Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0021051 (
immunodeficiency
)
71,517
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Macroautophagy/autophagy is an auto-digestive pro-survival pathway activated in response to stress to target cargo for lysosomal degradation. In recent years, autophagy has become prominent as an innate antiviral defense mechanism through multiple processes, such as targeting virions and viral components for elimination. These exciting findings have encouraged studies on the ability of autophagy to restrict HIV. However, the role of autophagy in HIV infection remains unclear. Whereas some reports indicate that autophagy is detrimental for HIV, others have claimed that HIV deliberately activates this pathway to increase its infectivity. Moreover, these contrasting findings seem to depend on the cell type investigated. Here, we show that autophagy poses a hurdle for HIV replication, significantly reducing virion production. However, HIV-1 uses its accessory protein Nef to counteract this restriction. Previous studies have indicated that Nef affects autophagy maturation by preventing the fusion between autophagosomes and lysosomes. Here, we uncover that Nef additionally blocks autophagy initiation by enhancing the association between BECN1 and its inhibitor BCL2, and this activity depends on the cellular E3 ligase PRKN. Remarkably, the ability of Nef to counteract the autophagy block is more frequently observed in pandemic HIV-1 and its simian precursor SIV
cpz
infecting chimpanzees than in HIV-2 and its precursor SIV
smm
infecting sooty mangabeys. In summary, our findings demonstrate that HIV-1 is susceptible to autophagy restriction and define Nef as the primary autophagy antagonist of this antiviral process.
Abbreviations:
3-MA: 3-methyladenine; ACTB: actin, beta; ATG16L1: autophagy related 16 like 1; BCL2: bcl2 apoptosis regulator; BECN1: beclin 1; cDNA: complementary DNA; EGFP: enhanced green fluorescence protein; ER: endoplasmic reticulum; Gag/p55: group-specific antigen; GFP: green fluorescence protein; GST: glutathione S transferase; HA: hemagglutinin; HIV: human
immunodeficiency
virus; IP: immunoprecipitation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nef: negative factor; PRKN: parkin RBR E3 ubiquitin ligase; PtdIns3K: phosphatidylinositol 3 kinase; PtdIns3P: phosphatidylinositol 3 phosphate; PTM: post-translational modification; RT-qPCR: reverse transcription followed by quantitative PCR; RUBCN: rubicon autophagy regulator; SEM: standard error of the mean; SERINC3: serine incorporator 3; SERINC5:
serine incorporator 5
; SIV: simian
immunodeficiency
virus; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; UVRAG: UV radiation resistance associated gene; VSV: vesicular stomatitis virus; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.
...
PMID:HIV-1 Nef counteracts autophagy restriction by enhancing the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner. 3209 85
Infection of human
immunodeficiency
virus type 1 (HIV-1) is subject to restriction by cellular factors.
Serine incorporator 5
(
SERINC5
) and interferon-inducible transmembrane 3 (IFITM3) proteins represent two of these restriction factors, which inhibit HIV-1 entry into target cells. Both proteins impede fusion of the viral membrane with the cellular membrane and the formation of a viral fusion pore, and both are countered by the HIV-1 envelope glycoprotein (Env). Given the immense and lasting pressure which Env endures from host adaptive immune responses, it is important to understand whether and how HIV-1 Env is able to maintain the resistance to
SERINC5
and IFITM3 throughout the course of infection. We have thus examined a panel of HIV-1 Env clones that were isolated at different stages of viral infection-transmission, acute, and chronic. While HIV-1 Env clones from the transmission stage are resistant to both
SERINC5
and IFITM3, as infection progresses into the acute and chronic stages, the resistance to IFITM3 but not to
SERINC5
is gradually lost. We further discovered a significant correlation between the resistance of HIV-1 Env to soluble CD4 inhibition and the resistance to
SERINC5
but not to IFITM3. Interestingly, the miniprotein CD4 mimetic M48U1 sensitizes HIV-1 Env to the inhibition by
SERINC5
but not IFITM3. Together, these data indicate that
SERINC5
and IFITM3 exert differential inhibitory pressures on HIV-1 Env over different stages of HIV-1 infection and that HIV-1 Env uses varied strategies to resist these two restriction factors.
IMPORTANCE
HIV-1 Env protein is exposed to the inhibition not only by humoral response, but also by host restriction factors, including
serine incorporator 5
(
SERINC5
) and interferon-inducible transmembrane 3 (IFITM3). This study investigates how HIV-1 envelope glycoprotein (Env) manages to overcome the pressures from all these different host inhibition mechanisms over the long course of viral infection. HIV-1 Env preserves the resistance to
SERINC5
but becomes sensitive to IFITM3 when infection progresses into the chronic stage. Our study also supports the possibility of using CD4 mimetic compounds to sensitize HIV-1 Env to the inhibition by
SERINC5
as a potential therapeutic strategy.
...
PMID:Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection. 3249 21
SERINC5 is a multi-pass transmembrane protein that is thought to play a role in serine incorporation during cellular membrane biosynthesis. This protein has also been identified as a human
immunodeficiency
virus Type 1 (HIV-1) restriction factor. The paucity of monoclonal antibodies (mAbs) against SERINC5 has posed a challenge for the study of the endogenous protein. Here we report the development of novel anti-SERINC5 mAbs that target three distinct loops on the protein. We demonstrate that these SERINC5 mAbs can be used to detect endogenously expressed
SERINC5 protein
in various cell lines using Western blot, whole-cell ELISA, flow cytometry, and immunocytochemistry. We further show that some of these antibodies can detect SERINC5 that is present in HIV-1 viral stocks. These antibodies will aid in the characterization of the functions and mechanisms of action of SERINC5 in different cell types.
...
PMID:Novel monoclonal antibodies to the SERINC5 HIV-1 restriction factor detect endogenous andvirion-associated SERINC5. 3283 2
