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Query: UMLS:C0019693 (
HIV
)
170,526
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
HIV
-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of
HIV
-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and
SERINC5
into
HIV
-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and
SERINC5
precisely phenocopied the effects of Nef and glycoGag on
HIV
-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4(+) T cells that lack both SERINC3 and
SERINC5
, and re-expression experiments confirmed that the absence of SERINC3 and
SERINC5
accounted for the infectivity enhancement. Furthermore, SERINC3 and
SERINC5
together restricted
HIV
-1 replication, and this restriction was evaded by Nef. SERINC3 and
SERINC5
are highly expressed in primary human
HIV
-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat
HIV
/AIDS.
...
PMID:SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. 2645 23
HIV
-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of
HIV
-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein
SERINC5
, and to a lesser extent SERINC3, as a potent inhibitor of
HIV
-1 particle infectivity that is counteracted by Nef.
SERINC5
localizes to the plasma membrane, where it is efficiently incorporated into budding
HIV
-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects
SERINC5
to a Rab7-positive endosomal compartment and thereby excludes it from
HIV
-1 particles. The ability to counteract
SERINC5
was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of
SERINC5
as a potent anti-retroviral factor.
...
PMID:HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. 2645 23
The Nef protein is an accessory gene product encoded by human immunodeficiency virus types 1 and 2 (
HIV
-1/-2) and simian immunodeficiency virus (SIV) that boosts virus replication in the infected host and accelerates disease progression. Unlike the
HIV
-1 accessory proteins Vif, Vpr and Vpu, Nef was, until recently, not known to antagonize the antiviral activity of a host cell restriction factor. Two recent reports now describe the host cell proteins serine incorporator 3 and 5 (SERINC3 and
SERINC5
) as potent inhibitors of
HIV
-1 particle infectivity and demonstrate that Nef counteracts these effects. These findings establish SERINC3/5 as restrictions to
HIV
replication in human cells and define a novel activity for the
HIV
pathogenesis factor Nef.
...
PMID:Spotlight on HIV-1 Nef: SERINC3 and SERINC5 Identified as Restriction Factors Antagonized by the Pathogenesis Factor. 2670 15
SERINC3 (serine incorporator 3) and
SERINC5
are recently identified host cell inhibitors of
HIV
-1 particle infectivity that are counteracted by the viral pathogenesis factor Nef. Here we confirm that
HIV
-1 Nef, but not
HIV
-1 Vpu, antagonizes the particle infectivity restriction of
SERINC5
.
SERINC5
antagonism occurred in parallel with other Nef activities, including cell surface receptor downregulation, trans-Golgi network targeting of Lck, and inhibition of host cell actin dynamics. Interaction motifs with host cell endocytic machinery and the Nef-associated kinase complex, as well as CD4 cytoplasmic tail/HIV-1 protease, were identified as essential Nef determinants for
SERINC5
antagonism. Characterization of antagonism-deficient Nef mutants revealed that counteraction of
SERINC5
occurs in the absence of retargeting of the restriction factor to intracellular compartments and reduction of
SERINC5
cell surface density is insufficient for antagonism. Consistent with virion incorporation of
SERINC5
being a prerequisite for its antiviral activity, the infectivity of
HIV
-1 particles produced in the absence of a
SERINC5
antagonist decreased with increasing amounts of virion
SERINC5
. At low levels of
SERINC5
expression, enhancement of virion infectivity by Nef was associated with reduced virion incorporation of
SERINC5
and antagonism-defective Nef mutants failed to exclude
SERINC5
from virions. However, at elevated levels of
SERINC5
expression, Nef maintained infectious
HIV
particles, despite significant virion incorporation of the restriction factor. These results suggest that in addition to virion exclusion, Nef employs a cryptic mechanism to antagonize virion-associated
SERINC5
. The involvement of common determinants suggests that the antagonism of Nef to
SERINC5
and the downregulation of cell surface CD4 by Nef involve related molecular mechanisms.
...
PMID:The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor. 2768 Nov 40
The lentivirus equine infectious anemia virus (EIAV) encodes the small protein S2, a pathogenic determinant that is important for virus replication and disease progression in horses. No molecular function had been linked to this accessory protein. We report that S2 can replace the activity of Negative factor (Nef) in
HIV
-1 infectivity, being required to antagonize the inhibitory activity of Serine incorporator (SERINC) proteins on Nef-defective
HIV
-1. Like Nef, S2 excludes
SERINC5
from virus particles and requires an ExxxLL motif predicted to recruit the clathrin adaptor, Adaptor protein 2 (AP2). Accordingly, functional endocytic machinery is essential for S2-mediated infectivity enhancement, and S2-mediated enhancement is impaired by inhibitors of clathrin-mediated endocytosis. In addition to retargeting
SERINC5
to a late endosomal compartment, S2 promotes host factor degradation. Emphasizing the similarity with Nef, we show that S2 is myristoylated, and, as is compatible with a crucial role in posttranslational modification, its N-terminal glycine is required for anti-
SERINC5
activity. EIAV-derived vectors devoid of S2 are less susceptible than
HIV
-1 to the inhibitory effect of both human and equine
SERINC5
. We then identified the envelope glycoprotein of EIAV as a determinant that also modulates retroviral susceptibility to
SERINC5
, indicating that EIAV has a bimodal ability to counteract the host factor. S2 shares no sequence homology with other retroviral factors known to counteract
SERINC5
. Like the primate lentivirus Nef and the gammaretrovirus glycoGag, the accessory protein from EIAV is an example of a retroviral virulence determinant that independently evolved
SERINC5
-antagonizing activity.
SERINC5
therefore plays a critical role in the interaction of the host with diverse retrovirus pathogens.
...
