Apoptosis of uninfected cells induced by HIV envelope glycoproteins

Apoptosis, or programmed cell death, is a key event in biologic homeostasis but is also involved in the pathogenesis of many human diseases including human immunodeficiency virus (HIV) infection. Although multiple mechanisms contribute to the gradual T cell decline that occurs in HIV-infected patients, programmed cell death of uninfected bystander T lymphocytes, including CD4+ and CD8+ T cells, is an important event leading to immunodeficiency. The HIV envelope glycoproteins (Env) play a crucial role in transducing this apoptotic signal after binding to its receptors, the CD4 molecule and a coreceptor, essentially CCR5 and CXCR4. Depending on Env presentation, the receptor involved and the complexity of target cell contact, apoptosis induction is related to death receptor and/or mitochondria-dependent pathways. This review summarizes current knowledge of Env-mediated cell death leading to T cell depletion and clinical complications and covers the sometimes conflicting studies that address the possible mechanisms of T cell death

Differential Role of Autophagy in CD4 T Cells and Macrophages during X4 and R5 HIV-1 Infection

BACKGROUND: HIV-1 can infect and replicate in both CD4 T cells and macrophages. In these cell types, HIV-1 entry is mediated by the binding of envelope glycoproteins (gp120 and gp41, Env) to the receptor CD4 and a coreceptor, principally CCR5 or CXCR4, depending on the viral strain (R5 or X4, respectively). Uninfected CD4 T cells undergo X4 Env-mediated autophagy, leading to their apoptosis, a mechanism now recognized as central to immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate here that autophagy and cell death are also induced in the uninfected CD4 T cells by HIV-1 R5 Env, while autophagy is inhibited in productively X4 or R5-infected CD4 T cells. In contrast, uninfected macrophages, a preserved cell population during HIV-1 infection, do not undergo X4 or R5 Env-mediated autophagy. Autophagosomes, however, are present in macrophages exposed to infectious HIV-1 particles, independently of coreceptor use. Interestingly, we observed two populations of autophagic cells: one highly autophagic and the other weakly autophagic. Surprisingly, viruses could be detected in the weakly autophagic cells but not in the highly autophagic cells. In addition, we show that the triggering of autophagy in macrophages is necessary for viral replication but addition of Bafilomycin A1, which blocks the final stages of autophagy, strongly increases productive infection. CONCLUSIONS/SIGNIFICANCE: Taken together, our data suggest that autophagy plays a complex, but essential, role in HIV pathology by regulating both viral replication and the fate of the target cells

La phagocytose associée à LC3 (LAP)

International audienc

The HBZ-SP1 isoform of human T-cell leukemia virus type I represses JunB activity by sequestration into nuclear bodies

BACKGROUND: The human T-cell leukemia virus type I (HTLV-I) basic leucine-zipper factor (HBZ) has previously been shown to modulate transcriptional activity of Jun family members. The presence of a novel isoform of HBZ, termed HBZ-SP1, has recently been characterized in adult T-cell leukemia (ATL) cells and has been found to be associated with intense nuclear spots. In this study, we investigated the role of these nuclear bodies in the regulation of the transcriptional activity of JunB. RESULTS: Using fluorescence microscopy, we found that the HBZ-SP1 protein localizes to intense dots corresponding to HBZ-NBs and to nucleoli. We analyzed the relative mobility of the EGFP-HBZ-SP1 fusion protein using fluorescence recovery after photobleaching (FRAP) analysis and found that the deletion of the ZIP domain perturbs the association of the HBZ-SP1 protein to the HBZ-NBs. These data suggested that HBZ needs cellular partners, including bZIP factors, to form HBZ-NBs. Indeed, by cotransfection experiments in COS cells, we have found that the bZIP factor JunB is able to target delocalized form of HBZ (deleted in its nuclear localization subdomains) into the HBZ-NBs. We also show that the viral protein is able to entail a redistribution of JunB into the HBZ-NBs. Moreover, by transfecting HeLa cells (known to express high level of JunB) with a vector expressing HBZ-SP1, the sequestration of JunB to the HBZ-NBs inhibited its transcriptional activity. Lastly, we analyzed the nuclear distribution of HBZ-SP1 in the presence of JunD, a Jun family member known to be activated by HBZ. In this case, no NBs were detected and the HBZ-SP1 protein was diffusely distributed throughout the nucleoplasm. CONCLUSION: Our results suggest that HBZ-mediated sequestration of JunB to the HBZ-NBs may be causing the repression of JunB activity in vivo

Proteomic analysis of the cellular responses induced in uninfected immune cells by cell-expressed X4 HIV-1 envelope

International audienc

LC3B conjugation machinery promotes autophagy-independent HIV-1 entry in CD4+ T lymphocytes

HIV-1 entry into CD4+ T lymphocytes relies on the viral and cellular membranes’ fusion, leading to viral capsid delivery in the cytoplasm of target cells. The conjugation of ATG8/LC3B protein, process referred to as ATG8ylation and mainly studied in the context of autophagy, occurs transiently in the early stages of the HIV-1 replication cycle in CD4+ T lymphocytes. Despite numerous studies investigating the interplays of HIV-1 with autophagy machinery, the impact of ATG8ylation in the early stages of HIV-1 infection remains unknown. Here we found that HIV-1 exposure leads to the rapid enrichment of LC3B towards the target cell plasma membrane, in close proximity with the incoming viral particles. Furthermore, we demonstrated that ATG8ylation is a key event that facilitates HIV-1 fusion with target CD4+ T cells. Interestingly, this effect is independent of the canonical autophagy pathway as ATG13 silencing does not prevent HIV-1 entry. Together, our results provide an unconventional role of LC3B conjugation subverted by HIV-1 to achieve a critical early step of its replication cycle. Teaser HIV-1 induces LC3B enrichment towards its target cell entry site and uses the conjugation of this protein to favor its entry step

LC3B conjugation machinery promotes autophagy-independent HIV-1 entry in CD4+ T lymphocytes

HIV-1 entry into CD4+ T lymphocytes relies on the viral and cellular membranes’ fusion, leading to viral capsid delivery in the cytoplasm of target cells. The conjugation of ATG8/LC3B protein, process referred to as ATG8ylation and mainly studied in the context of autophagy, occurs transiently in the early stages of the HIV-1 replication cycle in CD4+ T lymphocytes. Despite numerous studies investigating the interplays of HIV-1 with autophagy machinery, the impact of ATG8ylation in the early stages of HIV-1 infection remains unknown. Here we found that HIV-1 exposure leads to the rapid enrichment of LC3B towards the target cell plasma membrane, in close proximity with the incoming viral particles. Furthermore, we demonstrated that ATG8ylation is a key event that facilitates HIV-1 fusion with target CD4+ T cells. Interestingly, this effect is independent of the canonical autophagy pathway as ATG13 silencing does not prevent HIV-1 entry. Together, our results provide an unconventional role of LC3B conjugation subverted by HIV-1 to achieve a critical early step of its replication cycle. Teaser HIV-1 induces LC3B enrichment towards its target cell entry site and uses the conjugation of this protein to favor its entry step