Identification of human genes interacting with HIV attachment receptors and potentially involved in disease pathogenesis based on multi-network bioinformatics analysis

The aim of the study was to search for candidate genes interacting with HIV attachment receptors (CCR5, CXCR4, CCR2, CD4) and potentially involved in disease pathogenesis, based on complex in silico network algorithms.

Materials and methods. A number of web applications were used to analyse genetic and protein-protein networks, the algorithms and databases of which are complementary. The CD4 receptor and chemokine co-receptor genes CCR5, CXCR4 and CCR2 were used as background/baseline genes in all cases, as their protein products play a key role in the process of virus attachment to the cell. The data were analysed, including a two-stage ranking of the identified candidate genes according to their interaction with background genes and their presence in the results of network analysis of different web resources.

Results and discussion. According to the results, candidate genes were identified using three web resources: HumanNet — 451 candidate genes, GeneMania — 86, STRING — 61. Based on the results of crossing the three web resources, the total number of candidate genes associated with background genes was 511. The total number of genes with a rank above 4 points was 68. Of these, 31 genes (45.6%) encoding C-C/C-X-C family chemokine ligands, 12 genes (17.6%) encoding C-C/C-XC receptors, 8 genes (11.8%) encoding receptors of other types, and 17 genes (25%) encoding proteins of other types. The following receptors and proteins that are not members of the C-C/C/C-X-C families of the indicated groups have been identified: ARRB2, TLR2, ADRA1A, ARRB1, FPR1, FPR3, GNAI1, PF4, PIK3CG, PPIA, S1PR3, GNA11, GNAI2, GNG2, PTPRC, ADRA1B, ADRB1, AFP, CD164, DBN1, GNB1, ITCH, RNF113A, SLC1A1, USP14.

Conclusion. Most of the identified candidate genes interacting with HIV attachment receptors and potentially involved in the pathogenesis of the disease were those encoding chemokine receptors and their C-C/C-X-C family ligands, the role of which in the progression of HIV infection is known or under active investigation. At the same time, genes whose products have never been considered as possible participants in the pathogenesis of the disease were identified, but the results suggest that they may play a role in the regulation of virus entry and/or in the modulation of the immune response of the organism. Further bioinformatic and experimental studies of the functions and polymorphic variants of these genes will help to improve the understanding of the genetic basis of HIV pathogenesis and identify new directions for therapeutic approaches.

1. Global HIV & AIDS statistics — Fact sheet / UNAIDS 2023 epidemiological estimates. https://www.unaids.org/en/resources/fact-sheet (access date: 08.05.2024).

2. Kiertiburanakul S., Sungkanuparph S. Emerging of HIV drug resistance: epidemiology, diagnosis, treatment and prevention // Curr. HIV Res. 2009. Vol. 7, No. 3. Р. 273–278. doi: 10.2174/157016209788347976.

3. Shchemelev A.N., Ostankova Y.V., Zueva E.B., Semenov A.V., Totolian A.A. Detection of Patient HIV-1 Drug Resistance Mutations in Russia’s Northwestern Federal District in Patients with Treatment Failure // Diagnostics (Basel). 2022. Vol. 12, No. 8. Р. 1821. doi: 10.3390/diagnostics12081821.

4. Rana S., Besson G., Cook D.G. et al. Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the delta ccr5 mutation // J. Virol. 1997. Vol. 71, No. 4. Р. 3219–3227. doi: 10.1128/JVI.71.4.3219-3227.

5. Mabuka J.M., Mackelprang R.D., Lohman-Payne B. et al. CCR2–64I polymorphism is associated with lower maternal HIV-1 viral load and reduced vertical HIV-1 transmission // J. Acquir Immune Defic. Syndr. 2009. Vol. 51, No. 2. Р. 235–237. doi: 10.1097/QAI.0b013e31819c155b. PMID: 19465829; PMCID: PMC2732713.

