Frequent transmission of cytotoxic-T-lymphocyte escape mutants of human immunodeficiency virus type 1 in the highly HLA-A24-positive Japanese population.

Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Journal of Virology (Impact Factor: 4.65). 08/2004; 78(16):8437-45. DOI: 10.1128/JVI.78.16.8437-8445.2004
Source: PubMed

ABSTRACT Although Japan is classified as a country with a low prevalence of human immunodeficiency virus type 1 (HIV-1), domestic sexual transmission has been increasing steadily. Because 70% of the Japanese population expresses HLA-A24 (genotype HLA-A*2402), we wished to assess the effect of the dominant HLA type on the evolution and transmission of HIV-1 among the Japanese population. Twenty-three out of 25 A24-positive Japanese patients had a Y-to-F substitution at the second position [Nef138-10(2F)] in an immunodominant A24-restricted CTL epitope in their HIV-1 nef gene (Nef138-10). None of 12 A24-negative Japanese hemophiliacs but 9 out of 16 patients infected through unprotected sexual intercourse had Nef138-10(2F) (P < 0.01). Two of two A24-positive but none of six A24-negative Australians had Nef138-10(2F). Nef138-10(2F) peptides bound well to the HLA-A*2402 heavy chain; however, Nef138-10(2F) was expressed poorly on the cell surface from the native protein. Thus, HIV-1 with Nef138-10(2F) appears to be a cytotoxic-T-lymphocyte escape mutant and has been transmitted frequently by sexual contact among the highly A24-positive Japanese population.

Download full-text


Available from: Noriaki Hosoya, Nov 21, 2014
  • Source
    • "PBMCs from each patient were used as effectors cells. The protocol of Elispot assay was described previously [Furutsuki et al., 2004]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immuno-genetherapy using dendritic cells (DCs) can be applied to human immunodeficiency virus type 1 (HIV-1) infection. Sendai virus (SeV) has unique features such as cytoplasmic replication and high protein expression as a vector for genetic manipulation. In this study, we compared the efficiency of inducing green fluorescent protein (GFP) and HIV-1 gene expression in human monocyte-derived DCs between SeV and adenovirus (AdV). Human monocyte-derived DCs infected with SeV showed the maximum gene expression 24 hr after infection at a multiplicity of infection (MOI) of 2. Although SeV vector showed higher cytopathic effect on DCs than AdV, SeV vector induced maximum gene expression earlier and at much lower MOI. In terms of cell surface phenotype, both SeV and AdV vectors induced DC maturation. DCs infected with SeV as well as AdV elicited HIV-1 specific T-cell responses detected by interferon gamma (IFN-gamma) enzyme-linked immunospot (Elispot). Our data suggest that SeV could be one of the reliable vectors for immuno-genetherapy for HIV-1 infected patients.
    Journal of Medical Virology 03/2008; 80(3):373-82. DOI:10.1002/jmv.21052 · 2.22 Impact Factor
  • Source
    • "This happens in HIV, where the CTL selective pressure is defined and restricted by HLA, and is determined by the haplotype of each individual [14] [15] [16]. Even though escape mutations frequently come at a substantial cost to viral fitness, CTL escape mutants can be transmitted and maintained in another host lacking the original selecting HLA allele [17] [18] [19] [20], thus increasing their potential of accumulating in the population as the epidemic progresses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptive immune responses, cellular restrictive factors and antiretroviral drugs, target multiple regions in the Human Immunodeficiency Virus (HIV) proteome, imposing diverse pressures to viral adaptation. However, the virus is remarkably able to escape from these pressures as mutations are selected. In many cases these mutants have diminished viral fitness. We propose that the concerted action of strategically placed agents and pressures in a host can limit HIV variation capacity while inhibiting its replication. These mechanisms would corner HIV by selecting conflicting adaptive mutations, each having a disadvantage in face of another selective pressure. This would keep the virus unable to efficiently escape the suppressive effects of selective pressures. Cornering between antiretroviral drugs and cytotoxic T lymphocytes may explain recent observations, and can be predicted and used in viral control strategies. This idea can be extended to numerous other identified sites in the viral genome that confer selective pressures. We describe these other sites and how they could be induced to interact in prophylactic or therapeutic cornering strategies, as well as their experimental verifications. Cornering would control HIV infection better than current strategies, focused on few, albeit important, sites in the HIV genome.
    Medical Hypotheses 02/2007; 69(2):422-31. DOI:10.1016/j.mehy.2006.12.012 · 1.07 Impact Factor
  • Source
    • "ith es - cape from CTL epitopes restricted by these common HLA alleles . Such studies include HLA - B57 positive individ - uals in South Africa , HLA - A24 expression subjects in the Japanese population and others that have been used to track potential CTL epitopes by reverse genetic approaches [ Allen et al . , 2004 ; de Oliveira et al . , 2004 ; Furutsuki et al . , 2004 ; Leslie et al . , 2005 ] . Furthermore , in a recent work from our laboratory , population wide adaptation may even have rendered an HLA allele , in this case HLA - B * 1503 , from being associated with reduced viral load in a popu - lation with low allele frequency to a an allele associated with higher than average viral load in the p"
    [Show abstract] [Hide abstract]
    ABSTRACT: I-A-1 T cell immunity in HIV infection HIV specific cytotoxic T lymphocytes (CTL) and T-helper cells (Th) remain one of the cornerstones of a potential HIV vaccine, and a number of vaccine trials and recent in vitro studies point towards the importance of the close interplay between these two arms of the cellular immune response in HIV infection. As more and more vaccine candidates find their way to clinical trials, not only the question of vaccine immunogen selection but also that of the appropriate in vitro monitoring of vaccine success be-come increasingly critical issues. The chosen approaches will need to balance the optimal sensitivity with the need of inter-trial comparability, and several efforts are under way to establish widely applicable in vitro antigen test sets to monitor several parallel vaccine trials in the future. The challenge for this undertaking is considerable, given that many vaccine trials are based on non-clade B immunogens, and thus require a comprehensive knowledge of immuno-genic regions in various HIV clades, with the most pressing one likely being clade C. Part of this characterization will be the detailed delineation of the optimal CTL epitopes and their HLA restriction that are contained in these re-gions, so that reliable predictions can be made in terms of population coverage and how well local viral diversity is reflected by the vaccine sequence(s). Thus, although few laboratories nowadays follow through on identifying the precise nature of the targeted, optimal CTL epitopes in their various immunogens, we feel that epitope defi-nition is not only desirable but actually urgently needed for an optimal vaccine design and appropriate analyses of induced responses. As in the past years, we here present an updated compilation of optimally defined CTL epitopes in all regions of HIV, which increasingly also includes epi-topes defined in non-clade B infection. As argued above, especially non-clade B derived CTL epitopes will be most, editors. Publisher: Los Alamos Na-tional Laboratory, Theoretical Biology and Biophysics, Los Alamos, New Mexico. LA-UR 06-0036. p. 3–20. useful in refining vaccine approaches in the future and we thus include annotations to the epitopes indicating the test sequence used to identify the epitope. We feel that both of these additional pieces of information are important considerations as they can profoundly impact the detection rate of responses in vivo and obviously need to be included in vaccine immunogen design as well.
Show more