Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1.
BACKGROUND
Completion of HIV life cycle in CD4(+) T lymphocytes needs cell activation. We recently reported that treatment of resting CD4(+) T lymphocytes with exosomes produced by HIV-1 infected cells induces cell activation and susceptibility to HIV replication. Here, we present data regarding the effects of these exosomes on cells latently infected with HIV-1.


RESULTS
HIV-1 latently infecting U937-derived U1 cells was activated upon challenge with exosomes purified from the supernatant of U937 cells chronically infected with HIV-1. This effect was no more detectable when exosomes from cells infected with HIV-1 strains either nef-deleted or expressing a functionally defective Nef were used, indicating that Nef is the viral determinant of exosome-induced HIV-1 activation. Treatment with either TAPI-2, i.e., a specific inhibitor of the pro-TNFα-processing ADAM17 enzyme, or anti-TNFα Abs abolished HIV-1 activation. Hence, similar to what previously demonstrated for the exosome-mediated activation of uninfected CD4(+) T lymphocytes, the Nef-ADAM17-TNFα axis is part of the mechanism of latent HIV-1 activation. It is noteworthy that these observations have been reproduced using: (1) primary CD4(+) T lymphocytes latently infected with HIV-1; (2) exosomes from both primary CD4(+) T lymphocytes and macrophages acutely infected with HIV-1; (3) co-cultures of HIV-1 acutely infected CD4(+) T lymphocytes and autologous lymphocytes latently infected with HIV-1, and (4) exosomes from cells expressing a defective HIV-1.


CONCLUSIONS
Our results strongly suggest that latent HIV-1 can be activated by TNFα released by cells upon ingestion of exosomes released by infected cells, and that this effect depends on the activity of exosome-associated ADAM17. These pieces of evidence shed new light on the mechanism of HIV reactivation in latent reservoirs, and might also be relevant to design new therapeutic interventions focused on HIV eradication.
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. claudia.arenaccio@guest.iss.it.|Department of Sciences, University Roma Tre, Rome, Italy. claudia.arenaccio@guest.iss.it.
Claudia
C
Arenaccio
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. simona.anticoli@iss.it.
Simona
S
Anticoli
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. francesco.manfredi@iss.it.
Francesco
F
Manfredi
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. chiara.chiozzini@iss.it.
Chiara
C
Chiozzini
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. eleonora.olivetta@iss.it.
Eleonora
E
Olivetta
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. maurizio.federico@iss.it.
Maurizio
M
Federico
D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D020298:U937 Cells; D014775:Virus Activation / Q000235:genetics; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D006877:Hydroxamic Acids; C099410:TAPI-2; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human