6. Alkhatib G., Berger E.A. HIV coreceptors: from discovery and designation to new paradigms and promise // Eur. J. Med. Res. 2007. Vol. 12, No. 9. Р. 375–384. PMID: 17933717.

7. Deng H., Liu R., Ellmeier W. et al. Identification of a major co-receptor for primary isolates of HIV-1 // Nature. 1996. Vol. 381, No. 6584. Р. 661– 666. doi: 10.1038/381661a0.

8. Feng Y., Broder C.C., Kennedy P.E., Berger E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor // Science. 1996. Vol. 272, No. 5263. Р. 872–877. doi: 10.1126/science.272.5263.872.

9. Kim C.Y., Baek S., Cha J. et al. HumanNet v3: an improved database of human gene networks for disease research // Nucleic Acids Res. 2022. Vol. 50, No. D1. Р. D632–D639. doi: 10.1093/nar/gkab1048.

10. Franz M., Rodriguez H., Lopes C. et al. GeneMANIA update 2018 // Nucleic Acids Res. 2018. Vol. 46, No. W1. Р. W60–W64. doi: 10.1093/nar/gky311.

11. Szklarczyk D., Kirsch R., Koutrouli M. et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest // Nucleic Acids Res. 2023. Vol. 51 (D1), Р. D638–D646. doi: 10.1093/nar/gkac1000.

12. Wang Z., Shang H., Jiang Y. Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency // Front Immunol. 2017. Vol. 8. Р. 1274. doi: 10.3389/fimmu.2017.01274. PMID: 29085362; PMCID: PMC5650658.

13. Ajasin D.O., Rao V.R., Wu X. et al. CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release // eLife. 2019. Vol. 8. e35546. doi: 10.7554/eLife.35546.

14. Xu H., Lin S., Zhou Z. et al. New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine // Cell Mol. Immunol. 2023. Vol. 20, No. 7. Р. 739–776. doi: 10.1038/s41423–023–01032-x. Epub 2023 May 17. PMID: 37198402; PMCID: PMC10189238.

15. Baltoumas F.A., Theodoropoulou M.C., Hamodrakas S.J. Interactions of the -subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: a critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials // J. Struct. Biol. 2013. Vol. 182, No. 3. Р. 209–218. doi: 10.1016/j.jsb.2013.03.004.

16. Lamb T.D., Pugh E.N. G-protein cascades: gain and kinetics // Trends in Neuroscience. 1992. Vol. 15, No. 8. Р. 291–298. doi: 10.1016/01662236(92)90079-n.

17. Langer S., Yin X., Diaz A. et al. The E3 Ubiquitin-Protein Ligase Cullin 3 Regulates HIV-1 Transcription // Cells. 2020. Vol. 9, No. 9. Р. 2010. doi: 10.3390/cells9092010.

18. Dabbagh D., He S., Hetrick B. et al. Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors // Viruses. 2021. Vol. 13, No. 5. Р. 832. doi: 10.3390/v13050832. PMID: 34064525; PMCID:PMC8147968.

19. Lear T., Dunn S.R., McKelvey A.C. et al. RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling // American Journal of Physiology. Cell Physiology. 2017. Vol. 313, No. 5. Р. C584–C592. doi: 10.1152/ajpcell.00193.

20. Rocha-Perugini V., Gordon-Alonso M., Sánchez-Madrid F. Role of Drebrin at the Immunological Synapse // Advances in Experimental Medicine and Biology. 2017. Vol. 1006. Р. 271–280. doi: 10.1007/978-4-431-56550-5_15.

21. Madlala P., Singh R., An P. et al. Association of Polymorphisms in the Regulatory Region of the Cyclophilin A Gene (PPIA) with Gene Expression and HIV/AIDS Disease Progression // Journal of Acquired Immune Deficiency Syndromes (1999). 2016. Vol. 72, No. 5 Р. 465–473. doi: 10.1097/QAI.0000000000001028.

