To the Editor:
HIV-1 and Mycobacterium tuberculosis are the two leading infectious agents causing death worldwide. Increasing morbidity and mortality among HIV-1-infected individuals in areas where M tuberculosis is endemic are attributable to tuberculosis (TB) to a large extent. Because of the pivotal role of the human leukocyte antigen (HLA) genes and gene products in controlling the immune response, the association between HLA genes and infectious diseases has been extensively studied. Various studies have identified an association between HLA genes (class I and class II) and HIV-1 infection and disease progression. Most of the studies carried out in whites and Africans have indicated that HLA-B27 and HLA-B57 are associated with a slow progression to AIDS and that HLA-B35 is associated with rapid disease progression.1,2 Further, studies carried out in Asian populations have linked the development of pulmonary TB with the HLA class II region, specifically HLA-DR2.1 In the context of HIV-1 and M tuberculosis coinfection, there is a dearth of reports on the HLA genes predisposing to development of TB in HIV-1-infected individuals. In the present study, we have explored the possible association between HLA (-A, -B, and -DR loci) and HIV-1 with and without TB in a group of south Indian patients.
The study population comprised 151 HIV-1-seropositive subjects without TB (HIV+TB−) (64 male, mean age ± SD: 32.1 ± 6.9 years; 87 female, mean age ± SD: 28.6 ± 6.7 years) and 108 HIV-1-seropositive subjects with active TB (HIV+TB+) (78 male, mean age ± SD: 35.3 ± 5.7 years; 30 female, mean age ± SD: 31.0 ± 7.1 years) recruited from the HIV and TB clinics of the Tuberculosis Research Center, Chennai, India, and 170 healthy controls from the same ethnic background (104 male, mean age ± SD: 33.0 ± 8.0 years; 66 female, mean age ± SD: 32.9 ± 8.8 years). The diagnosis of TB was based on sputum smear examination for acid-fast bacilli and confirmed by culture for M tuberculosis. HIV-1 was diagnosed using 2 rapid tests (HIV tridot, J. Mitra, India; CombAids, Span Diagnostics, India), and a positive result was confirmed by a third test (Western blot, J. Mitra, India). The present study was approved by the institutional ethical committee, and written informed consent was obtained from all the participants of the study. The patients and controls represented the same ethnic group of the south Indian population from the state of Tamilnadu. HLA-A and HLA-B typing was carried out using a 2-stage microlymphocytotoxicity test. HLA-DR genotyping was studied by polymerase chain reaction and sequence-specific oligo probe method. The frequencies of HLA antigens of patients and controls were compared using the χ2 test. P values with Yates correction and odds ratios were calculated using the Statcalc program (Epi Info version 6.04, Centers for Disease Control and Prevention, Atlanta, GA, July 1996) with 95% confidence intervals. The P values were further corrected by the Bonferroni inequality method, wherein the P values obtained were multiplied with the number of antigens studied in each locus and expressed as P-corrected (Pc) values.
Among the antigens studied, a decreased frequency of HLA-A11, HLA-B17, HLA-B35, and HLA-DR7 and an increased frequency of HLA-A19 (32 + 33), HLA-B18, HLA-B40, and HLA-DR2 were observed in the HIV+TB− and HIV+TB+ groups compared with healthy controls. The difference attained statistical significance only in the case of HLA-A11 (overall HIV-1-infected vs. controls: Pc = 0.00066), HLA-B40 (Pc = 0.019), and HLA-DR2 (Pc = 0.037). When the HIV-1+TB− and HIV-1+TB+ groups were compared, HLA-A11 alone showed marginal significance (P = 0.0179, Pc = 0.196; Table 1).
In the present study, an increased prevalence of HLA-B40 and HLA-DR2 antigens was observed in HIV-1-infected and HIV-1 and M tuberculosis-coinfected individuals, suggesting their association with susceptibility to HIV-1 and HIV-1 and M tuberculosis coinfection. On the other hand, a decreased prevalence of HLA-A11 was observed in both HIV patient groups. This suggests that the presence of A11 may be associated with protection against HIV-1 and, more strongly, against HIV-1 and M tuberculosis coinfection. Moreover, our study also revealed that HLA-A11 is not associated with any protection against TB infection (HIV−TB+ patients: HLA-A11 frequency of 26.5%; data not shown). This suggests that strong protection observed is against HIV-1 and M tuberculosis coinfection. Because this is a cross-sectional study, further follow-up studies may delineate the role of HLA-A11 in protection against HIV-1 infection and HIV-1 and M tuberculosis coinfection.
