Misplaced Pages

#149850

38-464: Gp41 is coded with gp120 as one gp160 by the env gene of HIV. Gp160 is then extensively glycosylated and proteolytically cleaved by furin , a host cellular protease . The high glycosylation of the env -coded glycoproteins allows them to escape the human body's immune system . In contrast to gp120, however, gp41 is less glycosylated and more conserved (less prone to genetic variations ). Once gp160 has been cleaved into its individual subunits,

76-700: A bridging sheet . Gp120 is anchored to the viral membrane , or envelope, via non-covalent bonds with the transmembrane glycoprotein , gp41 . Three gp120s and gp41s combine in a trimer of heterodimers to form the envelope spike, which mediates attachment to and entry into the host cell. Since gp120 plays a vital role in the ability of HIV-1 to enter CD4 cells, its evolution is of particular interest. Many neutralizing antibodies bind to sites located in variable regions of gp120, so mutations in these regions will be selected for strongly. The diversity of env has been shown to increase by 1-2% per year in HIV-1 group M and

114-416: A non-covalent bond with gp120 . Gp120 binds to a CD4 and a co-receptor ( CCR5 or CXCR4 ), found on susceptible cells such as Helper T cells and macrophages . As a result, a cascade of conformational changes occurs in the gp120 and gp41 proteins. These conformational changes start with gp120 that rearranges to expose the binding sites for the coreceptors mentioned above. The core of gp41 then folds into

152-621: A "conserved" portion of gp120 that outlasts many of its mutations, affecting 17/24 tested strains at low doses. Another bNAb was discovered that acted on protein gp41 across many strains. Antibodies require antigens to trigger them and these were not originally identified. Over time more bNAbs were isolated, while single cell antibody cloning made it possible to produce large quantities of the antibodies for study. Low levels of bNAbs are now found in up to 25% of HIV patients. bNAbs evolve over years, accumulating some three times as many mutations as other antibodies. By 2006, researchers had identified

190-427: A Malawian man joined a study within weeks of becoming infected. Over a year, he repeatedly donated blood, which researchers used to create a timeline of changes in his virus' gp120, his antibody response and the ultimate emergence of a bNAb. Researchers want to direct this evolution in other subjects to achieve similar results. A screen of massive gp120 libraries led to one that strongly bound both an original antibody and

228-579: A broadly neutralising antibody, IgG1-b12. NIH research published in Science reports the isolation of 3 antibodies that neutralize 90% of HIV-1 strains at the CD4bs region of gp120, potentially offering a therapeutic and vaccine strategy. [1] However, most antibodies that bind the CDbs region of gp120 do not neutralize HIV, and rare ones that do such as IgG1-b12 have unusual properties such as asymmetry of

266-543: A few so-called "broadly neutralizing antibodies" (bNAbs) that worked on multiple HIV strains. They analyzed 1800 blood samples from HIV-infected people from Africa, South Asia and the English-speaking world . They individually probed 30,000 of one woman's antibody-producing B cells and isolated two that were able to stop more than 70% of 162 divergent HIV strains from establishing an infection. Since 2009, researchers have identified more than 50 HIV bNAbs. In 2006,

304-415: A much higher affinity for binding when compared to its monomer, C34 also inhibits T-20 resistant HIV very well, which makes it a potentially good alternative to treatments involving enfuviritide. Small-molecule inhibitors that are able to bind to two hydrophobic pockets at once have also been shown to be 40-60 times more potent and have potential for further developments. Most recently, the gp120-gp41 interface

342-483: A relatively long half-life which makes it a potential target for therapeutic intervention and inhibitory peptides. Enfuvirtide (also known as T-20) is a 36-residue alpha-peptide fusion inhibitor drug that binds to the pre-hairpin structure and prevents membrane fusion and HIV-1 entry to the cell. The vulnerability of this structure has initiated development towards a whole spectrum of fusion preventing drugs. In developing these drugs, researchers face challenges because

380-515: A six helical bundle (a coiled coil) structure exposing the previously hidden hydrophobic gp41 fusion peptides that are inserted in the host cell membrane allowing fusion to take place. This fusion process is facilitated by the hairpin conformational structure. The inner core of this conformation is 3 NHRs which have hydrophobic pockets that allow it to bind anti-parallel to specific residues on the CHR. The activation process occurs readily, which suggests that

418-449: A vital role in attachment to specific cell surface receptors . These receptors are DC-SIGN , Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor , particularly on helper T-cells . Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral membrane with the host cell membrane . Binding to CD4

SECTION 10

#1732765229150

456-554: Is an example of Red Queen evolutionary dynamics. Continuing evolutionary adaptation is required for the viral envelope protein to maintain fitness relative to the continuing evolutionary adaptations of the host immune neutralizing antibodies, and vice versa, forming a coevolving system. Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. Efforts to develop HIV vaccines targeting gp120, however, have been hampered by