22. Ding J., Chang T.L. TLR2 activation enhances HIV nuclear import and infection through T cell activation-independent and -dependent pathways // Journal of Immunology (Baltimore, Md.: 1950). 2012. Vol. 188, No. 3. Р. 992–1001. doi: 10.4049/jimmunol.1102098.

23. Li Y., Lefebvre F., Nakku-Joloba E. et al. Upregulation of PTPRC and Interferon Response Pathways in HIV-1 Seroconverters Prior to Infection // The Journal of Infectious Diseases. 2023. Vol. 227, No. 5. Р. 714–719. doi: 10.1093/infdis/jiac498.

24. Rathore A., Iketani S., Wang P. et al. CRISPR-based gene knockout screens reveal deubiquitinases involved in HIV-1 latency in two Jurkat cell models // Scientific Reports. 2020. Vol. 10, No. 1. Р. 5350. doi: 10.1038/s41598-020-62375-3.

25. Parker Z.F., Rux A.H., Riblett A.M. et al. Platelet Factor 4 Inhibits and Enhances HIV-1 Infection in a Concentration-Dependent Manner by Modulating Viral Attachment // AIDS Research and Human Retroviruses. 2016. Vol. 32, No. 7. Р. 705–717. doi: 10.1089/AID.2015.0344.

26. LoPiccolo J., Blumenthal G.M., Bernstein W.B., Dennis P.A. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical consid-erations // Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy. 2008. Vol. 11, No. 1–2. Р. 32–50. doi: 10.1016/j.drup.2007.11.

27. Heredia A., Le N., Gartenhaus R.B. et al. Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice // Proceedings of the National Academy of Sciences of the United States of America. 2015. Vol. 112, No. 30. Р. 9412–9417. doi: 10.1073/pnas.

28. Chen H., Egan J.O., Chiu J.F. Regulation and activities of alpha-fetoprotein // Critical Reviews in Eukaryotic Gene Expression. 1997. Vol. 7, No. 1–2. Р. 11–41. doi: 10.1615/critreveukargeneexpr.v7.i1–2.20.

29. Yeo Y.H., Lee Y.T., Tseng H.R. et al. Alpha-fetoprotein: Past, present, and future // Hepatology Communications. 2024. Vol. 8, No. 5. e0422. doi: 10.1097/HC9.0000000000000422. PMID: 38619448; PMCID: PMC11019827.

30. Morsica G., Galli L., Messina E. et al. Levels of Alpha-Fetoprotein and Association with Mortality in Hepatocellular Carcinoma of HIV-1-Infected Patients // Journal of Oncology. 2022. Vol. 3586064. doi: 10.1155/2022/3586064.

31. Underhill S.M., Wheeler D.S., Li M. et al. Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons // Neuron. 2014. Vol. 83, No. 2. Р. 404–416. doi: 10.1016/j.neuron.2014.05.

32. Kleinz M.J., Davenport A.P. Emerging roles of apelin in biology and medicine // Pharmacology & Therapeutics. 2005. Vol. 107, No 2. Р. 198– 211. doi: 10.1016/j.pharmthera.2005.04.001.

33. Zou M.X., Liu H.Y., Haraguchi Y. et al. Apelin peptides block the entry of human immunodeficiency virus (HIV) // FEBS Letters. 2000. Vol. 473, No. 1. Р. 15–18. doi: 10.1016/s0014-5793(00)01487-3.

34. Crawford K.S., Volkman B.F. Prospects for targeting ACKR1 in cancer and other diseases // Frontiers in Immunology. 2023. Vol. 14. Р. 1111960. doi: 10.3389/fimmu.2023.1111960. PMID: 37006247; PMCID: PMC10050359.

35. Landires I., Núñez-Samudio V., Thèze J. Short communication: nuclear JAK3 and its involvement in CD4 activation in HIV-infected patients // AIDS Research and Human Retroviruses. 2013. Vol. 29, No. 5. Р. 784–787. doi: 10.1089/aid.2012.0249.