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.
