Inhibition of Endosomal/Lysosomal Degradation Increases the Infectivity of Human Immunodeficiency Virus

Fredericksen, Brenda L.; Wei, Bangdong L.; Yao, Jian; Luo, Tzy-Jiun M.; García, J. Víctor

doi:10.1128/jvi.76.22.11440-11446.2002

Cited by 192 publications

(194 citation statements)

References 46 publications

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“…Indeed, in this particular cell type, fusion promotes productive infection whereas endocytosis leads to viral degradation. Given that endosome inhibitors increase HIV-1 infectivity in CD4 ϩ T cells and in an epithelial cell line (i.e., MAGI), it was proposed that fusion within the endosomes is a possible process when viral particles are spared from degradation (56,57). We found that the mechanism associated with HIV-1 infection of polarized trophoblasts is utterly different.…”

Section: Discussionmentioning

confidence: 56%

Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

Vidricaire

Tremblay

2005

The Journal of Immunology

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Trophoblasts, the structural cells of the placenta, are thought to play a determinant role in in utero HIV type 1 (HIV-1) transmission. We have accumulated evidence suggesting that HIV-1 infection of these cells is associated with uptake by an unusual clathrin/caveolae-independent endocytic pathway and that endocytosis is followed by trafficking through multiple organelles. Furthermore, part of this trafficking involves the transit of HIV-1 from transferrin-negative to EEA1 and transferrin-positive endosomes, suggesting a merger from nonclassical to classical endocytic pathways in these cells. In the present article, the relationship between the presence of HIV-1 within specific endosomes and infection was studied. We demonstrate that viral infection is virtually lost when endosome inhibitors are added shortly after exposure to HIV-1. Thus, contrary to what is seen in CD4+ T lymphocytes, the initial presence of HIV-1 within the endosomes is mandatory for infection to take place. Importantly, this process is independent of the viral envelope proteins gp120 and gp41. The Rab family of small GTPases coordinates the vesicular transport between the different endocytic organelles. Experiments performed with various expression vectors indicated that HIV-1 infection in polarized trophoblasts relies on Rab5 and Rab7 without the contribution of Arf6 or Rab11. Furthermore, we conclude that Rab5 drives movements from raft-rich region to early endosomes, and this transit is required for subsequently reaching late endosomes via Rab7. This complex trafficking is mandatory for HIV-1 infection to proceed in human polarized trophoblasts.

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Section: Discussionmentioning

confidence: 56%

Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

Vidricaire

Tremblay

2005

The Journal of Immunology

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“…This large vesicle, not present in iDC, is suggestive of a multivesicular body; in addition, its mildly acidic pH preserves HIV-1 infectivity (6, 37). However, HLA-II Ag presentation depends on endosomal/lysosomal maturation and acidification (34), and inhibition of endosomal acidification was reported to increase HIV-1 infectivity (38). Some studies even showed that intracellular HIV-1 degradation occurs faster in iDC than in mDC LPS (6, 37, 40).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Capture and Antigen Presentation by Dendritic Cells: Enhanced Viral Capture Does Not Correlate with Better T Cell Activation

Rodriguez-Plata

Urrutia

Cardinaud

et al. 2012

The Journal of Immunology

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During HIV-1 infection, dendritic cells (DC) facilitate dissemination of HIV-1 while trying to trigger adaptive antiviral immune responses. We examined whether increased HIV-1 capture in DC matured with LPS results in more efficient Ag presentation to HIV-1–specific CD4+ and CD8+ T cells. To block the DC-mediated trans-infection of HIV-1 and maximize Ag loading, we also evaluated a noninfectious integrase-deficient HIV-1 isolate, HIVNL4-3ΔIN. We showed that higher viral capture of DC did not guarantee better Ag presentation or T cell activation. Greater HIVNL4-3 uptake by fully LPS-matured DC resulted in higher viral transmission to target cells but poorer stimulation of HIV-1–specific CD4+ and CD8+ T cells. Conversely, maturation of DC with LPS during, but not before, viral loading enhanced both HLA-I and HLA-II HIV-1–derived Ag presentation. In contrast, DC maturation with the clinical-grade mixture consisting of IL-1β, TNF-α, IL-6, and PGE2 during viral uptake only stimulated HIV-1–specific CD8+ T cells. Hence, DC maturation state, activation stimulus, and time lag between DC maturation and Ag loading impact HIV-1 capture and virus Ag presentation. Our results demonstrate a dissociation between the capacity to capture HIV-1 and to present viral Ags. Integrase-deficient HIVNL4-3ΔIN was also efficiently captured and presented by DC through the HLA-I and HLA-II pathways but in the absence of viral dissemination. HIVNL4-3ΔIN seems to be an attractive candidate to be explored. These results provide new insights into DC biology and have implications in the optimization of DC-based immunotherapy against HIV-1 infection.

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“…To verify that lysosomal trafficking and processing is required for the ADC efficacy, cytotoxicity experiments were conducted in the presence or absence of ammonium chloride (NH 4 Cl), a lysosomotropic agent that disrupts trafficking and lysosomal processing by neutralising the acidic environment of the endosomal/lysosomal compartments (Fredericksen et al, 2002;Sutherland et al, 2006). Hep3B cells were preincubated with NH 4 Cl (5 or 10 mM) before addition of 400 ng ml À1 anti-CD133 ADC and controls.…”

Section: Subcellular Localisation Of Anti-cd133 Adc In Sensitive and mentioning

confidence: 99%

CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers

et al. 2008

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CD133/prominin-1 is a pentaspan transmembrane glycoprotein overexpressed in various solid tumours including colorectal and glioblastomas. CD133 was found here to be highly expressed in X50% of pancreatic, gastric and intrahepatic cholangiocarcinomas. Quantitative flow cytometric analysis showed that a panel of established hepatocellular, pancreatic and gastric cancer cell lines expressed CD133 at levels higher than normal epithelial cells or bone marrow progenitor cells. A murine anti-human CD133 antibody (AC133) conjugated to a potent cytotoxic drug, monomethyl auristatin F (MMAF), effectively inhibited the growth of Hep3B hepatocellular and KATO III gastric cancer cells in vitro with IC 50 values of 2 -7 ng ml À1 . MMAF induced apoptosis in the cancer cells as measured by caspase activation. The anti-CD133-drug conjugate (AC133-vcMMAF) was shown to internalise and colocalised with the lysosomal marker CD107a in the sensitive cell lines. In contrast, in the resistant cell line Su.86.86, the conjugate internalised and colocalised with the caveolae marker, Cav-1. Addition of ammonium chloride, an inhibitor of lysosomal trafficking and processing, suppressed the cytotoxic effect of AC133-vcMMAF in both Hep3B and KATO III. Anti-CD133-drug conjugate treatment resulted in significant delay of Hep3B tumour growth in SCID mice. Anti-CD133 antibody-drug conjugates warrant further evaluation as a therapeutic strategy to eradicate CD133 þ tumours.

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Inhibition of Endosomal/Lysosomal Degradation Increases the Infectivity of Human Immunodeficiency Virus

Cited by 192 publications

References 46 publications

Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

HIV-1 Capture and Antigen Presentation by Dendritic Cells: Enhanced Viral Capture Does Not Correlate with Better T Cell Activation

CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers

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