Endocytosis of endogenously synthesized HIV-1 envelope protein. Mechanism and role in processing for association with class II MHC.

CD4+ T cell clones specific for the HIV-1 envelope (env) protein are able to recognize not only uninfected APC that have taken up and processed exogenous env protein, but also virally infected cells expressing the env protein. We have evaluated the hypothesis that endocytosis of endogenously synthesized env protein from the plasma membrane of infected cells permits entry of the protein into the MHC class II-restricted Ag processing pathway. We show here that the env protein of HIV-1 is internalized at a surprisingly high rate through a mechanism that is dependent upon a tyrosine-containing motif located in the cytoplasmic domain of the gp41 subunit.

Studies of the mechanism of cytolysis by HIV-1-specific CD4+ human CTL clones induced by candidate AIDS vaccines.

Vaccine-induced, virus-specific CTLs may rapidly eliminate the host cells that first become infected after virus exposure, thereby preventing disseminated infection. Thus, there is much interest in the ability of candidate AIDS vaccines to elicit CTLs. All HIV-1 envelope (env) protein-based vaccines tested to date in seronegative humans induce CTLs from the CD4+ subset.

Cytokines from vaccine-induced HIV-1 specific cytotoxic T lymphocytes: effects on viral replication.

Cytolytic T lymphocytes (CTLs) specific for the human immunodeficiency virus (HIV-1) envelope glycoproteins have been cloned from HIV-1-seronegative human volunteers immunized with HIV-1 gp160-based candidate vaccines. Although vaccine-induced CTLs can potentially contribute to the antiviral response by direct lysis of infected cells, these CTLs may also produce cytokines that alter HIV-1 gene expression in other infected cells present in the microenvironment where CTL-target cell interactions occur. Vaccine-induced CTL clones were therefore examined for production of cytokines that affect HIV-1 gene expression in chronically infected T lymphocytic and promonocytic cell lines.

Human CD4+ cytolytic T lymphocyte responses to a human immunodeficiency virus type 1 gp160 subunit vaccine.

The development of an effective vaccine against human immunodeficiency virus type 1 (HIV-1) may require immunization protocols that elicit cytolytic T lymphocytes (CTL) in addition to neutralizing antibodies. This report demonstrates that vaccination of 4 HIV-1-seronegative volunteers with a recombinant HIV-1 gp160 vaccine produced in mammalian cells elicited a CTL response in 3. The observed CTL activity was not mediated by classic CD8+ CTL but rather by cells of the CD4+ phenotype.

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

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.

Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines.

The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported.

Clonal analysis of T-cell responses to the HIV-1 envelope proteins in AIDS vaccine recipients.

Both CD4+ and CD8+ CTL responses specific for the HIV-1 envelope proteins can be elicited in seronegative humans by candidate AIDS vaccines. The phenotype of the responding CTL depends upon the nature of the vaccine, with CD8+ CTL being found exclusively in recipients of live virus vaccines. Both types of CTL are active against HIV-1-infected cells in vitro.

Production of transmembrane and secreted forms of tumor necrosis factor (TNF)-alpha by HIV-1-specific CD4+ cytolytic T lymphocyte clones. Evidence for a TNF-alpha-independent cytolytic mechanism.

Candidate AIDS vaccines consisting of recombinant forms of the HIV-1 envelope glycoprotein induce, in seronegative human volunteers, an env-specific T cell response that includes CD4+, MHC class II-restricted CTL capable of lysing HIV-1-infected target cells. In this study, we have analyzed the production of the cytokines TNF-alpha and lymphotoxin (LT) by a set of env-specific CD4+ human CTL clones. TNF-alpha and LT are of interest because of their potential role in target cell destruction by CD4+ CTL.

Characterization of a conserved T cell epitope in HIV-1 gp41 recognized by vaccine-induced human cytolytic T cells.

A human CTL epitope located in a region of the HIV-1 envelope protein gp41 that is highly conserved among various HIV-1 strains was identified. This epitope was recognized by CD4+ CTL clones that were induced in seronegative humans by immunization with recombinant gp160. Fusion proteins carrying portions of the HIV-1 env gene and synthetic peptides were used to localize this epitope to amino acids 584-595 of the HIV-1 BRU env sequence.

Feasibility of an alcoholism health insurance benefit.

The present study examined the impact of alcoholism treatment upon the subsequent utilization of health care services. Information gathered on a sample of 2,362 alcoholic clients at time of admission and six months later, was utilized to compare the savings in medical care expenses with the costs of alcoholism treatment. For the first year following treatment, costs exceeded savings by an average of $263 per client (benefit-cost ratio = 0.