Person: KHAN, MOHAMMAD ASİF
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Publication Metadata only Dissecting the Dynamics of HIV-1 Protein Sequence Diversity(2013-04-01T00:00:00Z) Hu, Yongli; Tan, Paul ThiamJoo; Tan, Tin Wee; August, J. Thomas; KHAN, MOHAMMAD ASİF; KHAN, MOHAMMAD ASİFThe rapid mutation of human immunodeficiency virus-type 1 (HIV-1) and the limited characterization of the composition and incidence of the variant population are major obstacles to the development of an effective HIV-1 vaccine. This issue was addressed by a comprehensive analysis of over 58,000 clade B HIV-1 protein sequences reported over at least 26 years. The sequences were aligned and the 2,874 overlapping nonamer amino acid positions of the viral proteome, each a possible core binding domain for human leukocyte antigen molecules and T-cell receptors, were quantitatively analyzed for four patterns of sequence motifs: (1) -index-, the most prevalent sequence; (2) -major- variant, the most common variant sequence; (3) -minor- variants, multiple different sequences, each with an incidence less than that of the major variant; and (4) -unique- variants, each observed only once in the alignment. The collective incidence of the major, minor, and unique variants at each nonamer position represented the total variant population for the position. Positions with more than 50% total variants contained correspondingly reduced incidences of index and major variant sequences and increased minor and unique variants. Highly diverse positions, with 80 to 98% variant nonamer sequences, were present in each protein, including 5% of Gag, and 27% of Env and Nef, each. The multitude of different variant nonamer sequences (i.e. nonatypes; up to 68%) at the highly diverse positions, represented by the major, multiple minor, and multiple unique variants likely supported variants function both in immune escape and as altered peptide ligands with deleterious T-cell responses. The patterns of mutational change were consistent with the sequences of individual HXB2 and C1P viruses and can be considered applicable to all HIV-1 viruses. This characterization of HIV-1 protein mutation provides a foundation for the design of peptide-based vaccines and therapeutics.Publication Metadata only Analysis of viral diversity for vaccine target discovery(2017-12-01T00:00:00Z) Khan, Asif M.; Hu, Yongli; Miotto, Olivo; Thevasagayam, Natascha M.; Sukumaran, Rashmi; Raman, Hadia Syahirah Abd; Brusic, Vladimir; Tan, Tin Wee; August, J. Thomas; KHAN, MOHAMMAD ASİFBackground: Viral vaccine target discovery requires understanding the diversity of both the virus and the human immune system. The readily available and rapidly growing pool of viral sequence data in the public domain enable the identification and characterization of immune targets relevant to adaptive immunity. A systematic bioinformatics approach is necessary to facilitate the analysis of such large datasets for selection of potential candidate vaccine targets.Publication Metadata only West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands(2012-07-01T00:00:00Z) Jung, Keun-Ok; KHAN, MOHAMMAD ASİF; Tan, Benjamin Yong Liang; Hu, Yongli; Simon, Gregory G.; Nascimento, Eduardo J. M.; Lemonnier, Francois; Brusic, Vladimir; Miotto, Olivo; Tan, Tin Wee; Marques, Ernesto T. A.; Dhalia, Rafael; Salmon, Jerome; August, J. Thomas; KHAN, MOHAMMAD ASİFPhylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirus protein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restricted West Nile virus (WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in similar to >= 88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design of Flavivirus vaccines.Publication Metadata only Dendritic Cell Mediated Delivery of Plasmid DNA Encoding LAMP/HIV-1 Gag Fusion Immunogen Enhances T Cell Epitope Responses in HLA DR4 Transgenic Mice(2010-01-01T00:00:00Z) Simon, Gregory G.; Hu, Yongli; KHAN, MOHAMMAD ASİF; Zhou, Jingshi; Salmon, Jerome; Chikhlikar, Priya R.; Jung, Keun-Ok; Marques, Ernesto T. A.; August, J. Thomas; KHAN, MOHAMMAD ASİFThis report describes the identification and bioinformatics analysis of HLA-DR4-restricted HIV-1 Gag epitope peptides, and the application of dendritic cell mediated immunization of DNA plasmid constructs. BALB/c (H-2d) and HLA-DR4 (DRA1*0101, DRB1*0401) transgenic mice were immunized with immature dendritic cells transfected by a recombinant DNA plasmid encoding the lysosome-associated membrane protein-1/HIV-1 Gag (pLAMP/gag) chimera antigen. Three immunization protocols were compared: 1) primary subcutaneous immunization with 1x10(5) immature dendritic cells transfected by electroporation with the pLAMP/gag DNA plasmid, and a second subcutaneous immunization with the naked pLAMP/gag DNA plasmid; 2) primary immunization as above, and a second subcutaneous immunization with a pool of overlapping peptides spanning the HIV-1 Gag sequence; and 3) immunization twice by subcutaneous injection of the pLAMP/gag DNA plasmid. Primary immunization with