Research Article
Year 2025,
Volume: 8 Issue: 2, 76 - 83, 30.06.2025
Abstract
Amaç: İnsan immün yetmezlik virüsü-1 (HIV-1) yüksek morbidite ve mortaliteye sahiptir ve özellikle HIV-1 için benzersiz bir rezervuar olan CD4+ T hücrelerini hedef alır. İmmün yanıtı düzenlemede ve diğer immün hücreleri aktive etmede rol oynayan CD4+ T hücreleri, İnsan Lökosit Antijeni (HLA) Sınıf I molekülleri tarafından sunulan HIV-1 antijenlerini tanır. HLA-B, diğer HLA sınıflarıyla karşılaştırıldığında hastalık sonuçlarıyla en güçlü şekilde ilişkilidir. HIV-1 enfeksiyonu üzerindeki etkilerini belirlemek için HLA-B alellerinin varlığını tespit etmek önemlidir. HIV-1 ile enfekte olmayan ve HIV-1 ile yaşayan kişiler (PLWH) arasındaki HLA-B alel sıklığındaki farkı göstererek, bu alellerin PLWH'deki varlığı ve CD4+ T hücre sayısı ile viral replikasyon seviyeleri arasındaki ilişkiyi göstermeyi amaçladık.
Gereç ve Yöntemler: 412 PLWH ve 406 sağlıklı bireyde HLA-B alel sıklığını ve HIV-1 enfeksiyon sonuçlarıyla ilişkisini değerlendirdik. Genomik DNA'lar saflaştırıldıktan sonra PCR-SSP ve Luminex teknolojisi PCR-SSO yöntemleri ile HLA-B alellerini tanımladık.
Bulgular: HLA-B*07, *18, *35, *44 ve *51 alellerinin hasta grubunda %5'ten daha yüksek bir sıklıkta olduğunu gördük. PLWH'de HLA B*57 alelinin sıklığının kontrol grubuna göre daha düşüktü ve HLA B*57:01 alel pozitifliği %1,6 olarak görüldü. HLA-B*57:01 alel pozitifliği olan tüm hastalarda viral load (VL) <100.000 kopya/ml idi. HLA-B*07 ve HLA-B*35 alellerine sahip hastalar daha düşük CD4+ T hücre sayıları (hücre/mm³) ve daha yüksek HIV RNA seviyeleri (kopya/mL) sergilediler.
Sonuç: Bulgularımız antijen sunumunda sınıf I HLA moleküllerinin geleneksel rolünün ötesine uzanan diğer moleküler mekanizmaların dahil olduğunu ima etmektedir. HLA B alellerinin HIV-1 enfeksiyonunu ve hastalık ilerlemesini nasıl etkilediğine dair araştırmalar, kimin HIV-1'e daha duyarlı olduğunu ve hastalığın farklı bireylerde nasıl evrimleşeceğini anlamamıza yardımcı olacaktır. Bu faktör üzerinde daha fazla araştırma yapılması önemlidir çünkü etkili bir HIV aşısının yıllarca süren devam eden arayışı için önemli çıkarımlar taşımaktadır.
Keywords
References
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- Schellens IM, Nanlohy NM, Spits HB, Borghans JA, van Baarle D. Differential effects of the protective HLA alleles B27 and B57 on CTL responses restricted by other HLA molecules in HIV-1 infection. Impact of HLA class I restricted T cells on HIV-1 disease progression. 2009:117. google scholar
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- Carlson JM, Listgarten J, Pfeifer N, Tan V, Kadie C, Walker BD, et al. Widespread impact of HLA restriction on immune control and escape pathways of HIV-1. J Virol 2012;86(9):5230-43. google scholar
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- McLaren PJ, Coulonges C, Ripke S, Van Den Berg L, Buchbinder S, Carrington M, et al. Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. PLoS Pathogens 2013;9(7):e1003515. google scholar
- Rahmouni M, De Marco L, Spadoni J-L, Tison M, Medina-Santos R, Labib T, et al. The HLA-B* 57: 01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control. Frontiers Immunol 2023;14:1305856. google scholar
- Kawashima Y, Kuse N, Gatanaga H, Naruto T, Fujiwara M, Dohki S, et al. Long-term control of HIV-1 in hemophiliacs carrying slow-progressing allele HLA-B* 5101. J Virol 2010;84(14):7151-60. google scholar
- Lazaryan A, Song W, Lobashevsky E, Tang J, Shrestha S, Zhang K, et al. The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans. Human Immunol 2011;72(4):312-8. google scholar
- Ngumbela K, Day C, Mncube Z, Nair K, Ramduth D, Thobakgale C, et al. Targeting of a CD8 T cell env epitope presented by HLA-B* 5802 is associated with markers of HIV disease progression and lack of selection pressure. AIDS Res Human Retroviruses 2008;24(1):72-82. google scholar
- Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, et al. A whole-genome association study of major determinants for host control of HIV-1. Science 2007;317(5840):944-7. google scholar
- McLaren PJ, Coulonges C, Bartha I, Lenz TL, Deutsch AJ, Bashirova A, et al. Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load. Proceedings National Acad Sci 2015;112(47):14658-63. google scholar
- Pelak K, Goldstein DB, Walley NM, Fellay J, Ge D, Shianna KV, et al. Host determinants of HIV-1 control in African Americans. J Infect Dis 2010;201(8):1141-9. google scholar
- Zhang Y, Chikata T, Kuse N, Murakoshi H, Gatanaga H, Oka S, et al. Immunological Control of HIV-1 Disease Progression by Rare Protective HLA Allele. J Virol 2022;96(22):e01248-22. google scholar
- Kolou M, Poda A, Diallo Z, Konou E, Dokpomiwa T, Zoungrana J, et al. Prevalence of human leukocyte antigen HLA-B* 57: 01 in individuals with HIV in West and Central Africa. BMC Immunol 2021;22:1-8. google scholar
- Small CB, Margolis DA, Shaefer MS, Ross LL. HLA-B* 57: 01 allele prevalence in HIV-infected North American subjects and the impact of allele testing on the incidence of abacavir-associated hypersensitivity reaction in HLA-B* 57: 01-negative subjects. BMC Infect Dis 2017;17:1-6. google scholar
- Leszczyszyn-Pynka M, Aksak-W^s B, Urbanska A, Parczewski M. Protective effect of HLA-B* 5701 and HLA-C-35 genetic variants in HIV-positive Caucasians from Northern Poland. PloS One 2015;10(6):e0127867. google scholar
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Year 2025,
Volume: 8 Issue: 2, 76 - 83, 30.06.2025
Abstract
Objective: Human Immunodeficiency Virus-1 (HIV-1) has high morbidity and mortality and specifically targets CD4+ T cells, a unique reservoir for HIV-1. CD4+ T cells, which have a role in regulating the immune response and activating other immune cells, recognise HIV-1 antigens presented by Human Leukocyte Antigen (HLA) Class I molecules. HLA-B is most strongly linked to the potential disease outcomes when compared with other HLA classes. It is important to detect HLA-B alleles to determine their effects on HIV-1 infection. By demonstrating the difference in HLA B allele frequency between HIV-1 uninfected and people living with HIV-1 (PLWH), we aimed to demonstrate the correlation between the presence of these alleles in PLWH and the CD4+ T cell count and viral replication levels.
Material and Methods: We evaluated the HLA-B allele frequency and its association with HIV-1 infection outcomes in 412 PLWH and 406 healthy individuals. After purification of the genomic DNAs, we identified the HLA-B alleles using PCR-SSP and Luminex technology PCR-SSO methods.
Results: We found that the HLA-B*07, *18, *35, *44, and *51 alleles occurred at a frequency greater than 5% in the patient group. In PLWH, the frequency of the HLA-B*57 allele was observed to be lower than that in the control group. The HLA-B*57:01 allele positivity was determined as 1.6%. All patients with HLA-B*57:01 allele positivity had VL <100,000 copies/ml. Patients with the HLA-B*07 and HLA-B*35 alleles exhibited lower CD4+ T cell counts (cells/ mm³) and higher HIV RNA levels (copies/mL).
Conclusion: Our findings strongly imply the involvement of other molecular mechanisms, extending beyond the traditional role of class I HLA molecules in antigen presentation. Research into how HLA-B alleles influence HIV-1 infection and disease progression will help us understand who is more susceptible to HIV-1 and how the disease will evolve in different individuals. Further research is essential on this factor, as it holds significant implications for the ongoing, years-long pursuit of an effective HIV vaccine.
