Human immunodeficiency virus (HIV) possesses a major threat to the human life largely due to the unavailability of an efficacious vaccine and poor access to the antiretroviral drugs against this deadly virus. High mutation rate in the viral genome underlying the antigenic variability of the viral proteome is the major hindrance as far as the antibody based vaccine development is concerned. Although the exact mechanism by which CTL epitopes and the restricting HLA alleles mediate their action towards slow disease progression is still not clear, the important CTL restricted epitopes for controlling viral infections can be utilized in future vaccine design. This study was designed for the characterization the HIV-1 optimal CTL epitopes and their corresponding HLA alleles. CTL epitope cluster distribution analysis revealed only two HIV-1 proteins, namely, Nef and Gag, which have significant cluster forming capacity. We have found the role of specific HLA supertypes such as HLA B*07, HLA B*58, and HLA A*03 in selecting the hydrophobic and conserved amino acid positions within Nef and Gag proteins, to be presented as epitopes. The analyses revealed that the clusters of optimal epitopes for Nef and p24 proteins of HIV-1 could potentially serve as a source of vaccine. 1. Introduction Human immunodeficiency virus (HIV), a retrovirus that belongs to the Lentiviridae family, is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV genome is composed of 9.8？Kb positive-sense, single-stranded RNA which is reverse transcribed by the enzyme reverse transcriptase to viral DNA upon its entry into the host cell [1]. Between the two types of HIV (HIV-1 and HIV-2), HIV-1 is more virulent and responsible for most of the HIV infections globally. Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide [2]. In Asia, an estimated 4.9 million people were living with HIV in 2009, about the same as 5 years earlier. Most national HIV epidemics appear to have stabilized. Incidence fell by more than 25% in India, Nepal, and Thailand between 2001 and 2009. The epidemic remained stable in Malaysia and Sri Lanka during this time period. Incidence increased by 25% in Bangladesh and Philippines between 2001 and 2009 even as the countries continue to have relatively low epidemic levels [3]. Although the antiretroviral therapy has proven to be effective in controlling the infection in the developed world, only one-fourth populations in the developing world can afford these medications due to less
References
[1]
M. D. Moore and W. S. Hu, “HIV-1 RNA dimerization: it takes two to tango,” AIDS Reviews, vol. 11, no. 2, pp. 91–102, 2009.
[2]
United Nations Programme on HIV/AIDS. Global Report fact sheet: the global AIDS epidemic, 2010, http://www.unaids.org/documents/20101123_FS_Global_em_en.pdf.
[3]
Report on the Global AIDS Epidemic, UNAIDS, 2013.
[4]
J. M. Costin, “Cytopathic mechanisms of HIV-1,” Virology Journal, vol. 4, article 100, 2007.
[5]
J. Hemelaar, E. Gouws, P. D. Ghys, and S. Osmanov, “Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004,” AIDS, vol. 20, no. 16, pp. W13–W23, 2006.
[6]
M. M. Thomson, L. Pérez-álvarez, and R. Nájera, “Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy,” The Lancet Infectious Diseases, vol. 2, no. 8, pp. 461–471, 2002.
[7]
I. M. Roitt and P. J. Delves, Roitt's Essential Immunology, Blackwell Science, London, UK, 10th edition, 2001.
[8]
M. Lucchiari-Hartz, V. Lindo, N. Hitziger et al., “Differential proteasomal processing of hydrophobic and hydrophilic protein regions: contribution to cytotoxic T lymphocyte epitope clustering in HIV-1-Nef,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 13, pp. 7755–7760, 2003.
[9]
M. P. Davenport and J. Petravic, “CD8+ T cell control of HIV—a known unknown,” PLoS Pathogens, vol. 6, no. 1, Article ID e1000728, 2010.
[10]
P. Kunwar, N. Hawkins, W. L. Dinges, et al., “Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design,” PLoS ONE, vol. 8, no. 5, Article ID e64405, 2013.
[11]
M. E. Severino, N. V. Sipsas, P. T. Nguyen et al., “Inhibition of human immunodeficiency virus type 1 replication in primary CD4+ T lymphocytes, monocytes, and dendritic cells by cytotoxic T lymphocytes,” Journal of Virology, vol. 74, no. 14, pp. 6695–6699, 2000.
[12]
Y. Zhou, R. Bao, N. L. Haigwood, Y. Persidsky, and W. Ho, “SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans,” Retrovirology, vol. 10, no. 89, 2013.
[13]
P. J. Goulder and D. I. Watkins, “Impact of MHC class I diversity on immune control of immunodeficiency virus replication,” Nature Reviews Immunology, vol. 8, no. 8, pp. 619–630, 2008.
