Multiple T-cell Epitopes Overlap Positively-selected Residues in the P1 Spacer Protein of HIV-1 Gag

Overview

Journal AIDS

Specialty Infectious Diseases

Date 2009 Mar 17

PMID 19287301

Citations 4

Authors

Christina A Semeniuk

Lyle McKinnon

Harold O Peters

Michael Gubbins

Xiaojuan Mao

Terry B Ball

Ma Luo

Francis A Plummer

Affiliations

Soon will be listed here.

Abstract

Objectives: The p1 region of HIV-1 gag contains the frameshift stem-loop, gag-pol transframe and a protease cleavage site that are crucial for viral assembly, replication and infectivity. Identifying and characterizing CD8+ epitopes that are under host immune selection in this region will help in designing effective vaccines for HIV-1.

Design: An approach combining bioinformatical analysis and interferon gamma enzyme-linked immunosorbent spot (ELISPOT) assays is used to identify and characterize the epitopes. Potential human leukocyte antigen (HLA)-restricted epitopes were identified by correlating the positively-selected mutations with host HLA alleles.

Methods: ELISPOT analysis with overlapping peptides was used to confirm and characterize the epitopes.

Results: Four positively-selected residues were significantly associated with HLA class I alleles, including HLA B*1302 (K4R, P = 0.0008 and I5L, P = 0.0108), A*7401 (S9N, P = 0.0002) and A*30 genotypes (P7S, P = 0.009), suggesting epitopes restricted by these alleles are present in this region. ELISPOT analysis with patient peripheral blood mononuclear cells (PBMCs) identified seven novel epitopes restricted by the 3 alleles. Two types of epitopes were observed in this region based on the ELISPOT responses, Type I: the positively-selected variation does not affect CD8+ T-cell responses; and Type II: the CD8+ T-cell responses are determined by the epitope variants.

Conclusion: We identified and characterized seven novel CD8+ epitopes in the p1 spacer protein region. Classifying the effects of positively-selected variants on CD8+ T-cell responses will help in designing effective vaccines for HIV-1.

Citing Articles

Interplay between HIV-1 and Host Genetic Variation: A Snapshot into Its Impact on AIDS and Therapy Response.

Sampathkumar R, Shadabi E, Luo M Adv Virol. 2012; 2012:508967.

PMID: 22666249 PMC: 3361994. DOI: 10.1155/2012/508967.

For protection from HIV-1 infection, more might not be better: a systematic analysis of HIV Gag epitopes of two alleles associated with different outcomes of HIV-1 infection.

Luo M, Daniuk C, Diallo T, Capina R, Kimani J, Wachihi C J Virol. 2011; 86(2):1166-80.

PMID: 22072744 PMC: 3255815. DOI: 10.1128/JVI.05721-11.

HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703.

Matthews P, Adland E, Listgarten J, Leslie A, Mkhwanazi N, Carlson J J Immunol. 2011; 186(10):5675-86.

PMID: 21498667 PMC: 3738002. DOI: 10.4049/jimmunol.1003711.

Identification and characterization of HLA-A*0301 epitopes in HIV-1 gag proteins using a novel approach.

Semeniuk C, Capina R, Mendoza M, Kimani J, Ball T, Luo M J Immunol Methods. 2009; 352(1-2):118-25.

PMID: 19903485 PMC: 2836169. DOI: 10.1016/j.jim.2009.11.002.

References

Walker B, Goulder P . AIDS. Escape from the immune system. Nature. 2000; 407(6802):313-4. DOI: 10.1038/35030283. View

Peters H, Mendoza M, Capina R, Luo M, Mao X, Gubbins M . An integrative bioinformatic approach for studying escape mutations in human immunodeficiency virus type 1 gag in the Pumwani Sex Worker Cohort. J Virol. 2007; 82(4):1980-92. PMC: 2258736. DOI: 10.1128/JVI.02742-06. View

Kumar S, Tamura K, Nei M . MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform. 2004; 5(2):150-63. DOI: 10.1093/bib/5.2.150. View