pLAMP/gag-transfected dendritic cells elicited the greatest number of peptide specific T-cell responses, as measured by ex vivo IFN-gamma ELISpot assay, both in BALB/c and HLA-DR4 transgenic mice. The pLAMP/gag-transfected dendritic cells prime and naked DNA boost immunization protocol also resulted in an increased apparent avidity of peptide in the ELISpot assay. Strikingly, 20 of 25 peptide-specific T-cell responses in the HLA-DR4 transgenic mice contained sequences that corresponded, entirely or partially to 18 of the 19 human HLA-DR4 epitopes listed in the HIV molecular immunology database. Selection of the most conserved epitope peptides as vaccine targets was facilitated by analysis of their representation and variability in all reported sequences. These data provide a model system that demonstrates a) the superiority of immunization with dendritic cells transfected with LAMP/gag plasmid DNA, as compared to naked DNA, b) the value of HLA transgenic mice as a model system for the identification and evaluation of epitope-based vaccine strategies, and c) the application of variability analysis across reported sequences in public databases for selection of historically conserved HIV epitopes as vaccine targets.Publication Metadata only Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes(2013-10-01T00:00:00Z) Nascimento, Eduardo J. M.; Mailliard, Robbie B.; KHAN, MOHAMMAD ASİF; Sidney, John; Sette, Alessandro; Guzman, Nicole; Paulaitis, Michael; de Melo, Andrea Barbosa; Cordeiro, Marli T.; Gil, Laura V. G.; Lemonnier, Francoir; Rinaldo, Charles; August, J. Thomas; Marques, Ernesto T. A.; KHAN, MOHAMMAD ASİFAnti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naive T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter-and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design.Publication Metadata only g-FLUA2H: a web-based application to study the dynamics of animal-to-human mutation transmission for influenza viruses(2015-01-01T00:00:00Z) Sjaugi, Muhammad Farhan; Tan, Swan; Abd Raman, Hadia Syahirah; Lim, Wan Ching; Mohamed, Nik Elena Nik; August, J. Thomas; Khan, Asif M.; KHAN, MOHAMMAD ASİFg-FLUA2H is a web-based application focused on the analysis of the dynamics of influenza virus animal-to-human (A2H) mutation transmissions. The application only requires the viral protein sequences from both the animal and human host populations as input datasets. The comparative analyses between the co-aligned sequences of the two viral populations is based on a sliding window approach of size nine for statistical significance and data application to the major histocompatibility complex (MHC) and T-cell receptor (TCR) immune response mechanisms. The sequences at each of the aligned overlapping nonamer positions for the respective virus hosts are classified as four patterns of characteristic diversity motifs, as a basis for quantitative analyses: (i) -index-, the most prevalent sequence; (ii) -major- variant, the second most common sequence and the single most prevalent variant of the index, with at least one amino acid mutation; (iii) -minor- variants, multiple different sequences, each with an incidence (percent occurrence) less than that of the major variant; and (iv) -unique- variants, each with only one occurrence in the alignment. The diversity motifs and their incidences at each of the nonamer positions allow evaluation of the mutation transmission dynamics and selectivity of the viral sequences in relation to the animal and the human hosts. g-FLUA2H is facilitated by a grid back-end for parallel processing of large sequence datasets. The web-application is publicly available at http://bioinfo.perdanauniversity.edu.my/g-FLUA2H. It can be used for a detailed characterization of the composition and incidence of mutations present in the proteomes of influenza viruses from animal and human host populations, for a better understanding of host tropism.Publication Metadata only Highly conserved influenza A sequences as T cell epitopes-based vaccine targets to address the viral variability(2011-04-01T00:00:00Z) Tan, Paul ThiamJoo; KHAN, MOHAMMAD ASİF; August, J. Thomas; KHAN, MOHAMMAD ASİFVaccines are the only proven effective method for prevention of human infectious diseases. Almost all traditional vaccines require activating immunological memory B cells to secrete neutralizing antibodies against invading pathogens. The complication with influenza viruses is the high viral mutation rate that results in immune escape through modification of the B cell epitopes. Studies of T cell immunity to influenza infection provide an alternative vaccine strategy based on highly conserved T cell epitopes. In this review, we discuss the importance of T cell-mediated immunity in influenza infection and the need for a targeted vaccine approach focused on highly conserved T cell epitopes to mitigate immune escape. We propose 15 highly conserved pan-influenza sequences as potential T cell epitopes-based vaccine targets for broad protection and lasting immunity against variant influenza strains.