494-579: Is being considered as a target for bNAbs. Gp120 Envelope glycoprotein GP120 (or gp120 ) is a glycoprotein exposed on the surface of the HIV envelope . It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes from its molecular weight of 120 kDa . Gp120 is essential for virus entry into cells as it plays

532-478: Is cage-like with a hollow center that inhibits antibody access. While gp120 sits on the surface of the viral envelope, gp41 is the transmembrane portion of the spike protein complex with a portion of the glycoprotein buried within the viral envelope at all times. Gp41 has three prominent regions within the sequence: the ectodomain, the transmembrane domain, and the cytoplasmic domain. The ectodomain, which comprises residues 511-684, can be further broken down into

570-530: Is mainly electrostatic although there are van der Waals interactions and hydrogen bonds . Gp120 is coded by the HIV env gene , which is around 2.5 kb long and codes for around 850 amino acids. The primary env product is the protein gp160, which gets cleaved to gp120 (~480 amino acids) and gp41 (~345 amino acids) in the endoplasmatic reticulum by the cellular protease furin . The crystal structure of core gp120 shows an organization with an outer domain, an inner domain with respect to its termini and

608-400: Is normally buried or hidden by the non-covalent interactions between gp120 and gp41, at a point which looks torus -like. This prevents the fusion peptide from interacting with other regions that are not its intended target region. In a free virion , the fusion peptides at the amino termini of gp41 are buried within the envelope complex in an inactive non-fusogengic state that is stabilized by

646-499: Is one region that has been studied as a potential target because of its ability to be recognized by broadly neutralizing antibodies (bNAbs) , but it hasn't been a very good target because the immune response it elicits isn't very strong and because it is the portion of gp41 that enters the cell membrane (and it cannot be reached by antibodies then). In addition to antigen binding regions on MPER kinks, there are other targets that could prove to be effective antigen binding regions, including

684-436: The fusion peptide region (residues 512-527), the helical N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). In addition to these regions, there is also a loop region that contains disulfide bonds that stabilize the hairpin structure (the folded conformation of gp41) and a region called the membrane proximal external region (MPER) which contains kinks that are antigen target regions. The fusion peptide region

722-587: The targeted epitopes will still exist. In contrast, non-bNAbs are specific for individual viral strains with unique epitopes. The discovery of bNAbs has led to an important area of research, namely, discovery of a vaccine, not only limited to HIV , but also other rapidly mutating viruses like influenza . The following table shows the characteristics of various HIV-1 bNAbs In addition to targeting conserved epitopes, bNAbs are known to have long variable regions on their immunoglobulin (Ig) isotypes and subclasses. When compared to non-bNAbs, sequence variability from

760-510: The Fab arms or in their positioning. Unless a gp120-based vaccine can be designed to elicit antibodies with strongly neutralizing antiviral properties, there is concern that breakthrough infection leading to humoral production of high levels of non-neutralizing antibodies targeting the CD4 binding site of gp120 is associated with faster disease progression to AIDS. The protein gp120 is necessary during

798-472: The PNGS number decreases substantially, then the virus is too easily detected by neutralizing antibodies. Therefore, a stabilizing selection balance between low and high glycan densities is likely established. A lower number of bulky glycans improves viral replication efficiency and higher number on the exposed loops aids host immune evasion via disguise. The relationship between gp120 and neutralizing antibodies

SECTION 20

#1732765229150

836-505: The binding of long-chain carbohydrates to the high variability regions of gp120, so the authors hypothesize that the number of PNGSs in env might affect the fitness of the virus by providing more or less sensitivity to neutralizing antibodies. The presence of large carbohydrate chains extending from gp120 might obscure possible antibody binding sites. The boundaries of the potential to add and eliminate PNGSs are naively explored by growing viral populations following each new infection. While

874-410: The chemical and structural properties of gp120, which make it difficult for antibodies to bind to it. gp120 can also easily be shed from the surface of the virus and captured by T cells due to its loose binding with gp41. A conserved region in the gp120 glycoprotein that is involved in the metastable attachment of gp120 to CD4 has been identified and targeting of invariant region has been achieved with

912-486: The conformation that allows for inhibition occurs very quickly and then rearranges. Enfuviritide specifically has a low oral availability and is quickly processed and expelled by the body. Certain strains of HIV have also developed resistance to T-20. In order to circumvent the difficulties that come with using T-20, researchers have sought out peptide-based inhibitors. A variety of naturally occurring molecules have also been shown to bind gp41 and prevent HIV-1 entry. The MPER

950-464: The discovery of new HIV bNAbs. In 1990, researchers identified the first HIV bNAb, far more powerful than any antibody seen before. They described the exact viral component, or epitope that triggered the antibody. Six amino acids at the tip of HIV's surface protein, gp120 , were responsible. The first bNAb turned out to be clinically irrelevant, but in 1994 another team isolated a bNAb that worked on cells taken from patients. This antibody attached to