Takiguchi M . [Role of HLA in HIV-1 infection]. Uirusu. 2000; 50(1):47-55. View

Rousseau C, Daniels M, Carlson J, Kadie C, Crawford H, Prendergast A . HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load. J Virol. 2008; 82(13):6434-46. PMC: 2447109. DOI: 10.1128/JVI.02455-07. View

Hill M, Shehu-Xhilaga M, Crowe S, Mak J . Proline residues within spacer peptide p1 are important for human immunodeficiency virus type 1 infectivity, protein processing, and genomic RNA dimer stability. J Virol. 2002; 76(22):11245-53. PMC: 136739. DOI: 10.1128/jvi.76.22.11245-11253.2002. View

Luo M, Blanchard J, Pan Y, Brunham K, Brunham R . High-resolution sequence typing of HLA-DQA1 and -DQB1 exon 2 DNA with taxonomy-based sequence analysis (TBSA) allele assignment. Tissue Antigens. 1999; 54(1):69-82. DOI: 10.1034/j.1399-0039.1999.540108.x. View

Brumme Z, Tao I, Szeto S, Brumme C, Carlson J, Chan D . Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection. AIDS. 2008; 22(11):1277-86. DOI: 10.1097/QAD.0b013e3283021a8c. View

Fowke K, Nagelkerke N, Kimani J, Simonsen J, Anzala A, Bwayo J . Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet. 1996; 348(9038):1347-51. DOI: 10.1016/S0140-6736(95)12269-2. View

10.

McKinnon L, Ball T, Wachihi C, McLaren P, Waruk J, Mao X . Epitope cross-reactivity frequently differs between central and effector memory HIV-specific CD8+ T cells. J Immunol. 2007; 178(6):3750-6. DOI: 10.4049/jimmunol.178.6.3750. View

11.

Gudmundsdotter L, Bernasconi D, Hejdeman B, Sandstrom E, Alaeus A, Lidman K . Cross-clade immune responses to Gag p24 in patients infected with different HIV-1 subtypes and correlation with HLA class I and II alleles. Vaccine. 2008; 26(40):5182-7. DOI: 10.1016/j.vaccine.2008.03.094. View

12.

G Prado J, Honeyborne I, Brierley I, Puertas M, Martinez-Picado J, Goulder P . Functional consequences of human immunodeficiency virus escape from an HLA-B*13-restricted CD8+ T-cell epitope in p1 Gag protein. J Virol. 2008; 83(2):1018-25. PMC: 2612351. DOI: 10.1128/JVI.01882-08. View

13.

Kaul R, Dong T, Plummer F, Kimani J, Rostron T, Kiama P . CD8(+) lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J Clin Invest. 2001; 107(10):1303-10. PMC: 209302. DOI: 10.1172/JCI12433. View

14.

Stewart J, Watts P, Litwin S . An algorithm for mapping positively selected members of quasispecies-type viruses. BMC Bioinformatics. 2001; 2:1. PMC: 31333. DOI: 10.1186/1471-2105-2-1. View

15.

Hill M, Bellamy-McIntyre A, Vella L, Campbell S, Marshall J, Tachedjian G . Alteration of the proline at position 7 of the HIV-1 spacer peptide p1 suppresses viral infectivity in a strain dependent manner. Curr HIV Res. 2007; 5(1):69-78. DOI: 10.2174/157016207779316323. View

16.

Honeyborne I, Prendergast A, Pereyra F, Leslie A, Crawford H, Payne R . Control of human immunodeficiency virus type 1 is associated with HLA-B*13 and targeting of multiple gag-specific CD8+ T-cell epitopes. J Virol. 2007; 81(7):3667-72. PMC: 1866034. DOI: 10.1128/JVI.02689-06. View

17.

van Opijnen T, de Ronde A, Boerlijst M, Berkhout B . Adaptation of HIV-1 depends on the host-cell environment. PLoS One. 2007; 2(3):e271. PMC: 1803020. DOI: 10.1371/journal.pone.0000271. View