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Keywords:

  • Env glycoprotein;
  • Env incorporation;
  • membrane microdomains;
  • Gag;
  • human immunodeficiency virus type 1

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

The Env and Gag proteins of HIV-1 are the two major structural proteins of this retrovirus. The interactions between Env and Gag proteins and their regulation in HIV-1 are required for several steps of the replication cycle, involving not only virus assembly, specifically Env incorporation, but also entry steps after virus maturation. A large number of host factors and certain membrane microdomains appear to engage both in transport/trafficking of Env and/or Gag proteins, and in the interactions of these two proteins. The present review briefly summarizes our current knowledge regarding the roles of the interactions between Env and Gag proteins in the virus replication cycle.

List of Abbreviations: 
AP

adaptor protein

CA

p24 capsid

CT

cytoplasmic tail

DRM

detergent-resistant membrane

EE

early endosome

Env

Env glycoprotein

ER

endoplasmic reticulum

ESCRT

endosomal sorting complex required for transport

HIV-1

human immunodeficiency virus type 1

HTLV-1

human T-cell leukemia virus type 1

LE

late endosome

MA

p17 matrix

MDCK

Madin-Darby canine kidney

M-PMV

Maizon-Pfizer monkey virus

MPR

mannose 6-phosphate receptor

MuLV

murine leukemia virus

MVB

multivesicular bodies

NC

p7 nucleocapsid

PI(4,5)P2

phosphatidylinositol-(4,5)-bisphosphate

PM

plasma membrane

RE

recycling endosome

1 SIV

simian immunodeficiency virus

TEM

tetraspanin-enriched microdomain

TGN

trans-Golgi network

TIP47

tail-interacting protein of 47 kDa

VLP

virus-like particle

VSV

vesicular stomatitis virus

The Env and Gag proteins of HIV-1, like those of other retroviruses, are two major structural proteins of the virus. The Env protein is synthesized as a precursor (gp160), glycosylated and oligomerized in the ER. Gp160 is then processed into gp120 and gp41 by a host protease and transported to the cell surface, eventually incorporating into virions to form infectious virus particles. The Gag proteins, however, are synthesized as a polyprotein named Pr55Gag on cytosolic polysomes and transported to PM. Pr55Gag is necessary and sufficient for the assembly of non-infectious VLP. During or shortly after virus release from the virus-infected cells, Pr55Gag is proteolytically cleaved by the HIV-1 protease, yielding the mature Gag proteins MA, CA, NC, and p6. This processing is an essential step for forming mature and infectious virus particles that are able to start the next round of infection. During the late steps of the HIV-1 replication cycle, Env and Gag (Pr55Gag) proteins should interact with each other when Env is incorporated into virions. In contrast, virion maturation and the Env-Gag interaction must be coordinated when the progeny viruses enter into the target cell and initiate a new round of infection. In the present review, we will focus on the roles of the interactions between Env and Gag proteins of HIV-1 during its replication cycle, especially Env incorporation and virus entry steps.

SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

Human immunodeficiency virus type 1 Env is synthesized as a 160-kD precursor on ribosomes associated with the ER. This precursor protein (gp160) is cotranslationally glycosylated and oligomerized before going through the Golgi complex. Further trimming of oligosaccharide chains, resulting in the formation of mature N-linked oligosaccharide chains, is performed from the high-mannose core precursor during the Env transport in the Golgi complex. The majority of oligomeric Env is trimeric. Gp160 is processed or cleaved by a cellular enzyme, furin, or other enzymes within or near the TGN to generate the mature surface glycoprotein (SU) (gp120) and transmembrane protein (TM) (gp41), both of which form a complex through a non-covalent interaction. This Env processing is essential for transport of the Env complex to PM and membrane fusion induced by the Env (1).