Keywords
Ethical Statement
ETİK NO: 1154166/12.11.2024
References
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- van Heuvel Y, Schatz S, Rosengarten JF, Stitz J. Infectious RNA: human immunodeficiencY virus (HIV) biologY, therapeutic intervention, and the quest for a vaccine. Toxins 2022;14(2):138. google scholar
- Lunardi LW, Bragatte MAdS, Vieira GF. The influence of HLA/HIV genetics on the occurrence of elite controllers and a need for therapeutics geotargeting view. Brazilian Journal of Infectious Diseases 2021;25(05):101619. google scholar
- Goulder PJ, Walker BD. HIV and HLA class I: an evolving relationship. ImmunitY 2012;37(3):426-40. google scholar
- Boyd MA, van Bockel D, Munier CML, Kelleher AD. Navigating the complexity of chronic HIV-1 associated immune dysregulation. Current Opinion Immunol 2022;76:102186. google scholar
- Li S, Moog C, Zhang T, Su B. HIV reservoir: antiviral immune responses and immune interventions for curing HIV infection. Chinese Med J 2022;135(22):2667-76. google scholar
- Duan S, Liu S. Targeting NK cells for HIV-1 treatment and reservoir clearance. Frontiers Immunol 2022;13:842746. google scholar
- Boyer Z, Palmer S. Targeting immune checkpoint molecules to eliminate latent HIV. Frontiers Immunol 2018;9:2339. google scholar
- Emu B, Sinclair E, Hatano H, Ferre A, Shacklett B, Martin JN, et al. HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. J Virol 2008;82(11):5398-407. google scholar
- Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, et al. HLA B* 5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proceedings National Acad Sci 2000;97(6):2709-14. google scholar
- Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah A, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Natura Med 1996;2(4):405-11. google scholar
- Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 2008;197(4):563-71. google scholar
- Schellens IM, Nanlohy NM, Spits HB, Borghans JA, van Baarle D. Differential effects of the protective HLA alleles B27 and B57 on CTL responses restricted by other HLA molecules in HIV-1 infection. Impact of HLA class I restricted T cells on HIV-1 disease progression. 2009:117. google scholar
- den Uyl D, van der Horst-Bruinsma IE, van Agtmael M. Progression of HIV to AIDS: a protective role for HLA-B27. AIDS Rev 2004;6(2):89-96. google scholar
- Lazaryan A, Lobashevsky E, Mulenga J, Karita E, Allen S, Tang J, et al. Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans. J Virol 2006;80(12):6056-60. google scholar
- Carlson JM, Listgarten J, Pfeifer N, Tan V, Kadie C, Walker BD, et al. Widespread impact of HLA restriction on immune control and escape pathways of HIV-1. J Virol 2012;86(9):5230-43. google scholar
- Naranbhai V, Carrington M. Host genetic variation and HIV disease: from mapping to mechanism. Immunogenetics 2017;69:489-98. google scholar
- Study IHC. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 2010;330(6010):1551-7. google scholar
- Gao X, O'Brien TR, Welzel TM, Marti D, Qi Y, Goedert JJ, et al. HLA-B alleles associate consistently with HIV heterosexual transmission, viral load, and progression to AIDS, but not susceptibility to infection. Aids 2010;24(12):1835-40. google scholar
- Li SS, Hickey A, Shangguan S, Ehrenberg PK, Geretz A, Butler L, et al. HLA-B. 46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype. Cell host & Microbe 2022;30(8):1173-85. e8. google scholar
- O'Brien SJ, Gao X, Carrington M. HLA and AIDS: a cautionary tale. Trend Molecular Med 2001;7(9):379-81. google scholar
- Hendel H, Caillat-Zucman S, Lebuanec H, Carrington M, O’Brien S, Andrieu J-M, et al. New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 1999;162(11):6942-6. google scholar
- McLaren PJ, Coulonges C, Ripke S, Van Den Berg L, Buchbinder S, Carrington M, et al. Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. PLoS Pathogens 2013;9(7):e1003515. google scholar
- Rahmouni M, De Marco L, Spadoni J-L, Tison M, Medina-Santos R, Labib T, et al. The HLA-B* 57: 01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control. Frontiers Immunol 2023;14:1305856. google scholar
- Kawashima Y, Kuse N, Gatanaga H, Naruto T, Fujiwara M, Dohki S, et al. Long-term control of HIV-1 in hemophiliacs carrying slow-progressing allele HLA-B* 5101. J Virol 2010;84(14):7151-60. google scholar