PMID:S2 from equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3. 2780 22
SERINC5
is able to restrict
HIV
-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the
HIV
-1 Nef protein counters
SERINC5
through downregulating
SERINC5
from the cell surface and preventing the virion incorporation of
SERINC5
. In addition, the Env proteins of some
HIV
-1 strains can also overcome
SERINC5
inhibition. However, it is unclear how
HIV
-1 Env does so and why
HIV
-1 has two mechanisms to resist
SERINC5
inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic
SERINC5
from being incorporated into
HIV
-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated
SERINC5
. Testing of a panel of
HIV
-1 Env proteins from different subtypes revealed a high frequency of
SERINC5
-resistant Envs. Interestingly, although the
SERINC5
-bearing viruses were not inhibited by
SERINC5
itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the
SERINC5
-free viruses, which suggests a possible influence of
SERINC5
on Env function. We conclude that
HIV
-1 Env is able to overcome
SERINC5
without preventing
SERINC5
virion incorporation.
...
PMID:Effect of HIV-1 Env on SERINC5 Antagonism. 2792 4
The host proteins, SERINC3 and
SERINC5
, have been recently shown to incorporate into
HIV
-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein. Envelope (Env) glycoproteins from different
HIV
-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with
HIV
-1 fusion remains unclear. Here, we show that incorporation of
SERINC5
into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells. Strikingly, we found that
SERINC5
promotes spontaneous functional inactivation of sensitive but not resistant Env glycoproteins. Although
SERINC5
-Env interaction was not detected by co-immunoprecipitation, incorporation of this protein enhanced the exposure of the conserved gp41 domains and sensitized the virus to neutralizing antibodies and gp41-derived inhibitory peptides. These results imply that
SERINC5
restricts
HIV
-1 fusion at a step prior to small pore formation by selectively inactivating sensitive Env glycoproteins, likely through altering their conformation. The increased
HIV
-1 sensitivity to anti-gp41 antibodies and peptides suggests that SER5 also delays refolding of the remaining fusion-competent Env trimers.
...
PMID:SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins. 2817 29
The viral restriction factor
SERINC5
inhibits
HIV
-1 infection via unknown mechanisms. Sood and co-workers now show that
SERINC5
suppresses
HIV
-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion machinery. This work advances our understanding of host-virus interactions and provides a compelling case for considering the host immune system in studies of restriction factor mechanisms.
...
PMID:Exposing HIV's weaknesses. 2838 78
The host-cell restriction factor
SERINC5
potently suppresses the infectivity of
HIV
, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which
SERINC5
restricts
HIV
-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of
HIV
particles is a major determinant of the infectious potential of the particles, we tested whether
SERINC5
-mediated restriction of
HIV
particle infectivity involves alterations of membrane lipid composition. We produced and purified
HIV
-1 particles from SERINC5293T cells with very low endogenous
SERINC5
levels under conditions in which ectopically expressed
SERINC5
restricts
HIV
-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS.
SERINC5
restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and
HIV
particles. Sphingosine metabolism kinetics were also unaltered by
SERINC5
expression. Moreover, the levels of phosphatidylserine on the surface of
HIV
-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of
SERINC5
or Nef. Finally, saturating the phosphatidylserine-binding sites on
HIV
target cells did not affect
SERINC5
restriction or Nef antagonism. These results demonstrate that the restriction of
HIV
-1 particle infectivity by
SERINC5
does not depend on alterations in lipid composition and organization of
HIV
-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of
SERINC5
.
...
PMID:The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles. 3181 Oct 51
Nef-specific CD8
+
T lymphocytes (CD8TL) are linked to extraordinary control of primate lentiviral replication, but the mechanisms underlying their efficacy remain largely unknown. The immunodominant, Mamu-B*017:01
+
-restricted Nef
195-203
MW9 epitope in SIVmac239 partially overlaps a sorting motif important for interactions with host AP-2 proteins and, hence, downmodulation of several host proteins, including Tetherin (CD317/BST-2), CD28, CD4, SERINC3, and
SERINC5
. We reasoned that CD8TL-driven evolution in this epitope might compromise Nef's ability to modulate these important molecules. Here, we used deep sequencing of SIV from nine B*017:01
+
macaques throughout infection with SIVmac239 to characterize the patterns of viral escape in this epitope and then assayed the impacts of these variants on Nef-mediated modulation of multiple host molecules. Acute variation in multiple Nef
195-203
MW9 residues significantly compromised Nef's ability to downregulate surface Tetherin, CD4, and CD28 and reduced its ability to prevent
SERINC5
-mediated reduction in viral infectivity but did not impact downregulation of CD3 or major histocompatibility complex class I, suggesting the selective disruption of immunomodulatory pathways involving Nef AP-2 interactions. Together, our data illuminate a pattern of viral escape dictated by a selective balance to maintain AP-2-mediated downregulation while evading epitope-specific CD8TL responses. These data could shed light on mechanisms of both CD8TL-driven viral control generally and on Mamu-B*017:01-mediated viral control specifically.
IMPORTANCE
A rare subset of humans infected with
HIV
-1 and macaques infected with SIV can control the virus without aid of antiviral medications. A common feature of these individuals is the ability to mount unusually effective CD8 T lymphocyte responses against the virus. One of the most formidable aspects of
HIV
is its ability to evolve to evade immune responses, particularly CD8 T lymphocytes. We show that macaques that target a specific peptide in the SIV Nef protein are capable of better control of the virus and that, as the virus evolves to escape this response, it does so at a cost to specific functions performed by the Nef protein. Our results help show how the virus can be controlled by an immune response, which could help in designing effective vaccines.
...
PMID:Maintenance of AP-2-Dependent Functional Activities of Nef Restricts Pathways of Immune Escape from CD8 T Lymphocyte Responses. 2923 31
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