The gp120-gp41 complex undergoes endocytosis after reaching the cell surface. Several lines of evidence indicate that a membrane-proximal, Tyr-based (YXXL) sequence in the gp41 CT and analogous motifs are responsible for rapid internalization of HIV-1, HIV-2, and SIV Env (2, 3). The internalization is mediated by the interaction of the μ2 chain of the AP-2 clathrin adaptor complexes with the Tyr-based motif (4, 5), although the Tyr-motif can also interact with the μ1 chain of the AP-1 clathrin adaptor complexes (6). Interestingly, this motif is also critical for basolateral targeting of virus budding in polarized MDCK cells (7). In addition, a C-terminal dileucine motif is considered to mediate endocytosis of HIV-1 Env through interaction with clathrin and AP-2 (8). It has also been reported that the C-terminal dileucine motif affects the cell surface expression and subcellular localization of Env through interaction with AP-1 (9). Rapid internalization of HIV-1 Env could restrict the susceptibility of virus-infected cells to the host immune response to help viral evasion. TIP47 (tail-interacting protein of 47 kDa), which is mainly located in the cytoplasm, has been shown to be necessary for retrograde transport (LE to the TGN) of MPR (10). Like MPR, HIV-1 Env was also reported to bind to TIP47 through its gp41 CT, specifically Y802W803 residues (11). This binding allows HIV-1 Env to be targeted from LE to the TGN. Mutation of this motif in the gp41 CT abolished both TIP47 binding and the targeting of the Env to the TGN. As we discuss in detail below (12), the interaction between HIV-1 Env and TIP47 is also thought to be required for Env incorporation into virions. Although targeting of HIV-1 Env to the PM through intracellular CTLA-4-containing secretory granules has been reported (13), little is known about how the HIV-1 Env is transported from the TGN to the PM. Current understanding of intracellular trafficking of Env and Gag proteins is illustrated in Figure 1.

image

Figure 1. Sorting pathways for assembly and release of HIV-1. Env proteins are transported from the TGN to the PM, undergoing endocytosis to the EE. The Env could traffic back to the PM through the RE. Gag proteins are targeted to the PM directly or through the LE/MVB. A large number of host factors such as AP complexes, and TIP47 are thought to be involved in trafficking of Env and/or Gag proteins. Membrane microdomains at the PM such as lipid rafts and TEM appear to be a scaffold for virus assembly, including Env-Gag and Gag-Gag interactions.

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SYNTHESIS AND TRAFFICKING OF GAG

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

Like other retroviruses, HIV-1 Gag proteins play an essential role in virus assembly and release. The Gag proteins themselves are necessary and sufficient for the formation of VLP. The Pr55Gag consists of p17 MA, p24 CA, p7 NC, p6, and two spacer peptides, SP1 (originally called p2) and SP2 (originally called p1). Gag proteins are involved in the following retrovirus steps: (i) membrane binding and PM targeting; (ii) Gag-Gag multimerization; (iii) incorporation of the viral genome and Env proteins into virions; and (iv) budding and release of virions (14, 15). The N-terminal myristate and a cluster of highly basic residues in MA are required for membrane binding of Gag. As will be discussed later, these basic residues are also involved in PM targeting. The region stretching from the C-terminal domain of the CA to part of the NC is considered to be important for Gag-Gag multimerization. HIV-1 budding and release are dependent on the interaction between p6 and host proteins, named ESCRT (endosomal sorting complex required for transport)-I, -II, -III complexes (16–18), which mediate delivery of cargo proteins into the lumen of the lysosome for degradation.

Gag proteins are synthesized as a precursor named Pr55Gag on cytosolic polysomes, and eventually targeted to the PM. Two models have been proposed for intracellular trafficking of HIV-1 Gag to the PM (Fig. 1). In one model, HIV-1 Gag or virus particle is targeted to the PM through MVB/LE. Although HIV-1 Gag is mainly localized in the PM in most of the cell types, many studies have shown that Gag and virus particles are observed in MVB/LE (19–23). One of the above studies demonstrated that newly synthesized Gag proteins appear in MVB/LE before trafficking to the PM (22). In this model, Gag assembly and HIV-1 release occur at the PM if fusion of MVB with the PM is rapid, whereas the virus assembles and buds into MVB if targeting of Gag to the PM is slow (24). It is noteworthy that other retroviruses such as HTLV-1, MuLV, and M-PMV use MVB and other endosomal compartments for trafficking of Gag proteins to the PM (25–28). In contrast, another model proposes that HIV-1 Gag or virus particles are directly targeted to the PM, probably via interaction between the MA of Pr55Gag and the lipid PI(4,5)P2 (29, 30) without being routed through the MVB/LE. The following two independent results demonstrate that PI(4,5)P2 is a key lipid that regulates HIV-1 Gag targeting to the PM (29). (i) Reduction of cellular PI(4,5)P2 levels inhibits Gag localization to the PM and HIV-1 production. (ii) Induction of PI(4,5)P2-rich intracellular vesicles alters Gag localization from the PM to the endosomal compartment, resulting in reduced HIV-1 release. By using fluorescent imaging of HIV-1 Gag in living cells, nascent Gag is shown mostly to accumulate rapidly at the PM in HeLa and Jurkat T cells (31). A MA mutant that is defective in PM targeting shows a marked defect in virus production while accumulating its Gag proteins in MVB in HeLa cells (21). Furthermore, recent reports using several complementary approaches demonstrate that HIV-1 assembly/release occurs primarily at the PM, but not at MVB/LE in both 293T cells and primary macrophages (32, 33). A novel ultrastructural approach also showed that in primary macrophages, HIV-1 assembles on an intracellular PM domain, which contains the tetraspanin marker proteins and is connected to the cell surface (34).

