 HIV-1+ patients co-infected with pulmonary tuberculosis and 200 healthy controls were included in HLA analysis.HLA typing was done molecularly by PCR-SSOP (Polymerase Chain reaction-Sequence Specific Oligonucleotide Probing) method using kit (Dynal Kit-Invitrogen).The frequencies of the HLA-A, B, HLA-DRB1 and DQB1 alleles were determined by using standard software.

Discussion
We have studied, HLA-A, B, DRB and DQB loci to find out the role of these HLA alleles in HIV+ve/PTB+ve co-infection.Significantly increased frequency of HLA-B*08:01:01 and HLA-DQB*03:01:03 in HIV+ve/PTB+ ve co-infected patients against controls may suggest that, these alleles play an associative role in HIV infection and PTB development.Our study reveals that, HLA-B*08:01:01and HLA-DQB*03:01:03 are associative to enhance HIV infection.The decreased frequency of HLA-DQB1*03:01:01 has been reported in PTB patients from China [6].In our study, HLA-DQB1* 03:01:01 is decreased in HIV+ve/PTB+ve co-infected patients compared to controls suggesting that it may play a protective role in HIV+ve/PTB+ve co-infection.Whereas HLA-DQB*03:01:03 is associative in HIV.Among South Indians an increased frequency of HLA-DQB1*06:01:01:01 has been reported in HIV-ve PTB+ve and HIV+ve PTB+ve patients, suggesting that HLA-DQB1**06:01:01:01 is associated with susceptibility to PTB as well as development of PTB in HIV patients [7].Further earlier association of HLA-DQB1* 06:01:01:01 with susceptibility to PTB has also been reported in south India [8].In contrast to the above two Table 1.Significant HLA alleles identified among the TB co-infected HIV patients from Western India.Tuberculosis Co-Infection from Western India studies on South Indian population, it is reported that HLA-DQB1*06:01:01:01 plays a protective role against HIV disease progression in Europeans [9].In our study a significantly increased frequency of HLA-DQB*06:01: 02 in HIV+ve/PTB+ve co-infected patients when compared to controls and HIV+ve PTB-ve patients may suggest its strong association with both HIV infection and PTB co-infection.On the contrary HLA-DRB1* 06:01:01:01 frequency was significantly decreased in HIV+ve/PTB+ ve co-infected patients compared to controls, thereby may protect from HIV infection and PTB development.
HLA-DQB1*05:02:01 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*05:02:01 is increased in HIV+ve/PTB+ve coinfected patients compared to healthy subjects to show that HLA-DQB1* 05:02:01 may be associated with HIV+ve/PTB+ve co-infection.There was no considerable change in frequency of HLA-A*26:01:01 in HIV+ ve/PTB+ve co-infected patients when compared with controls and decreased frequency was observed when compared with HIV+ve PTB-ve patients.This suggests that, HLA-A*26:01:01 may not be associated with HIV infection and may play a protective role in PTB development.HLA-A*31 and HLA-B*41 antigens and the HLA-DRB1*10 and HLA-DQB1*05 were over represented in Brazilian patients with AIDS and tuberculosis, suggesting association to tuberculosis with AIDS [11].

Conclusions
It can be concluded that different HLA alleles may render susceptibility or protection to an infection in different ethnic population.HLA alleles may influence immunopathogenesis from 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 PTB infection.