[14]
M. R. Betts, J. P. Casazza, and R. A. Koup, “Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production,” Immunology Letters, vol. 79, no. 1-2, pp. 117–125, 2001.
[15]
D. F. Nixon, A. R. M. Townsend, J. G. Elvin, C. R. Rizza, J. Gallwey, and A. J. McMichael, “HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides,” Nature, vol. 336, no. 6198, pp. 484–487, 1988.
[16]
A. Llanoa, N. Frahm, and C. Brander, “How to optimally define optimal cytotoxic T lymphocyte epitopes in HIV infection?” HIV Molecular Immunology, vol. 3, no. 24, 2009.
[17]
C. Zhang, J. L. Cornette, J. A. Berzofsky, and C. DeLisi, “The organization of human leucocyte antigen class I epitopes in HIV genome products: implications for HIV evolution and vaccine design,” Vaccine, vol. 15, no. 12-13, pp. 1291–1302, 1997.
[18]
K. Yusim, C. Kesmir, B. Gaschen et al., “Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation,” Journal of Virology, vol. 76, no. 17, pp. 8757–8768, 2002.
[19]
J. R. Currier, U. Visawapoka, S. Tovanabutra et al., “CTL epitope distribution patterns in the Gag and Nef proteins of HIV-I from subtype A infected subjects in Kenya: use of multiple peptide sets increases the detectable breadth of the CTL response,” BMC Immunology, vol. 7, article 8, 2006.
[20]
B. Culmann-Penciolelli, S. Lamhamedi-Cherradi, I. Couillin et al., “Identification of multirestricted immunodominant regions recognized by cytolytic T lymphocytes in the human immunodeficiency virus type 1 Nef protein,” Journal of Virology, vol. 68, no. 11, pp. 7336–7343, 1994.
[21]
C. L. Kuiken, B. T. Foley, E. Guzman, and B. T. Korber, Molecular Evolution of HIV, Johns Hopkins University Press, Baltimore, Md, USA, 1999.
[22]
A. Telenti and D. B. Goldstein, “Genomics meets HIV-1,” Nature Reviews Microbiology, vol. 4, no. 11, pp. 865–873, 2006.
[23]
M. Vajpayee, N. Negi, and S. Kurapati, “The enduring tale of T cells in HIV immunopathogenesis,” Indian Journal of Medical Research, vol. 138, pp. 682–699, 2013.
[24]
J. Fellay, K. V. Shianna, D. Ge et al., “A whole-genome association study of major determinants for host control of HIV-1,” Science, vol. 317, no. 5840, pp. 944–947, 2007.
[25]
S. G. E. Marsh, P. Parham, and L. D. Barber, The HLA Facts Book, Academic Press, London, UK, 2000.
[26]
X. Gao, G. W. Nelson, P. Karacki et al., “Effect of a single amino acid change in MHC class I molecules on the rate of progression to aids,” The New England Journal of Medicine, vol. 344, no. 22, pp. 1668–1675, 2001.
[27]
S. A. Migueles, M. S. Sabbaghian, W. L. Shupert et al., “HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 6, pp. 2709–2714, 2000.
[28]
J. R. Bailey, T. M. Williams, R. F. Siliciano, and J. N. Blankson, “Maintenance of viral suppression in HIV-1-infected HLA-B*57 + elite suppressors despite CTL escape mutations,” Journal of Experimental Medicine, vol. 203, no. 5, pp. 1357–1369, 2006.
[29]
R. Wagner, B. Leschonsky, E. Harrer et al., “Molecular and functional analysis of a conserved CTL epitope in HIV-1 p24 recognized from a long-term nonprogressor: Constraints on immune escape associated with targeting a sequence essential for viral replication,” Journal of Immunology, vol. 162, no. 6, pp. 3727–3734, 1999.
[30]
P. Klepiela, A. J. Leslie, I. Honeyborne et al., “Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA,” Nature, vol. 432, no. 7018, pp. 769–774, 2004.
[31]
F. Bihl, N. Frahm, L. Di Giammarino et al., “Impact of HLA-B alleles, epitope binding affinity, functional avidity, and viral coinfection on the immunodominance of virus-specific CTL responses,” Journal of Immunology, vol. 176, no. 7, pp. 4094–4101, 2006.
[32]
A. I. F. Costaa, X. Rao, E. LeChenadecb, D. V. Baarlea, and C. Kesmirb, “HLA-B molecules target more conserved regions of the HIV-1 proteome,” AIDS, vol. 24, pp. 211–215, 2010.
