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ABSTRACTCytotoxic T-lymphocyte (CTL) responses directed to different human immunodeficiency virus (HIV) epitopes vary in their protective efficacy. In particular, HIV-infected cells are much more sensitive to lysis by anti-Gag/p17(77-85)/HLA-A2 than to that by anti-polymerase/RT(476-484)/HLA-A2 CTL, because of a higher density of p17(77-85) complexes. This report describes multiple processing steps favoring the generation of p17(77-85) complexes: (i) the exact COOH-terminal cleavage of epitopes by cellular proteases occurred faster and more frequently for p17(77-85) than for RT(476-484), and (ii) the binding efficiency of the transporter associated with antigen processing was greater for p17(77-85) precursors than for the RT(476-484) epitope. Surprisingly, these peptides, which differed markedly in their antigenicity, displayed qualitatively and quantitatively similar immunogenicity, suggesting differences in the mechanisms governing these phenomena. Here, we discuss the mechanisms responsible for such differences.

We have optimized the induction of antiviral cytotoxic T lymphocytes (CTL) in rhesus macaques by a lipopeptide vaccine containing seven peptides from simian immunodeficiency virus (SIV) Nef and Gag proteins and a strong T-helper peptide from tetanus toxoid (TT) that is promiscuous in humans (peptide TT 830-846). Two of the eight immunized macaques showed T-helper (Th) cell proliferation and a specific synthesis of gamma interferon in response to TT 830-846 peptide. They also showed multispecific cytotoxic activity against three to five of the immunizing SIV peptides. These results show the importance of a strong specific type 1 Th response for inducing a multispecific CTL response in vivo, which is essential for the development of an anti-human immunodeficiency virus vaccine.

Human immunodeficiency virus (HIV) induces a profound disorganization of the lymphoid tissues with marked abnormalities of the immune system at the terminal stage of infection. Since the digestive mucosal immune system is by far the largest lymphoid organ of the body, we attempted to evaluate its functional activity in advanced stages of simian immunodeficiency virus (SIV) infection in the SIV-macaque model of HIV infection. Two chronically intravenously SIV-infected macaques, including one at the AIDS stage, were studied. Intestinal intraepithelial lymphocytes (IEL) were isolated, analyzed, and compared to lymphocytes obtained from blood, spleen, and different lymph nodes: IEL were predominantly CD8+ T lymphocytes expressing the alphaE beta7 integrin and lacking the CD28 coactivatory molecule. A direct ex vivo SIV-specific cytotoxic activity was prominently found in the IEL of both macaques and was weaker or absent in the other sites. To our knowledge, this is the first report of SIV-specific cytotoxic activity from small intestine IEL in SIV-infected macaques. Considering the high similitude of the SIV-macaque model with the HIV infection in humans, these results may be highly important for the pathogenesis of HIV infection and more generally important for the characterization and function of digestive CD8+ IEL population.

Peripheral blood mononuclear cells from a large number of human immunodeficiency virus (HIV)-seropositive donors were used to analyze the CD8+ T-cell response to each part of the Nef protein of HIV-1/LAI. This report identifies an immunodominant region (amino acids 73 to 144) in the Nef protein that was recognized by 97% of the NEF responder donors. This peptide sequence was dissected into four epitopic regions (amino acids 73 to 82, 83 to 97, 113 to 128, and 126 to 144), each of which was recognized under different HLA class I restrictions. Short overlapping peptides were used to sensitive the target cells for cytolysis and so to determine if these epitopic regions were multirestricted. Each region was found to contain several epitopes recognized with different HLA molecules. Thus, the central region of the Nef protein, a regulatory protein expressed early in HIV-infected cells, is rich in epitopic sequences which are found to be similar in many infected individuals and which can be recognized in association with at least ten HLA class I molecules. Their implications for the vaccination of humans with peptide sequences are discussed.

Human helper T-cell (Th) responses to influenza A virus were studied by analyzing T-cell receptor V beta gene diversity in hemagglutinin-specific Th lymphocytes. The T-lymphocyte population from peripheral blood became quickly oligoclonal when stimulated in vitro with the HA306-329 peptide, and T-cell receptor V beta 3 genes were mainly expanded. Moreover, specific junctional region oligonucleotide probes corresponding to hemagglutinin-specific clones were used to estimate temporal diversity during antigenic stimulations.

Distinct functional CD8+ T-cell populations have been observed during human immunodeficiency virus (HIV) infection. One of these functions is the inhibition of viral replication by a noncytotoxic mechanism, which was shown to be mediated by the CD8+CD28+ subpopulation. On the other hand, CD8+ T cells exert an HIV-specific cytotoxic activity. The present study shows that CD8+CD28- lymphocytes display this HIV-specific cytotoxic activity, which is detectable immediately after the cells are purified from peripheral blood. The CD28- population is also able to proliferate and to retain its cytotoxic activity after in vitro restimulation with autologous blast cells. Finally, HIV-specific cytotoxic T cells can be obtained in vitro from the CD8+CD28+ population.