Several AP complexes such as AP-1 (35), AP-2 (36), and AP-3 (37), which are involved in endocytic pathways, are reported to be important for subcellular localization of Gag and virus release. AP complexes are cytosolic protein complexes that play a major role in the ‘post-Golgi network’ including both the secretory and endocytic pathways (38, 39). MA, MA-CA junction, and H1 helix of MA are responsible for interactions with AP-1, AP-2, and AP-3, respectively, emphasizing the importance of MA regions in Gag targeting. Rab9, a small GTP-binding protein, has been reported to affect Gag localization and HIV-1 release, whereas another small GTP-binding protein, Rab11a, is also required for HIV-1 replication, although how this protein affects virus replication remains unknown (40). In addition, a ubiquitin ligase POSH is considered to be involved in HIV-1 release and Gag localization to the TGN (41). ABCE1/HP68, which was reported to be required for capsid assembly in murine cells (42), has been recently found to associate with HIV-1 Gag at the PM in simian cells until the onset of virus maturation (43). The double-stranded RNA-binding protein, Staufen 1, is also considered to play a role not only in genomic RNA trafficking but also in virus assembly by altering Gag-Gag multimerization (44, 45). Thus, a large number of host factors are involved in localization and/or trafficking of Gag, and release of HIV-1 particles.

ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

Lentiviruses, including HIV-1 and SIV, have TM protein (gp41 for HIV-1) with long CT compared with oncoretroviruses whose CT are 20–30 amino acid residues in length. The mechanism by which HIV-1 Env is incorporated into virions that are released from virus-infected cells is still not well understood. Several biochemical and genetic studies suggest that interaction between the gp41 CT of HIV-1 Env and MA is required for active incorporation. (i) Mutations in the MA region can block the Env incorporation into virions (46–48), whereas this incorporation defect can be restored by pseudotyping with heterologous Env glycoproteins such as MuLV Env and vesicular stomatitis virus (VSV)-G or by removing the gp41 CT (47, 49, 50). (ii) Small deletions or truncations of the gp41 CT cause a defect in Env incorporation, and a single amino acid change in MA restores the defect (51). (iii) HIV-1 Env directs Gag budding to the basolateral surface of polarized epithelial MDCK cells (7, 52, 53). It has also been shown that the Tyr-based motif is involved in polarized budding of HIV-1 in T cells (54). (iv) The gp41 CT is essential for efficient Env incorporation into virions in most cell lines and in primary cell types such as human peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM), although some cell lines, including HeLa or MT-4 cells, are tolerant of gp41 CT truncation (55, 56). (v) Coexpression of Pr55Gag suppressed endocytosis of HIV-1 Env mediated by the gp41 CT (57). (vi) Association of HIV-1 Env with detergent-resistant membranes was mediated by interaction with Pr55Gag (58). (vii) Direct interaction between HIV-1 MA and gp41 CT has been demonstrated in an in vitro system (59). Thus, it is evident that the gp41 CT is essential for the incorporation of full-length HIV-1 Env into virions. The cell-type dependent requirement of the gp41 CT suggests that some host factors are involved in the interaction of the gp41 CT and MA and play a role in Env incorporation. Indeed, it has been argued that a host cytosolic protein, TIP47, plays roles in trafficking of Env (11) as well as bridging the gp41 CT of Env and Gag (12). Therefore, TIP47 is considered to be one of the host factors that are required for HIV-1 Env incorporation into virus particles. Although TIP47 also appears to be involved in Env retrograde transport from LE to TGN, suggesting that Gag and Env could meet on LE or TGN, where and how the trimolecular complexes are formed among Env, Gag, and TIP47 remains to be determined.