988-410: The exposed variable loops of gp120. Consequently, insertions in env , which confer more PNGSs on gp120 may be more tolerated by the virus as higher glycan density promotes the viral ability to evade antibodies and thus promotes higher viral fitness. In considering how much PNGS density could theoretically change, there may be an upper bound to PNGS number due to its inhibition of gp120 folding, but if

1026-412: The first HIV bNAbs seen in a decade. The two broadest neutralizers were PGT151 and PGT152. They could block about two-thirds of a large panel of HIV strains. Unlike most other bNAbs, these antibodies do not bind to known epitopes, on Env or on Env's subunits (gp120 or gp41). Instead, they attach to parts of both. Gp120 and gp41 assemble as a trimer. The bNAbs binding site occurs only on the trimer structure,

1064-511: The germline immunoglobulin isotype is 7 fold. This implies that bNAbs develop from intense affinity maturation in the germinal centers hence the reason for high sequence variability on the variable Ig domain. Indeed HIV-1 patients who develop bNAbs have been shown to have high germinal center activity as exhibited by their comparatively higher levels of plasma CXCL13 , which is a biomarker of germinal center activity. Online databases like bNAber (now defunct) and LANL constantly report and update

1102-400: The host CD4 receptor. The HIV viral protein gp120 induces apoptosis of neuronal cells by inhibiting levels of furin and tissue plasminogen activator, enzymes responsible for converting pBDNF to mBDNF. gp120 induces mitochondrial-death proteins like caspases which may influence the upregulation of the death receptor Fas leading to apoptosis of neuronal cells, gp120 induces oxidative stress in

1140-656: The hydrophobic pockets of the NHR core that is formed following the conformational change in gp41 that creates the six-helix bundle. These pockets could potentially serve as targets for small molecule inhibitors. The fusion peptide on the N-terminus of the gp41 is also a potential target because it contains neutralizing antibody epitopes. N36 and C34, or NHR- and CHR-based peptides (or short sequences of amino acids that mimic portions of gp41) can also act as effective antigens because of their high affinity binding. In addition to having

1178-413: The immune system can cause toxic side effects, such as the anti-CD4 monoclonal antibody OKT4 . Targeting gp120 itself has proven extremely difficult due to its high degree of variability and shielding. Fostemsavir (BMS-663068) is a methyl phosphate prodrug of the small molecule inhibitor BMS-626529, which prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to

Gp41 - Misplaced Pages Continue

1216-412: The inactive state of gp41 is metastable and the conformational changes allow gp41 to achieve its more stable active state. Furthermore, these conformational changes are irreversible processes. The interaction of gp41 fusion peptides with the target cell causes a formation of an intermediate, pre-hairpin structure which bridges and fuses the viral and host membranes together. The pre-hairpin structure has

1254-417: The initial binding of HIV to its target cell. Consequently, anything which binds to gp120 or its targets can physically block gp120 from binding to a cell. Only one such agent, Maraviroc , which binds the co-receptor CCR5 is currently licensed and in clinical use. No agent targeting gp120's main first cellular interaction partner, CD4 , is currently licensed since interfering with such a central molecule of

1292-402: The mature bNAb that evolved from it. Giving patients a modified gp120 that contains little more than the epitope that both antibodies target could act to "prime" the immune system, followed by a booster that contains trimer spikes in the most natural configuration possible. However, it is still under study whether bNAbs could prevent HIV infection. In 2009, researchers isolated and characterized

1330-414: The neuronal cells, and it is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells. Broadly neutralizing HIV-1 antibodies Broadly neutralizing HIV-1 antibodies (bNAbs) are neutralizing antibodies which neutralize multiple HIV-1 viral strains. bNAbs are unique in that they target conserved epitopes of the virus, meaning the virus may mutate , but

1368-404: The subunits are then associated non-covalently on the surface of the viral envelope . Gp41 and gp120, when non-covalently bound to each other, are referred to as the envelope spike complex and are formed as a heterotrimer of three gp41 and three gp120. These complexes found on the surface of HIV are responsible for the attachment, fusion, and ultimately the infection of host cells. The structure

1406-489: The transmitting host has developed a neutralizing antibody response to gp120, the newly infected host lacks immune recognition of the virus. Sequence data shows that initial viral variants in an immunologically naïve host have few glycosylation sites and shorter exposed variable loops. This may facilitate viral ability to bind host cell receptors. As the host immune system develops antibodies against gp120, immune pressures seem to select for increased glycosylation, particularly on

1444-417: The variable units are notable for rapid changes in amino acid sequence length. Increases in gp120 variability result in significantly elevated levels of viral replication, indicating an increase in viral fitness in individuals infected by diverse HIV-1 variants. Further studies have shown that variability in potential N-linked glycosylation sites (PNGSs) also result in increased viral fitness. PNGSs allow for

#149850