Nathans, P. of Envelope proteinCreceptor interactions. An exosomal origin also predicts that retroviruses pose an unsolvable paradox for adaptive immune responses, that retroviral antigen vaccines are unlikely to provide prophylactic protection, and that alloimmunity is usually a central component of antiretroviral immunity. Finally, the Trojan exosome hypothesis has important implications for the fight against HIV and AIDS, including how to develop new antiretroviral therapies, assess the risk of retroviral contamination, and generate effective antiretroviral vaccines. Retroviruses are enveloped positive-strand RNA viruses that replicate through a DNA intermediate inserted in the host cell genome (1). Current models of retroviral biology adhere to basic principles of virology (2), explain most empirical data on retroviruses, and assume a complete reliance on retroviral Env proteins for the binding and fusion of retroviral particles with host cells (1, 2). However, these models do not provide a mechanistic explanation for many important properties of retroviruses, including the array of host cell molecules in retroviral particles (3C5), the observation of receptor-independent and Env-independent retroviral infections (6C8), and the ability of retroviruses to thrive in the presence of otherwise healthy adaptive immune systems (1, 2). In an effort to reconcile these observations with the main body of data on retroviral biology, we propose the Trojan exosome hypothesis. Many eukaryotic cells synthesize and release small extracellular vesicles called exosomes, which can fuse with membranes of neighboring cells to complete an intercellular vesicle trafficking pathway (9C12). The Trojan exosome hypothesis says that retroviruses use the preexisting, nonviral exosome biogenesis pathway for the formation of infectious particles, and the preexisting, PSEN1 nonviral pathway of exosome uptake for a receptor-independent, Oxyclozanide Env-independent mode Oxyclozanide of contamination. The following presents a portion of the empirical support for this hypothesis and its major implications for the fight against HIV and AIDS. Exosome Biogenesis and Uptake Exosomes are small (50C200 nm) membrane-bound vesicles that are released into the extracellular milieu (10C12). The early stages in exosome synthesis follow that of intralumenal vesicles (ILVs), which form by inward budding of the endosome membrane (13); endosomes enriched in ILVs are also referred to as multivesicular bodies (MVBs) (Fig. Oxyclozanide 1). The immediate fate of ILVs and their constituents can vary. For example, the ILV biogenesis pathway can be reversed, as when proteins that are targeted into discrete ILVs return to the endosomal limiting membrane (14). ILVs can also be degraded in lysosomes if the endosomes that carry them fuse with, or mature into, lysosomes (13). Alternatively, MVBs can fuse with the plasma membrane (PM), releasing ILVs Oxyclozanide into the extracellular milieu as exosomes (delayed exosome biogenesis). MVB-PM fusion also generates a patch of endosomal membrane at the cell surface that can shed exosomes directly into the extracellular fluid (immediate exosome biogenesis). Open in a separate windows Fig. 1. The formation (retrovirus, which is usually transmitted as efficiently in the absence of its Env gene as in the presence of its Env gene (7). Another example of Env-independent contamination comes from studies of and Figs. 2 and 3, which are published as supporting information around the PNAS web site) as well as a model of retroviral tropism that combines both Env-dependent and Env-independent pathways ((69), and ((65, 70C73). However, retroviral replication continues apace in the vast majority of HIV-infected patients. This pattern is also observed in HTLV-1-infected patients and in a variety of animals infected by their retroviruses (1, 2, 66). As for those rare HIV-infected individuals who appear to control their retroviral contamination (long-term nonprogressors), it is not clear whether adaptive immune responses are responsible for this apparent control, and in some cases there is strong evidence that it is not (74C78). Exosome Exchange and the Intrinsic Susceptibility of Immune System Cells. Retroviral resistance to adaptive immune responses is usually attributed to (and Table 1, which is usually published as supporting information around the PNAS web site). HTLV-1 represents a particularly good example of this theory because it primarily infects CD4+ T cells even though it displays no detectable preference for these cells (2, 79). Retroviral Targeting of Antigen-Specific T Cells. Another aspect of the Trojan exosome Oxyclozanide hypothesis that contributes to the failure of adaptive immunity is usually deduced from the role of exosomes in cellular immunity. Recent studies have established that exosomes are produced by nearly all antigen-presenting cells, are loaded with MHC/peptide complexes (21, 80C83), and are sufficient to stimulate and activate T cells in an MHC/peptide/T cell receptor (TCR)-dependent manner (16, 80, 84, 85). Moreover, activation of T cells stimulates their exosome exchange pathway (80, 86). Given that retrovirus-infected cells release Trojan exosomes carrying MHC proteins loaded with retroviral peptides, our hypothesis predicts the preferential contamination of T cells that express retrovirus-specific TCRs..
