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.^[1] Three gp120s, bound as heterodimers to a transmembrane glycoprotein, gp41, are thought to combine in a trimer to form the envelope spike,^[2] 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.

Variability[link]

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.^[3] 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.^[4] 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.^[5]

The boundaries of the potential to add and eliminate PNGSs are naively explored by growing viral populations following each new infection.^[6] 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.^[7] 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.^[8] 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.^[9] 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.^[6] 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.^[9]

Vaccine target[link]

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 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 now been identified and targeting of invariant region has been achieved with a broadly neutralising antibody, b12.^[10]

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,^[11] rendering it incapable of binding to lymphocytes.^[12] 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.^[12] 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.^[11] 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.^[12]

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. [1]

Competition[link]

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, 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%.^[13] 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[link]

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,^[14] gp120 induces oxidative stress in the neuronal cells,^[15] and it is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells.^[16]

References[link]

Further reading[link]

• Human Immunodeficiency Virus Glycoprotein 120

External links[link]

• 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[link]

• HIV structure and genome