An HIV-1 envelope protein vaccine elicits a functionally complex human CD4+ T cell response that includes cytolytic T lymphocytes

Abstract

T cell responses play a critical role in host defense against viral infection. Therefore, the functional properties of HIV-1-specific human T cells induced by an experimental AIDS vaccine were analyzed in detail at the clonal level. Seronegative human volunteers were immunized with a purified recombinant form of the HIV-1 envelope glycoprotein gp160 in a phase I vaccine trial. In a subset of gp160 recipients, this vaccine was shown to elicit a virus-specific CTL response. Antibody blocking and single cell cloning experiments demonstrated that the vaccine-induced cytolytic activity was mediated by CD4+, MHC class II-restricted T cells. Because little is known about the regulation of CD4+ CTL in any system, a detailed analysis of CTL responses in vaccinees was carried out. Longitudinal and cross-sectional studies revealed that the CD4+ CTL response was regulated in a complex manner and was not clearly correlated with MHC class II genotype, Ag dose, or number of immunizations. Cloning studies were carried out to determine what fraction of the vaccine-induced T cells were cytolytic and to examine patterns of cytokine production by vaccine-induced T cells. These experiments demonstrated that, for some vaccinees, CD4+ CTL dominated the in vitro T cell response to gp160 at certain time points. The level of cytolytic activity, which was a stable property of individual clones, varied among clones over a wide and continuous range. Analysis of cytokine secretion by gp160-specific CD4+ T cell clones revealed Th0-, Th1-, and Th2-like patterns, with CD4+ CTL clones showing Th0- or T'1-like patterns. Interestingly, many Th0- and Th1-like CTL clones produced very little IL-2, a finding that may explain the complicated regulation of this response. These results illustrate the complex nature of the human T cell response to subunit vaccines consisting of purified recombinant viral proteins.