Although individuals infected with the human immunodeficiency virus (HIV) develop relatively vigorous humoral and cellular immune responses, the vast majority will go on to develop progressive immunosuppression associated with a persistent, high titer viremia. However, early in the course of HIV infection, immune responses appear to be able to suppress viral infection, an observation which suggests that the development of AIDS may be due to the escape of HIV from initially effective immune responses. Although the immune mechanisms responsible for the suppression of HIV replication in vivo have not yet been precisely defined, cytotoxic T lymphocytes (CTL) are likely to play an important role. The goal of this proposal is to examine the mechanisms by which HIV may escape recognition by CTL. This detailed examination of possible mechanisms of escape will also address some of the limitations of previous studies of HIV-1-specific CTL, including the lack of data using target cells expressing viral antigens from homologous isolates and the paucity of information on the recognition of HIV-infected cells.
Specific aims i nclude: 1. Analysis of the role of sequence variation in HIV in producing viral mutants which can escape recognition by CTL. These experiments will focus on HIV-1 seropositive subjects in whom the infecting genotype is known and for whom recombinant vaccinia viruses are available which express homologous HIV-1 proteins. Goals of these experiments include: a. definition of epitopes recognized by CTL from these subjects; b. determination of the effects of amino acid variation within these epitopes on recognition by CTL; c. analysis of sequence variation in HIV-1 DNA coding for these CTL epitopes; and d. longitudinal analysis of the frequency of CTL escape mutants and their recognition by CTL. 2. Examination of the recognition of HIV-1-infected cells by CTL. These experiments will analyze the lysis of HIV-1 infected cells by CTL specific for HIV-1 structural proteins, the kinetics of HIV-1 replication in relation to susceptibility to lysis by HIV-1-specific CTL, and the recognition of chronically infected cell lines with minimal constitutive production of HIV-1 by CTL specific for HIV-1 regulatory proteins. 3. Determination of the role of down-modulation of cell surface antigens by HIV-1 infection in escape from immune recognition by CTL. HIV-infected cells will be examined at various time points following infection for susceptibility to lysis by CTL and the expression of various cell surface molecules including HLA class I, LFA-1 and LFA-3. The identification of mechanisms by which HIV may escape host defenses is likely to have important implications for efforts to develop effective vaccines against HIV and to implement therapeutic strategies to delay or prevent the onset of immunosuppression in those who are already infected. These experiments may also reveal mechanisms used by virus-induced tumors or other human retroviruses such as HTLV-1 to escape recognition by the host immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI033327-01
Application #
3456241
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1992-07-01
Project End
1997-04-30
Budget Start
1992-07-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Brander, C; Yang, O O; Jones, N G et al. (1999) Efficient processing of the immunodominant, HLA-A*0201-restricted human immunodeficiency virus type 1 cytotoxic T-lymphocyte epitope despite multiple variations in the epitope flanking sequences. J Virol 73:10191-8
Wang, F; Seldin, D C; Annis, B et al. (1998) Immune modulation of human B lymphocytes by gene transfer with recombinant Epstein-Barr virus amplicons. J Virol Methods 72:81-93
Wilson, C C; Kalams, S A; Wilkes, B M et al. (1997) Overlapping epitopes in human immunodeficiency virus type 1 gp120 presented by HLA A, B, and C molecules: effects of viral variation on cytotoxic T-lymphocyte recognition. J Virol 71:1256-64
Sipsas, N V; Kalams, S A; Trocha, A et al. (1997) Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1. J Clin Invest 99:752-62
Yang, O O; Kalams, S A; Rosenzweig, M et al. (1996) Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J Virol 70:5799-806
Johnson, R P; Hammond, S A; Trocha, A et al. (1994) Induction of a major histocompatibility complex class I-restricted cytotoxic T-lymphocyte response to a highly conserved region of human immunodeficiency virus type 1 (HIV-1) gp120 in seronegative humans immunized with a candidate HIV-1 vaccine. J Virol 68:3145-53
Kalams, S A; Johnson, R P; Trocha, A K et al. (1994) Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J Exp Med 179:1261-71