Abstract
Heat shock proteins (hsps) and cyclophilins (CypA) are intracellular chaperone molecules that facilitate protein folding and assembly. These proteins are selectively expressed in cells following exposure to a range of stress stimuli, including viral infection. Hsp species are highly immunogenic, eliciting humoral, cytotoxic T lymphocyte (CTL), and natural killer (NK) cell responses against viruses, tumours, and infectious diseases. This review discusses the roles of stress proteins in immunity and viral life cycles, vis-à-vis the development of Hsp-based therapeutic strategies against human immunodeficiency virus type-1 (HIV-1) infection. Cumulative findings are cited implicating the requirement of CypA in HIV-1 replication and formation of infectious virions. Studies by our group show the upregulated expression of hsp27 and hsp70 during single-cycle HIV infections. These species redistribute to the cell surface following HIV-infection and heat stress, serving as targets for NK and antibody-dependent cellular cytotoxicity. Co-immunoprecipitation and Western blot studies show that hsp27, hsp70, and hsp78 complex with HIV-1 viral proteins intracellularly. Hsp70, hsp56, and CypA are assembled into HIV-1 virions. The ability of hsps to interact with HIV-1 viral proteins, combined with their inherent adjuvant and immunogenic properties, indicates that hsps may serve as vehicles for antigen delivery and the design of vaccines against acquired immunodeficiency syndrome.
Highlights
Heat shock proteins and cyclophilins (CypA) are intracellular chaperone molecules that facilitate protein folding and assembly
Stress proteins have been implicated in host immunity to tumours and viral and microbial infections. 14-7 Select Hsp species represent major targets for humoral (B cell) and cell-mediated immunity. 4-e7 The immunogenic properties of hsps have led to considerable interest in their application in vaccine strategies. 6,7 Vaccinations with Hsp-peptide complexes have been shown to augment cytotoxic T lymphocyte (CTL), y8 T, natural killer (NK), and LAK cell responses against tumour and viral antigens. 16-z7 Reasons why highly conserved stress proteins play such a prominent role in immunity are still not well understood
Hsp[27] and hspT0 stress pathways are induced in CD4 cells concomitant to human immunodeficiency virus type-1 (HIV-1) infection, and these species can distribute on the cell surface of infected cells
Summary
The Hsp family of proteins, representing 2-15 % of total cellular protein, are among the most highly conserved proteins present in procaryotic and eucaryotic organisms."-s Classified by apparent molecular weight (hspT0, hsp[60], hsp[90], hsp27), hsps were first defined as those proteins selectively synthesized following cellular exposure to temperatures 5 to 10C above normal,s Hsps are referred to as stress proteins since they are induced in response to a vast spectrum of physiological and environmental insults, including viral infection, inflammation, fever, malignant transformation, and cellular exposure to oxidizing agents, cytotoxins and anoxia, s,6. Stress proteins function as chaperone molecules having innate abilities to bind to a broad range of cellular peptides, proteins, and multimeric complexes.-s Constitutive Hsp subspecies, referred to as "housekeeping" proteins, direct protein folding, biogenesis, assembly, trafficking, and degradation. Inducible Hsp subspecies rapidly reprogram cellular metabolic, proliferative, and functional events in response to distinct stress stimuli. 7 HspT0 homologues consist of peptide-binding and ATPase domains that stabilize protein structures in unfolded and assembly-competent states for extended periods of time.4,s In contrast, mitochondrial hsp[60] isoforms form ring-shaped oligomers wherein protein assembly to native states is facilitated.[4] Hsp[90] species associate with cellular tyrosine kinases, transcription factors, and glucocorticoid receptors, playing suppressor regulatory roles,s’7,9 Hsp[27] proteins suppress protein aggregation, protect against actin polymerization, and represent end components of stress and cytokine kinase (MAPK) cascades. BRENNER AND WAINBERG trans isomerization of peptidyl-prolyl bonds, key rate-limiting steps in protein folding
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