Identification of the viral molecules recognised by influenza specific human cytoxic T lymphocytes.

Human cytotoxic T cells specific for influenza A virus were tested for recognition of each of the ten influenza A virus proteins expressed in target cells using recombinant vaccinia viruses. They recognized the matrix M1, polymerase PB2, and nucleoproteins of influenza virus in association with MHC class I antigens. These internal viral proteins were seen by CTL in conjunction with one or more of the available dependent HLA gene products. There was no detectable recognition of influenza virus surface glycoproteins in target cells

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment

A proportion of human immunodeficiency virus (HIV)–infected patients develop persistent, stigmatizing human papillomavirus (HPV)–related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)–treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended

HLA B37 determines an influenza A virus nucleoprotein epitope recognized by cytotoxic T lymphocytes.

Human influenza A virus-specific, cytotoxic T cells have been shown previously to recognize the virus nucleoprotein on infected cells. CTL preparations from four HLA B37-positive donors were shown to recognize a synthetic peptide that corresponded to amino acids 335-349 of the nucleoprotein sequence. Influenza-specific CTL from 10 donors of other HLA types failed to recognize this epitope. CD8+ CTL lines were derived from lymphocytes of two HLA B37-positive donors and used to show that the peptide was represented on virus-infected cells and to determine the probable boundaries of the epitope

Lysis of allogeneic human lymphocytes by nonspecifically activated T-like cells.

In the generation of cytotoxic effector cells specific for influenza A virus-infected lymphocytes, three donors have given an unusual pattern of lytic activity, killing HLA-mismatched target cells. This has been analyzed in detail for one donor and one of the other two shows similar results. Activation only requires culture in medium between 1 and 4 days and parallels development of cell line K562-directed natural killer cells. Target lymphocytes do not need to be virus-infected and appear to be normal lymphocytes. The effector cells carry the surface markers T3 and T8 defined by OKT3/anti-Leu4 and OKT8/anti-Leu2a monoclonal antibodies, respectively. Unlike HLA class 1-restricted or -directed cytotoxic T cells, neither anti-Leu2a/nor anti-Leu4 blocked killing in the absence of complement. MHM23, a monoclonal antibody specific for the human lymphocyte function antigen, blocked lysis. The results indicate that these effector cells are related to cytotoxic T lymphocytes, but can lyse allogeneic target cells through a different recognition process. There is some specificity because autologous cells were not killed

Cytotoxic T cells recognize fragments of the influenza nucleoprotein.

Recent work has shown that a major population of murine influenza A specific cytotoxic T lymphocytes (CTL) recognize the viral nucleoprotein. In order to investigate the mechanism by which this nonglycoprotein component of the virus is recognized by CTL, a series of deletion mutants of an A virus NP gene were studied. The results showed that CTL recognize three distinct epitopes of the NP molecule. Both N- and C-terminal fragments of the protein are transported, independently of each other, to the site of recognition by CTL. These findings imply that a mechanism may exist for transport to the cell surface and presentation to CTL, of viral proteins and protein fragments that lack defined signal sequences

Class I cross-restricted T cells reveal low responder allele due to processing of viral antigen.

Cytotoxic T lymphocytes (CTL) recognize protein antigens which have been processed by the target cell and then presented in association with the relevant class I molecule of the major histocompatibility complex (MHC). Short synthetic peptides, which are able to associate directly with target cells, may substitute for these processed fragments in stimulating antigen-specific CTL responses. Using this approach, a dominant HLA-A2-restricted epitope has previously been mapped to residues 58-68 of influenza A virus matrix protein. Here we report HLA-A2-restricted CTL which are also able to recognize this short synthetic peptide in association with HLA-Aw69, but which fail to recognize HLA-Aw69 expressing cells infected with influenza A virus. Furthermore, individuals possessing HLA-Aw69 who respond to influenza A virus, do not respond to M58-68. These results imply that the low response to this epitope on infection of HLA-Aw69 individuals with influenza A is due to failure of the naturally processed product of matrix protein to associate with Aw69

A human lymphocyte-associated antigen involved in cell-mediated lympholysis.

Human lymphocyte function antigen (HLFA) is a cell surface protein defined by two monoclonal antibodies MHM23 and MHM24. It is present on both B and T lymphocytes but in greater amounts on the latter. Both antibodies precipitated antigen, from radiolabeled HSB-2 cells, which ran as two chains on sodium dodecyl sulfate polyacrylamide gel electrophoresis at 180 and 94 kDa. Neither antibody inhibited binding of the other, indicating that distinct epitopes were recognized. Both antibodies were shown to inhibit HLA-restricted lysis of influenza virus-infected and Epstein-Barr virus-transformed target cells by cytotoxic T lymphocytes. Blocking occurred at the level of the effector cells and in the presence of subsaturating concentrations of antibody. Both reagents also inhibited lysis of K562 cells, mediated by natural killer cells. These blocking effects differ from the inhibitory effects of monoclonal anti-HLA ABC and anti-suppressor cytotoxic T cell antibodies which inhibit only HLA-restricted lysis when present in saturating amounts. It is concluded therefore that HLFA is likely to be involved in the nonspecific adherence or lytic functions of killer cells rather than specific antigen recognition

Cytotoxic T-cell immunity to influenza.

In a study designed to determine whether cytotoxic T lymphocytes contribute to immunity against influenza virus infection, we inoculated 63 volunteers intranasally with live unattenuated influenza A/Munich/1/79 virus. Over the next seven days clinical observations were made, and the amount of virus shed was measured. The protective effects of preinfection serum antibody and of cytotoxic T-cell immunity against influenza A virus were assessed for each participant. All subjects with demonstrable T-cell responses cleared virus effectively. This response was observed in volunteers in all age groups, including those born after 1956, who did not have specific antibody and hence had probably not been exposed to this subtype of influenza A virus before. Cytotoxic T cells show cross-reactivity in their recognition of the different subtypes of influenza A virus, in contrast to the antibody response that is specific for each virus subtype. We conclude that cytotoxic T cells play a part in recovery from influenza virus infection