- Lazaryan A, Song W, Lobashevsky E, Tang J, Shrestha S, Zhang K, et al. The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans. Human Immunol 2011;72(4):312-8. google scholar
- Ngumbela K, Day C, Mncube Z, Nair K, Ramduth D, Thobakgale C, et al. Targeting of a CD8 T cell env epitope presented by HLA-B* 5802 is associated with markers of HIV disease progression and lack of selection pressure. AIDS Res Human Retroviruses 2008;24(1):72-82. google scholar
- Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, et al. A whole-genome association study of major determinants for host control of HIV-1. Science 2007;317(5840):944-7. google scholar
- McLaren PJ, Coulonges C, Bartha I, Lenz TL, Deutsch AJ, Bashirova A, et al. Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load. Proceedings National Acad Sci 2015;112(47):14658-63. google scholar
- Pelak K, Goldstein DB, Walley NM, Fellay J, Ge D, Shianna KV, et al. Host determinants of HIV-1 control in African Americans. J Infect Dis 2010;201(8):1141-9. google scholar
- Zhang Y, Chikata T, Kuse N, Murakoshi H, Gatanaga H, Oka S, et al. Immunological Control of HIV-1 Disease Progression by Rare Protective HLA Allele. J Virol 2022;96(22):e01248-22. google scholar
- Kolou M, Poda A, Diallo Z, Konou E, Dokpomiwa T, Zoungrana J, et al. Prevalence of human leukocyte antigen HLA-B* 57: 01 in individuals with HIV in West and Central Africa. BMC Immunol 2021;22:1-8. google scholar
- Small CB, Margolis DA, Shaefer MS, Ross LL. HLA-B* 57: 01 allele prevalence in HIV-infected North American subjects and the impact of allele testing on the incidence of abacavir-associated hypersensitivity reaction in HLA-B* 57: 01-negative subjects. BMC Infect Dis 2017;17:1-6. google scholar
- Leszczyszyn-Pynka M, Aksak-W^s B, Urbanska A, Parczewski M. Protective effect of HLA-B* 5701 and HLA-C-35 genetic variants in HIV-positive Caucasians from Northern Poland. PloS One 2015;10(6):e0127867. google scholar
- de Araüjo C, de Carvalho CV, de Souza Freire ME, Yamaguti A, Scaff IC, de Souza FJ, et al. Prevalence of human leukocyte antigen HLA-B* 5701 in HIV-1 infected individuals in Brazil. Open J Gen 2014;2014. google scholar
- Deveci A, Çoban AY, Durupınar B. HIV ile enfekte hastalarda insan lökosit antijeni (HLA)-B* 57: 01 prevalansı. Mikrobiyol Bul 2016;50(4):544-51. google scholar
- Toplu SA, Bayindir Y, Ersoy Y, Memisoglu F, Kose A, Otlu G. Evaluation of HLA-B* 57: 01 and its effect on antiretroviral therapy in patients with human immunodeficiency virus infection: Experience of a University Hospital. 2020. google scholar
- Darbas S, Inan D, Kilinc Y, Arslan HS, Ucar F, Boylubay O, et al. Relationship of HLA-B alleles on susceptibility to and protection from HIV infection in Turkish population. Northern Clin Istanbul 2023;10(1). google scholar
- Büyüktuna SA, Öksüz C, Tahmaz A, Sarıgül Yıldırım F, Kaya S, Çelik Ekinci S. HIV-1 enfekte bireylerde insan lökosit antijeni (HLA)-B* 57: 01 pozitifliği prevalansının dağılımı ve tedavi üzerine etkileri: Türkiye Haritası-BUHASDER Çalışma Grubu. Mikrobiyoloji Bülteni. 2024. google scholar
- Yılmaz E, Kurt AF, Dogruel M, Sevgi DY, Karaosmanoglu HK, Zerdali E, et al. Frequency of Human Leukocyte Antigen-B* 57: 01 Allele Carriers in People Living with HIV/AIDS in Türkiye. Current HIV Res 2024;22(4):266-9. google scholar
- Dalmasso C, Carpentier W, Meyer L, Rouzioux C, Goujard C, Chaix M-L, et al. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study. PloS One 2008;3(12):e3907. google scholar
- Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, et al. Common genetic variation and the control of HIV-1 in humans. PLoS Gen 2009;5(12):e1000791. google scholar
- van Manen D, Delaneau O, Kootstra NA, Boeser-Nunnink BD, Limou S, Bol SM, et al. Genome-wide association scan in HIV-1-infected individuals identifying variants influencing disease course. PLoS One 2011;6(7):e22208. google scholar
There are 43 citations in total.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences (Other) |
| Journal Section | Research Article |
| Authors | |
| Publication Date | June 30, 2025 |
| Submission Date | January 30, 2025 |
| Acceptance Date | May 6, 2025 |
| Published in Issue | Year 2025 Volume: 8 Issue: 2 |
