Gp120
Encyclopedia
Envelope glycoprotein GP120 (or gp120) is a glycoprotein
exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons. gp120 is essential for virus entry into cells as it plays a vital role in seeking out specific cell surface receptors for entry.
The crystal structure of gp120 complexed to D1D2 CD4 and a neutralizing antibody Fab was solved by Peter Kwong in 1998. It is organized with an outer domain, an inner domain with respect to its termini and a bridging sheet
. The gp120 gene, env, is around 1.5 kb long and codes for around 500 amino acids. Three gp120s, bound as heterodimers to a transmembrane glycoprotein, gp41
, are thought to combine in a trimer to form the envelope spike, which is involved in virus-cell attachment.
The Human Immunodeficiency Virus (HIV) can mutate frequently to stay ahead of the immune system
. There is however a highly conserved region in the virus genome near its receptor binding site. The glycoprotein gp120 is anchored to the viral membrane, or envelope, via non-covalent bonds with the transmembrane glycoprotein, gp41. It is involved in entry into cells by binding to CD4
receptors
, particularly helper T-cells. Binding to CD4 is mainly electrostatic although there are van der Waals
interactions and hydrogen bonds.
The boundaries of the potential to add and eliminate PNGSs are naively explored by growing viral populations following each new infection. While 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 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 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 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.
research. Efforts to develop HIV vaccines targeting gp120, however, have been hampered by 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 cell
s 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 now been identified and targeting of invariant region has been achieved with a broadly neutralising antibody, b12.
Research presented at the 17th International AIDS Conference
in Mexico City
provided the possibility of a new vaccine based on antibodies
that hydrolyze or cleave apart the gp120 protein, rendering it incapable of binding to lymphocyte
s. This binding is the first step in the process of HIV infection. The antibody, IgA
, is present in all human beings, but its potential for combating HIV was first recognized in patients with lupus
, who exhibited both an abnormal resistance to HIV
infection and an abnormally high concentration of IgA. Scientists confirmed that IgA purified from the blood plasma
and saliva
of HIV-seronegative subjects cleaved gp120 more effectively than the more naturally abundant IgG
did, which had little or no effect. To combat HIV, IgA could be administered in large doses as a drug to people already infected. Researchers have yet to make a vaccine
which stimulates the body to increase its own production of IgA.
NIH research published in Science
reports the discovery of antibodies that bind 91% of HIV-1 strains at the CD4bs region of gp120 potentially offering a therapeutic and vaccine strategy. http://www.sciencemag.org/cgi/content/abstract/science.1187659
EGCG
, a flavonoid
found in green tea
, binds to the same CD4 receptor that gp120 binds to, effectively competing for this receptor. Test tube studies suggested that EGCG concentrations as low as 0.2 mmols/L – the concentration of the molecule found in a cup of green tea – temporarily reduced HIV-CD4 cell binding by 40%. Further research is needed both to confirm that this one-time laboratory experiment can be repeated successfully and to see whether the result has any practical effect. For example, by binding to CD4, the flavonoid might slow the progression of AIDS, but it might also attract an antibody response against the non-human flavonoid that destroys an immune system. One important aspect of EGCG is that, unlike antiretroviral drugs, it can penetrate the blood brain barrier, and may help prevent the onset of AIDS-related dementia.
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons. gp120 is essential for virus entry into cells as it plays a vital role in seeking out specific cell surface receptors for entry.
The crystal structure of gp120 complexed to D1D2 CD4 and a neutralizing antibody Fab was solved by Peter Kwong in 1998. It is organized with an outer domain, an inner domain with respect to its termini and a bridging sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. The gp120 gene, env, is around 1.5 kb long and codes for around 500 amino acids. Three gp120s, bound as heterodimers to a transmembrane glycoprotein, gp41
Gp41
gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
, are thought to combine in a trimer to form the envelope spike, which is involved in virus-cell attachment.
The Human Immunodeficiency Virus (HIV) can mutate frequently to stay ahead of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. There is however a highly conserved region in the virus genome near its receptor binding site. The glycoprotein gp120 is anchored to the viral membrane, or envelope, via non-covalent bonds with the transmembrane glycoprotein, gp41. It is involved in entry into cells by binding to CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, particularly helper T-cells. Binding to CD4 is mainly electrostatic although there are van der Waals
Van der Waals
-People:* Fransje van der Waals , Dutch medical physician* Johannes Diderik van der Waals , Dutch physicist-Physics:* the Van der Waals force, named after the physicist* the Van der Waals equation, named after the physicist...
interactions and hydrogen bonds.