A higher frequency of HLA-A11 was observed among highly exposed persistently seronegative women of Thailand,3 which suggests the protective role of HLA-A11 against HIV-1 infection. Another recent report also corroborates the protective role of HLA-A11, wherein it describes that the immune system of individuals expressing HLA-A11 frequently elicits CD8+ T-cell responses against a common HLA-A11-restricted escape variant epitope in HIV-1 gag.4 A number of potential mechanisms have been put forward to explain the association of HLA-A11 with resistance to HIV-1 infection and HIV-1 and M tuberculosis coinfection. HLA-A11 is one of the most common class I alleles in the world, ranging from 4% to 33% depending on the particular ethnic background, and it is highly prevalent in Southeast Asia.5 A*1101 is the most prevalent variant of A11 and is known preferably to bind peptide residues with small or aliphatic side chains at position 2 and with positively charged side chains at the C-terminus position. The structural features of the A*1101 binding groove permit peptides to adopt a backbone conformation with two bulges separated by a secondary anchor residue. This may allow for binding of unrestricted specificity of viral peptides of various lengths, which substantially expands the repertoire of cytotoxic T lymphocyte (CTL) epitopes presented by A*1101 and confers the ability to eliminate HIV-1. Thus, in the context of viruses with high genetic variability, such as HIV-1, HLA-A11 may have a functional advantage by counteracting immune escape mechanisms based on mutations of CTL epitopes.6
In the present study, HLA-B40 was found to be associated with susceptibility to HIV-1 infection and HIV-1 and M tuberculosis coinfection. A preliminary study carried out in 38 HIV-1-infected patients from the Maharastrian population of India revealed an association between HLA-B*3520 and HLA-B*1801 with susceptibility to HIV-1 infection, however.7 This may be attributable to the ethnic differences between the study populations. Our study population is of Dravidian descent, whereas the Maharastrian population is of Aryan descent. Association of HLA-B40 with susceptibility to HIV-1 infection and HIV-1 and M tuberculosis coinfection may be attributable to the low frequency of HLA-B40 (splits 60 and 61)-specific peptide motifs in HIV-1 proteins8 and secreted antigens of M tuberculosis.9 This may result in a low CTL response against HIV-1 and M tuberculosis infection, which may lead to susceptibility.
The present study also revealed the association of HLA-DR2 with susceptibility to HIV-1 infection and HIV-1 and M tuberculosis coinfection. HLA-DR2 has been shown to be associated with higher levels of p24 antigen, a marker of viral replication, in HIV-1-infected Italian patients.10 Moreover, our earlier study also revealed the association of HLA-DR2 with susceptibility to pulmonary TB in the south Indian population.11 Therefore, individuals positive for HLA-DR2 who have HIV-1 infection latently infected with M tuberculosis may have a higher propensity to develop active disease.
The discrepancy in alleles providing resistance or susceptibility to an infection across the different ethnic groups suggests that evolution of pathogens represent a response to the distinctive HLA population profiles, and this hypothesis offers an explanation for population-specific HLA-mediated effects. The results obtained may be useful in designing a population-specific and more efficient HLA-based HIV-1 and HIV-1-M tuberculosis vaccine. Better understanding of the genetic factors involved in susceptibility to these two infections could also help in designing preventive strategies.
Financially supported by the Indian Council of Medical Research, New Delhi, under the HIV-TB Task Force Program. K. Alagarasu and S. Raghavan are research fellows working under the program.
Paramasivam Selvaraj, PhD
Soumya Swaminathan, MD
Kalichamy Alagarasu, MSc
Sampathkumar Raghavan, MSc
Gopalan Narendran, DTCD, DNB
Paranji R. Narayanan, PhD
Tuberculosis Research Center Indian Council of Medical Research Chetput, Chennai, India
1. Hill AV. The genomics and genetics of human infectious disease susceptibility. Annu Rev Genomics Hum Genet
2. Al Jabri AA. HLA and in vitro susceptibility to HIV infection. Mol Immunol
3. Sriwanthana B, Hodge T, Mastro TD, et al. HIV specific cytotoxic T lymphocytes, HLA-A11, and chemokine-related factors may act synergistically to determine HIV resistance in CCR5 Δ32-negative female sex workers in Chiang Rai, Northern Thailand. AIDS Res Hum Retroviruses
4. Allen TM, Yu XG, Kalife ET, et al. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T- lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol
5. Sidney J, Grey HM, Southwood S, et al. Definition of HLA-A3 like supermotif demonstrates the overlapping peptide-binding repertoire of common HLA molecules. Hum Immunol
6. Li L, Bouvier M. Structure of HLA-A*1101 complexed with immunodominant nonamer and decamer HIV-1 epitopes clearly reveals presence of a middle, secondary anchor residue. J Immunol
7. Shankarkumar U, Thakar M, Mehendale S, et al. Association of HLA B*3520 and B*1801 and Cw*1507 with HIV-1 infection in Maharastra, India. J Acquir Immune Defic Syndr
8. Nelson WG, Kaslow R, Mann DL. Frequency of HLA allele specific peptide motifs in HIV-1 proteins correlates with the allele's association with relative rates of disease progression after HIV-1 infection. Proc Natl Acad Sci USA
9. Bothamley GH. Differences between HLA-B44 and HLA-B60 in patients with smear-positive pulmonary tuberculosis and exposed controls. J Infect Dis
10. Fabio G, Marchini M, Smeraldi RS, et al. Possible association of HLA-DR2 phenotype and detectable human immunodeficiency virus (HIV) p24 antigen in HIV-positive patients. J Infect Dis
11. Selvaraj P, Uma H, Reetha AM, et al. HLA antigen profile in pulmonary tuberculosis patients and their spouses. Indian J Med Res