Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases. Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas. Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis, and several viral oncoproteins interact with p53 and modulate its biological activity. Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.
BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for smallmolecule inhibitors.
A herpesvirus with DNA sequences identical to those of KSHV can be propagated from skin lesions of patients with AIDS-associated Kaposi's sarcoma.
In this study, we have investigated the effect of specific mutations in human immunodeficiency virus type 1 (HIV-1) envelope (Env) on antibody production in an effort to improve humoral immune responses to this glycoprotein by DNA vaccination. Mice were injected with plasmid expression vectors encoding HIV Env with modifications in regions that might affect this response. Elimination of conserved glycosylation sites did not substantially enhance humoral or cytotoxic-T-lymphocyte (CTL) immunity. In contrast, a modified gp140 with different COOH-terminal mutations intended to mimic a fusion intermediate and stabilize trimer formation enhanced humoral immunity without reducing the efficacy of the CTL response. This mutant, with deletions in the cleavage site, fusogenic domain, and spacing of heptad repeats 1 and 2, retained native antigenic conformational determinants as defined by binding to known monoclonal antibodies or CD4, oligomer formation, and virus neutralization in vitro. Importantly, this modified Env, gp140⌬CFI, stimulated the antibody response to native gp160 while it retained its ability to induce a CTL response, a desirable feature for an AIDS vaccine.Plasmid DNA vaccination has been a useful technology for the development and analysis of immunogens. This method of vaccination allows relevant posttranslational modifications, appropriate intracellular trafficking, and antigen presentation. Direct injection of naked DNA either intramuscularly or intradermally readily induces protective immune responses in animal models. Though DNA vaccines readily elicit cell-mediated immune responses, their ability to induce high-titer antibody responses has been limited, particularly to human immunodeficiency virus type 1 (HIV-1) envelope (Env). However, plasmid expression vectors can be readily modified to express different forms of HIV envelope proteins, enabling rapid and systematic testing of alternative vaccine immunogens.To improve the immune response to native gp160 and to expose the core protein for optimal antigen presentation and recognition, we have analyzed the immune response to modified forms of the protein. The conserved N-linked glycosylation sites previously suggested to limit the antibody response (39) were comprehensively analyzed. In addition, the important coiled-coil hairpin region involved with formation of fusion intermediates has been studied. Expression vectors with deletions in the cleavage site (C), the fusion peptide (F), and the interspace (I) between the two heptad repeats, termed ⌬CFI deletions, were prepared. In this report, the immune response to Env candidates expressed in plasmids with codons modified to improve gene expression has been analyzed. Both antibody and cytotoxic-T-lymphocyte (CTL) responses were evaluated after injection of plasmid DNA into muscle. A modified gp140 DNA has been identified that better elicits antibody responses at the same time that it retains its capacity to induce CTL responses to HIV Env. This prototype may facilitate the identification of immunogens ...
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