Cytolytic T Lymphocytes (CTLs) from HIV-1 Subtype C–Infected Indian Patients Recognize CTL Epitopes from a Conserved Immunodominant Region of HIV-1 Gag and Nef
ABSTRACT Analysis of the human immunodeficiency virus type 1 (HIV-1) cytolytic T lymphocyte (CTL) epitopes recognized by the targeted population is critical for HIV-1 vaccine design. Peripheral blood mononuclear cells from 47 Indian subjects at different stages of HIV-1 infection were tested for HIV-1 Gag-, Nef-, and Env-specific T cell responses by interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) assay, using pools of overlapping peptides. The Gag and Nef antigens were targeted by 83% and 36% of responders. Five immunodominant regions, 4 in Gag and 1 in Nef, were identified in the study; these regions are conserved across clades, including the African subtype C clade. Three antigenic regions were also found to be recognized by CTLs of the study participants. These regions were not identified as immunodominant regions in studies performed in Africa, which highlights the importance of differential clustering of responses within HIV-1 subtype C. Twenty-six putative epitopes--15 Gag (10 in p24 and 5 in p17), 10 Nef, and 1 Env (gp 41)--were predicted using a combination of peptide matrix ELISPOT assay and CTL epitope-prediction software. Ninety percent of the predicted epitopes were clustered in the conserved immunodominant regions of the Gag and Nef antigens. Of 26 predicted epitopes, 8 were promiscuous, 3 of which were highly conserved across clades. Three Gag and 4 Nef epitopes were novel. The identification of conserved epitopes will be important in the planning of an HIV-1 vaccine strategy for subtype C-affected regions.
- SourceAvailable from: Ramesh S Paranjape[Show abstract] [Hide abstract]
ABSTRACT: The year 1986 saw first case of HIV infection as well as first report of AIDS case in India. Since then the epidemic has spread throughout the country.In the recent years there is evidence of epidemic being stabilized with decrease in new infections reported from some parts of the country. The absolute number of HIV infections in the country is expected to be close to 2.5 million and National AIDS Control Programme, phase III is geared to contain the epidemic. HIV viruses circulating in India predominantly belong to HIV-1 subtype C. However, there have been occasional reports of HIV-1 subtype A and B. Matter of concern is reports of A/C and B/C mosaic viruses that are being reported from different parts of the country. The data on HIV drug resistance from India is rather limited. Most of the studies have shown that the virus strains from drug naive patients do not show significant level of drug resistance mutations. The few immunological studies in Indian patients show that the Indian HIV infected patients show both HIV-specific CTL responses as well as neutralizing antibody response. Mapping of CTL epitopes showed that while Indian patients identify same regions of Gag antigen as recognized by South African subtype C infected patients, some regions are uniquely recognized by Indian patients. There are very few studies on host genetic factors in India in context with HIV infection.However there are evidences reported of association of host genetic factors such as HLA types and haplotypes and HIV disease.Journal of Biosciences 12/2008; 33(4):515-25. DOI:10.1007/s12038-008-0070-3 · 1.94 Impact Factor
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ABSTRACT: Genome sequence analysis of HIV-1 subtype C viruses from India shows monophyletic lineage and relatively limited genetic diversity. To understand its immunological implication, cross-reactivity of neutralizing antibody response was investigated. In primary screening, neutralizing antibody response to single heterologous primary HIV-1 subtype C isolate was assessed in plasma samples from 235 HIV-1 infected, anti-retroviral treatment naive individuals from Pune, India. Plasma samples that showed > or =90% neutralization and two randomly selected plasma samples that showed 50-60% neutralization were tested against a panel of primary HIV-1 subtype C isolates obtained from epidemiologically unlinked individuals from India. The neutralizing antibody response showed extensive cross-neutralization, suggesting presence of shared neutralization determinants among circulating HIV-1 subtype C viruses in India.Virology 03/2007; 359(2):295-301. DOI:10.1016/j.virol.2006.09.019 · 3.28 Impact Factor
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ABSTRACT: Influenza A viruses generate an extreme genetic diversity through point mutation and gene segment exchange, resulting in many new strains that emerge from the animal reservoirs, among which was the recent highly pathogenic H5N1 virus. This genetic diversity also endows these viruses with a dynamic adaptability to their habitats, one result being the rapid selection of genomic variants that resist the immune responses of infected hosts. With the possibility of an influenza A pandemic, a critical need is a vaccine that will recognize and protect against any influenza A pathogen. One feasible approach is a vaccine containing conserved immunogenic protein sequences that represent the genotypic diversity of all current and future avian and human influenza viruses as an alternative to current vaccines that address only the known circulating virus strains. Methodologies for large-scale analysis of the evolutionary variability of the influenza A virus proteins recorded in public databases were developed and used to elucidate the amino acid sequence diversity and conservation of 36,343 sequences of the 11 viral proteins of the recorded virus isolates of the past 30 years. Technologies were also applied to identify the conserved amino acid sequences from isolates of the past decade, and to evaluate the predicted human lymphocyte antigen (HLA) supertype-restricted class I and II T-cell epitopes of the conserved sequences. Fifty-five (55) sequences of 9 or more amino acids of the polymerases (PB2, PB1, and PA), nucleoprotein (NP), and matrix 1 (M1) proteins were completely conserved in at least 80%, many in 95 to 100%, of the avian and human influenza A virus isolates despite the marked evolutionary variability of the viruses. Almost all (50) of these conserved sequences contained putative supertype HLA class I or class II epitopes as predicted by 4 peptide-HLA binding algorithms. Additionally, data of the Immune Epitope Database (IEDB) include 29 experimentally identified HLA class I and II T-cell epitopes present in 14 of the conserved sequences. This study of all reported influenza A virus protein sequences, avian and human, has identified 55 highly conserved sequences, most of which are predicted to have immune relevance as T-cell epitopes. This is a necessary first step in the design and analysis of a polyepitope, pan-influenza A vaccine. In addition to the application described herein, these technologies can be applied to other pathogens and to other therapeutic modalities designed to attack DNA, RNA, or protein sequences critical to pathogen function.PLoS ONE 02/2007; 2(11):e1190. DOI:10.1371/journal.pone.0001190 · 3.53 Impact Factor