Exosomes are secreted, single membrane organelles of ∼100 nm diameter. Their biogenesis is typically thought to occur in a two-step process involving (1) outward vesicle budding at limiting membranes of endosomes (outward = away from the cytoplasm), which generates intralumenal vesicles, followed by (2) endosome–plasma membrane fusion, which releases these internal vesicles into the extracellular milieu as exosomes. In this study, we present evidence that certain cells, including Jurkat T cells, possess discrete domains of plasma membrane that are enriched for exosomal and endosomal proteins, retain the endosomal property of outward vesicle budding, and serve as sites of immediate exosome biogenesis. It has been hypothesized that retroviruses utilize the exosome biogenesis pathway for the formation of infectious particles. In support of this, we find that Jurkat T cells direct the key budding factor of HIV, HIV Gag, to these endosome-like domains of plasma membrane and secrete HIV Gag from the cell in exosomes.

We propose that retroviruses exploit a cell-encoded pathway of intercellular vesicle traffic, exosome exchange, for both the biogenesis of retroviral particles and a low-efficiency but mechanistically important mode of infection. This Trojan exosome hypothesis reconciles current paradigms of retrovirus-directed transmission with the unique lipid composition of retroviral particles, the host cell proteins present in retroviral particles, the complex cell biology of retroviral release, and the ability of retroviruses to infect cells independently of Envelope protein-receptor 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 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 infection, and generate effective antiretroviral vaccines.

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Infectious agents select for host immune responses that destroy infectious nonself yet maintain tolerance to self. Here we propose that retroviruses and other host-antigen associated pathogens (HAAPs) select for the genetic, biochemical, and cell biological properties of alloimmunity, also known as the histocompatibility or tissue rejection response. This hypothesis predicts the major observations regarding histocompatibility responses, including: (i) their existence in animals as diverse as sponges and humans; (ii) extreme polymorphism and balanced allele frequencies at histocompatibility loci, including the human MHC and blood group loci; (iii) the frequency dependent selection of histocompatibility alleles; (iv) the ancient age of many alloantigenic polymorphisms; (v) the high ratio of nonsynonymous mutations to synonymous mutations at histocompatibility loci; (vi) disassortative mating based on MHC alleles; (vii) the inability to explain the existence and continuing selection of histocompatibility alleles by other more conventional biochemical and genetic paradigms; and (viii) the susceptibility of HAAPs, particularly retroviruses such as HIV (human immunodeficiency virus), to histocompatibility reactions. In addition, the hypothesis that HAAPs select the forms and molecules of alloimmunity offers simple explanations for the evolution of histocompatibility systems over time, the initial selection of hypervariable immune mechanisms, and the genesis of adaptive immunity.