There are several questions as to the mechanism by which HIV-1 Env is incorporated into virions. (i) Are there any host factors that are required for Env incorporation in concert with or without TIP47? (ii) Where and how do Env and Gag proteins meet and assemble into HIV-1 particles? Env proteins are synthesized in the ER, processed in the Golgi, and transported to the PM, whereas Gag proteins are synthesized on free ribosomes in the cytosol, and transported to the inner phase of the PM. It has been suggested that complexes containing Env, Gag, and viral genomic RNA are preformed on endosomes before virus budding in the case of MuLV (25). Although it appears that HIV-1 Env directs virus release in polarized epithelial cells (52) and in rat neurons (60), accumulating evidence suggests that HIV-1 Env and Gag can interact intracellularly but assemble into virions only at the surface of cells. Several studies demonstrated that insertion of an ER retention signal at the C-terminus of HIV-1 Env or treatment with brefeldin A did not affect virus release without Env incorporation (61–63), suggesting lack of a functional interaction between Env and Gag proteins at an early step in Env transport. A study using SIV Env and Gag also shows that both proteins can interact intracellularly but assemble into virions only at the PM (64). In addition, strong colocalization of Gag and Env is observed at the PM using high-resolution confocal microscopy, suggesting that direct recruitment of Env by Pr55Gag to the assembly sites occurs at the PM (65). These results suggest that Env and Gag proteins could interact at the PM or on endosomes (or transport vesicles).

ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

Cellular membranes of the intracellular organelles or PM are not homogeneous lipid bilayers but rather contain various lipid microdomains with distinct lipid and protein compositions. One type of microdomain that is highly rich in sphingolipids and cholesterol is called ‘lipid raft(s)’. It is considered that eukaryotic cells use this microdomain as a scaffold for assembly of various molecules by which the cells perform several biological processes such as intracellular transport and signal transduction (66–68). Furthermore, enveloped viruses such as HIV-1 also use lipid rafts for their replication cycle, especially their entry and assembly (for review of lipid rafts and virus replication, see (69)).

It has been shown that HIV-1 envelopes contain relatively high amounts of sphingoglycolipids and cholesterol compared with the host plasma membrane (70, 71), suggesting that HIV-1 assembles in certain membrane domains, probably lipid rafts. Several lines of evidence support this hypothesis. HIV-1 Env proteins have been detected in detergent-resistant membrane (DRM) fractions (72, 73). It has been reported that palmitoylation of the two Cys residues in the gp41 CT is responsible for DRM association and Env incorporation (74). However, more detailed biochemical and virological analyses showed that Cys residues were not essential for Env incorporation and virus infectivity, suggesting that palmitoylation of the gp41 CT is not critical for virus replication (75, 76). The majority of Gag proteins have also been recovered in the DRM fractions (72, 73, 77–80). In addition, PM rafts are critical for HIV-1 assembly and release (80). Substitution of myristic acid for unsaturated fatty acids inhibits VLP production without altering the membrane-binding capacity of Gag (81). It has recently been demonstrated that depletion of cholesterol impairs membrane binding and high-order multimerization Gag (82). In terms of a role of lipid rafts in Env-Gag interactions, observation by confocal microscopy demonstrated that HIV-1 Env and Gag on the cell surface colocalized with raft markers such as CD59 and GM1 in the virus-infected or transfected cells, but did not colocalize with non-raft markers like CD45 (72, 78). More recently, association of HIV-1 Env with DRM was found to be mediated by interaction with Pr55Gag (58). Importantly, a mutation in the matrix region that causes a defect in Env incorporation in Pr55Gag eliminated Env association with DRM. In addition, mutations in the gp41 CT that abrogate Env incorporation also eliminated Env association with DRM. These results suggest that Gag recruits Env into lipid raft domains where Env and Gag interact for Env incorporation. Thus, lipid rafts appear to be a membrane microdomain that is essential for assembly (interactions not only between Gag and Gag but also between Env and Gag) and release of HIV-1.

Tetraspanins are a superfamily of cell-surface proteins that are expressed in a variety of tissues and cell types. Members of this family form large integrated complexes for signal transduction and immune response called ‘tetraspanin-enriched microdomains (TEM)’ in association with various molecules (83). Several lines of evidence suggest that tetraspanins are involved in the infection of several viruses such as hepatitis C virus (HCV), HTLV-1, and HIV-1 (84). Furthermore, it has been suggested that TEM are involved in virus assembly/release of HIV-1 (85, 86). Colocalization was observed between a surface TEM marker such as CD63, and not only HIV-1 Env/Gag, but also ESCRT-I components, TSG101 and Vps28. Further studies will determine how HIV-1 proteins are recruited to the TEM and the relationship between lipid rafts and TEM.

ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

During or shortly after virus budding from the infected cells, HIV-1 undergoes virus maturation by proteolytic cleavage with viral protease. The Gag and Gag-pol proteins are processed into mature virion proteins MA, CA, NC, p6 (from Gag), protease (PR), reverse transcriptase (RT), and integrase (IN) (from pol). Virus maturation converts non-infectious virus particles with electron-lucent cores to infectious particles with electron-dense, conical cores. It has been assumed that immature virions are non-infectious (87–89) and inhibitors of viral protease are widely used clinically to treat HIV-1-infected patients. However, the nature of the infectivity block has not been well addressed, although previous findings suggested that it appears to be an uncoating step (90). Functional interaction between the gp41 CT and the MA region of Pr55Gag has been suggested by a large number of studies, many of which are discussed above. In addition, it has also been suggested that ‘detergent-treated virions (viral cores)’ contain substantial amounts of Pr55Gag and gp41, and that the gp41 CT mediates this interaction (91). The growing evidence indicates that the CT of retroviral Env glycoproteins affects virus-cell or cell-to-cell fusion. Cleavage of the Env CT by viral protease after virus release activates Env fusogenecity in certain retroviruses such as MuLV and M-PMV, suggesting cooperative regulation of membrane fusion and virus maturation (92–94). Furthermore, truncation of the Env CT causes enhanced fusion activity not only in HTLV-1 (95) but also in SIV (96, 97) and HIV-1 (49, 98, 99). These results raise the possibility that HIV-1 Env-mediated membrane fusion is modulated by Gag processing instead of cleaving the Env CT, although HIV-1 could also activate fusogenecity by cleaving the CT under certain conditions where a cholesterol-binding compound inhibits HIV-1 entry (100). Indeed, it has been shown that immature HIV-1 virions are repressed for membrane fusion with target cells through the interaction with the gp41 CT, indicating that interaction between the gp41 CT and Pr55Gag couples HIV-1 fusion to virus maturation (Fig. 2) (101–103). The fusion defect by protease-negative virions was found to be due to defects in neither CD4 binding nor six-helix bundle formation (102). A recent report using a panel of gp41 CT mutants further dissected the regions responsible for the fusion repression from those involved in the interaction of the gp41 CT and Pr55Gag, demonstrating that removal of 28 or more amino acids relieves the dependence of HIV-1 fusion on maturation (104). Thus, stable association of the gp41 CT and Pr55Gag in immature virions is required but not sufficient for inhibition of fusion by immature virions. Interestingly, immature particles are reported to be more rigid than mature ones and truncation of the gp41 CT reduced the stiffness of immature virions to that of mature virions (105). Further studies are necessary to elucidate the mechanism of virus fusion modulated by the gp41 CT and Gag processing.

image

Figure 2. Possible model for coupling of virus-cell fusion to virus maturation. Gag processing allows Env trimers to diffuse and cluster in the plane of the viral membrane to form fusion-active, higher-order complexes.

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CONCLUSIONS

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES

In the present review, we discussed studies indicating that interactions between Env and Gag proteins are essential for Env incorporation into infectious HIV-1 virions, although Gag proteins are necessary and sufficient for formation of non-infectious VLP. Studies so far demonstrate that at least one host protein, TIP47, is required for the Env-Gag interaction during Env incorporation. Furthermore, virus maturation and fusogenecity of the HIV-1 Env are temporally and spatially regulated through the Env-Gag interaction. However, several questions still remain unanswered. In HIV-1, where and how do Env and Gag proteins assemble into infectious virions with genomic RNAs? What types of host factors are required for the Env-Gag interactions and Env incorporation with or without TIP47? Which membrane microdomains, lipid rafts or TEM or both, are highly involved in virus assembly, including Gag-Gag and Env-Gag interactions? Which stage of virus-cell fusion is regulated via Gag processing and the gp41 CT? Further studies to answer these and related questions will provide not only important virological findings but also useful information to develop anti-HIV-1 drugs with new modes of action.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. SYNTHESIS AND TRANSPORT/TRAFFICKING OF ENV
  4. SYNTHESIS AND TRAFFICKING OF GAG
  5. ROLE OF ENV-GAG INTERACTIONS IN ENV INCORPORATION INTO VIRIONS AND VIRUS RELEASE
  6. ROLE OF MEMBRANE MICRODOMAINS IN ENV-GAG INTERACTIONS AND HIV-1 ASSEMBLY
  7. ROLE OF ENV-GAG INTERACTIONS IN HIV-1 ENTRY
  8. CONCLUSIONS
  9. ACKNOWLEDGMENTS
  10. REFERENCES
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