Abstract
BackgroundA relevant burden of defective HIV-1 genomes populates PBMCs from HIV-1 infected patients, especially during HAART treatment. These viral genomes, although unable to codify for infectious viral particles, can express viral proteins which may affect functions of host cells as well as bystander ones. Cells expressing defective HIV-1 have a lifespan longer than that of cells producing infectious particles. Hence, their interaction with other cell types, including resting lymphocytes, is expected to occur frequently in tissues where HIV actively replicates. We investigated the effects of the expression of a prototype of functionally defective HIV-1 on bystander, unstimulated CD4+ T lymphocytes.ResultsWe observed that unstimulated human primary CD4+ T lymphocytes were activated and became permissive for HIV-1 replication when co-cultivated with cells expressing a functionally defective HIV-1 (F12/Hut-78 cells). This effect depended on the presence in F12/Hut-78 supernatants of nanovesicles we identified as exosomes. By inspecting the underlying mechanism, we found that ADAM17, i.e., a disintegrin and metalloprotease converting pro-TNF-α in its mature form, associated with exosomes from F12/Hut-78 cells, and played a key role in the HIV-1 replication in unstimulated CD4+ T lymphocytes. In fact, the treatment with an inhibitor of ADAM17 abolished both activation and HIV-1 replication in unstimulated CD4+ T lymphocytes. TNF-α appeared to be the downstream effector of ADAM17 since the treatment of unstimulated lymphocytes with antibodies against TNF-α or its receptors blocked the HIV-1 replication. Finally, we found that the expression of NefF12 in exosome-producing cells was sufficient to induce the susceptibility to HIV-1 infection in unstimulated CD4+ T lymphocytes.ConclusionsExosomes from cells expressing a functionally defective mutant can induce cell activation and HIV-1 susceptibility in unstimulated CD4+ T lymphocytes. This evidence highlights the relevance for AIDS pathogenesis of the expression of viral products from defective HIV-1 genomes.
Highlights
A relevant burden of defective HIV-1 genomes populates peripheral blood mononuclear cells (PBMCs) from HIV-1 infected patients, especially during highly active anti-retroviral therapy (HAART) treatment
Unstimulated CD4+ T lymphocytes become susceptible to HIV-1 infection when co-cultivated with cells expressing a defective HIV-1 strain We looked at possible effects of the expression of defective HIV-1 on bystander unstimulated CD4+ T lymphocytes by
We found that 60 μU of exosomes from F12/Hut-78 cells applied on 105 unstimulated CD4+ T lymphocytes cells generated a number of cells producing IL-2 significantly increased compared to untreated cells or cells treated with exosomes from parental Hut-78 cells (Figure 3A)
Summary
A relevant burden of defective HIV-1 genomes populates PBMCs from HIV-1 infected patients, especially during HAART treatment These viral genomes, unable to codify for infectious viral particles, can express viral proteins which may affect functions of host cells as well as bystander ones. Results: We observed that unstimulated human primary CD4+ T lymphocytes were activated and became permissive for HIV-1 replication when co-cultivated with cells expressing a functionally defective HIV-1 (F12/Hut-78 cells) This effect depended on the presence in F12/Hut-78 supernatants of nanovesicles we identified as exosomes. The high frequency of mutations occurring in HIV-1 retrotranscription can lead to the production of defective HIV-1 genomes They can persist in peripheral blood mononuclear cells (PBMCs) of HIV-1 infected patients since host cells are expected to have a lifetime longer than that of cells infected by replication-competent quasispecies. We provide evidence that exosomes released by F12/Hut-78 cells can influence the cell activation state of bystander, unstimulated CD4+ T lymphocytes
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