Variability
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 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 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 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 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 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 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.
Vaccine target
Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccineHIV vaccine
An HIV vaccine that protects vaccinated individuals from HIV infection is the goal of many HIV research programmes. Currently, there is no effective vaccine against HIV, the virus that causes AIDS...
research. Efforts to develop HIV vaccines targeting gp120, however, have been hampered by 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 cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s 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 now been identified and targeting of invariant region has been achieved with a broadly neutralising antibody, b12.
Research presented at the 17th International AIDS Conference
International AIDS Conference
The International AIDS Society is the custodian of the International AIDS Conference, the largest regular conference on any health or development issue. These conferences provide a forum for the interaction of science, community and leadership, and are claimed to strengthen an evidence-based...
in Mexico City
Mexico City
Mexico City is the Federal District , capital of Mexico and seat of the federal powers of the Mexican Union. It is a federal entity within Mexico which is not part of any one of the 31 Mexican states but belongs to the federation as a whole...
provided the possibility of a new vaccine based on antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
that hydrolyze or cleave apart the gp120 protein, rendering it incapable of binding to lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. This binding is the first step in the process of HIV infection. The antibody, IgA
Immunoglobulin A
Immunoglobulin A is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined; between three and five grams are secreted into the intestinal lumen each day....
, is present in all human beings, but its potential for combating HIV was first recognized in patients with lupus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
, who exhibited both an abnormal resistance to HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection and an abnormally high concentration of IgA. Scientists confirmed that IgA purified from the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
of HIV-seronegative subjects cleaved gp120 more effectively than the more naturally abundant IgG
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
did, which had little or no effect. To combat HIV, IgA could be administered in large doses as a drug to people already infected. Researchers have yet to make a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
which stimulates the body to increase its own production of IgA.
NIH research published in Science
Science
Science is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe...
reports the discovery of antibodies that bind 91% of HIV-1 strains at the CD4bs region of gp120 potentially offering a therapeutic and vaccine strategy. http://www.sciencemag.org/cgi/content/abstract/science.1187659
Competition
The protein gp120 is necessary during the initial binding of HIV to its target cell. Consequently, anything which binds to gp120's target can block gp120 from binding to a cell by being physically in the way. Many of these are toxic to the immune system, such as the anti-CD4 monoclonal antibody OKT4.EGCG
Epigallocatechin gallate
Epigallocatechin gallate , also known as epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin....
, a flavonoid
Flavonoid
Flavonoids , are a class of plant secondary metabolites....
found in green tea
Green tea
Green tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...
, binds to the same CD4 receptor that gp120 binds to, effectively competing for this receptor. Test tube studies suggested that EGCG concentrations as low as 0.2 mmols/L – the concentration of the molecule found in a cup of green tea – temporarily reduced HIV-CD4 cell binding by 40%. Further research is needed both to confirm that this one-time laboratory experiment can be repeated successfully and to see whether the result has any practical effect. For example, by binding to CD4, the flavonoid might slow the progression of AIDS, but it might also attract an antibody response against the non-human flavonoid that destroys an immune system. One important aspect of EGCG is that, unlike antiretroviral drugs, it can penetrate the blood brain barrier, and may help prevent the onset of AIDS-related dementia.
HIV dementia
The HIV viral protein gp120 induces apoptosis of neuronal cells. 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 the neuronal cells, and it is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells.Further reading
External links
- http://www.aidsmap.com/en/docs/4406022B-85D7-4A9B-B700-91336CBB6B18.asp
- http://www.mcld.co.uk/hiv/?q=gp120
- http://www.ebi.ac.uk/interpro/IEntry?ac=IPR000777
- http://www.ncbi.nlm.nih.gov/pubmed/19462280?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1
See also
- HIV structure and genomeHIV structure and genomeThe genome and proteins of HIV have been the subject of extensive research since the discovery of the virus in 1983. The discovery of the virus itself was not until two years after the first major cases of AIDS associated illnesses were reported in 1981.-Structure:...