JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Specific Human Leukocyte Antigen Alleles Associated With HIV-1 Infection in an Indian Population
Umapathy, Shankarkumar PhD; Pawar, Aruna PhD; Ghosh, Kanjaksha MD, MRCP, FRCPath
To the Editor:
Since the beginning of the AIDS epidemic, evidence has accumulated that genetic factors are involved in the pathogenesis of the disease.1 The role of host genes in the course of HIV-1 infection has been examined in different populations and among all major risk groups.2 Human leukocyte antigen (HLA) associations with HIV progression correlate well with the interaction between the pathogen and host.3
Most HLA polymorphisms are concentrated in the region that determines specificity for foreign peptide presentation. Three models have been proposed to explain maintenance of the HLA polymorphism: (1) balancing selection, where alleles confer resistance to one disease but confer susceptibility to another; (2) heterozygote advantage, where a unique HLA type increases the breadth of peptide recognition, and thereby immune defense against infectious organisms; and (3) frequency-dependent selection, where a pathogen evolves to escape an efficient immune response mediated by common alleles in the population but remains susceptible to responses mediated by low-frequency alleles. Each of these mechanisms has probably been operative under various host or environmental circumstances. Any change in primary structure may throttle a neutral allele into a deleterious one.4 HLA associations with HIV disease may be particularly apparent on investigation, because the recent epidemic has not had enough time to show diminished frequencies of deleterious alleles.5 The paucity of data on the association of HLA alleles with the predominant HIV-1 subtype C in India motivated us to undertake the present study.
Seventy-five cases of HIV-1 infection referred from various hospitals in Maharashtra were studied for HLA allele expression in comparison with 120 controls. None of the patients had AIDS. HIV status was diagnosed by 2 independent enzyme-linked immunosorbent assays (ELISAs) according to National AIDS Control Organization (NACO) guidelines. Polymerase chain reaction using biotinylated primers was followed by hybridization with sequence-specific oligonucleotide probe (PCR-SSOP) strips (Roche Molecular, Oakland, CA). The alleles were determined using the pattern interpretation software supplied with the kit. A statistical analysis was carried out. The distribution of HLA alleles is given in Table 1. The A*68011 allele was found in 11 of 75 patients with a frequency of 7.33% as compared with 1.66% in controls (P = 0.003). HLA A*2407 was observed with an allele frequency of 3.33% in the 120 controls but was present in only 1 patient with HIV-1. The alleles B*5701, B*15, and B*35 were observed with increased frequency in the patient group, with the B*3520 subtype showing the highest value of 12%. The Cw*0801 allele was seen in 4 (4%) of 50 patients, whereas Cw*1507 demonstrated a statistically significant incidence (P = 2.66; E-08). The HLA A*68011 allele from western Indian patients with HIV was hitherto unreported. Interestingly, the HLA B*3520 subtype was significantly associated with HIV in Marathas, the major caste group from Maharashtra, whereas B*3503 was commonly found among controls. HLA B*35 subtypes are divided into 2 groups according to peptide- binding specificity: the HLA B*35-PY and B*35-Px groups. An accelerated HIV progression among B*35-positive individuals is completely attributable to the B*35-Px group of alleles. HLA B*35 itself confers rapid progression to AIDS exclusively because of peptide-specific recognition.4 The B*350101 (PY) and B*3503 (Px) molecules differ by a single amino acid at position 116, which forms the floor of the peptide-anchoring F pocket, determines the size of the peptide carboxy-terminal residue, and directly interacts with residue P9 of the bound peptide.6 Variation at this position is critical not only in determining peptide preference but in facilitating interaction between HLA class I and the peptide repertoire.7,8 Other amino acid differences between the B*35-Px and B*35-PY groups also seem to distinguish the groups functionally, however. The variations at position 140 for B*3503 and at position 91 for B*3520 suggest their involvement in peptide recognition of the viral peptides. The HLA Cw*1507 allele association with HIV previously reported by us has been corroborated in the present study.9
The gene pool on the Indian subcontinent can be best described as “a melting pot of races,” with the area having experienced several foreign invasions from the East and West. HLA diversity within population groups is generated as a result of the founder effect, selection or random genetic drift, and intergenic recombination or population admixture. The sympatrically isolated caste and tribal populations of India, with diverse origins, migration patterns, and breeding habits, differ in their HLA expression and prevalence (relative risk) for a number of disease associations. In addition, alternative mechanisms, such as race-dependent differences in the unfolding of HIV proteins, proteasomal digestion, and T-cell repertoire, exist. Also, diverse HLA class I alleles with variable binding and presentation of the processed epitopes may contribute to the differential cytotoxic T-lymphocyte (CTL) responses. The predictability of a strong CTL response in HIV infection would help in designing a vaccine for the relevant population. Generation of such data for India is of paramount importance at present so as to combat the spread of AIDS in this country with a large population and limited treatment modalities.
Shankarkumar Umapathy, PhD
Aruna Pawar, PhD
Kanjaksha Ghosh, MD, MRCP, FRCPath
Institute of Immunohaematology (Indian Council of Medical Research)
King Edward Memorial Hospital
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