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58-478: 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

116-697: 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

174-411: A 1997 survey found that about 2% of HIV-positive samples were from Group O. Its zoonotic origin is SIVgor, which infects gorillas (rather than the more common source, SIVcpz). The group caused some concern because it could not be detected by early versions of the HIV-1 test kits. More advanced HIV tests have now been developed to detect both Group O and Group N. In 2009, a newly analyzed HIV sequence

232-577: 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

290-886: A differential diagnosis of HIV-2 should be considered when a person is of West African descent or has had sexual contact or shared needles with such a person. West Africa is at the highest risk as it is the origin of the virus. HIV-2 has been found to be less pathogenic than HIV-1. The mechanism of HIV-2 is not clearly defined, nor the difference from HIV-1, however the transmission rate is much lower in HIV-2 than HIV-1. Both viruses can lead to AIDS in infected individuals and both can mutate to develop drug resistance. Disease monitoring in patients with HIV-2 includes clinical evaluation and CD4 cell counts, while treatment includes anti-retroviral therapy (ART), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PI), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) with

348-417: A genetic relation to viruses indigenous to chimpanzees and gorillas that inhabit West Africa , while HIV-2 viruses are affiliated with viruses present in the sooty mangabey , a vulnerable West African primate. HIV-1 viruses can be further stratified into groups M, N, O, and P. Among these, HIV-1 group M viruses are the most prevalent, infecting nearly 90% of people living with HIV and are responsible for

406-528: A group P. Each group is believed to represent an independent transmission of simian immunodeficiency virus (SIV) into humans, excluding subtypes within a specific group. The complete genome sequence of HIV-1 contains a total of 39 open reading frames (ORFs) across all six possible reading frames (RFs), but only a few of them are functional. With 'M' for "major", this is by far the most common type of HIV, with more than 90% of HIV/AIDS cases caused by infection with HIV-1 group M viruses. This major HIV, which

464-483: A high set-point viral load, the host will live for a shorter amount of time and there is a lower probability that the virus will be transmitted to another individual. HIV has evolved to maximize the number of infections to other hosts, and this tendency for selection to favor intermediate strains shows that HIV undergoes stabilizing selection. The virus has also evolved to become more infectious between hosts. There are three different mechanisms that allow HIV to evolve at

522-770: A monkey species inhabiting the forests of Littoral West Africa. Phylogenetic analyses show that the virus most closely related to the two strains of HIV-2 which spread considerably in humans (HIV-2 groups A and B) is the SIVsmm found in the sooty mangabeys of the Tai forest , in western Ivory Coast . There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive from independent transmissions from sooty mangabeys to humans. Groups C and D have been found in two people from Liberia, groups E and F have been discovered in two people from Sierra Leone, and groups G and H have been detected in two people from

580-515: A number. CRF12_BF, for example, is a recombination between subtypes B and F. The spatial movement of these subtypes moved along the railways and waterways of the DRC from Kinshasa to these other areas. These subtypes are sometimes further split into sub-subtypes such as A1 and A2 or F1 and F2. In 2015, the HIV strain CRF19, a recombinant of subtype A, subtype D, and subtype G, with a subtype D protease ,

638-400: A population level. One includes the continuous battle to evolve and overcome the immune system which slows down the evolution of HIV and shifts the virus’ focus towards a population level. Another includes the slow evolution of viral load due to viral load mutations being neutral within the host. The last mechanism focuses on the virus' preference to transmit founding viral strains stored during

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696-653: A process that takes place in the rough endoplasmic reticulum and is carried out by the enzymes of the host cell. Cotranslational glycosylation take place at the asparagine in the Asn-X-Ser or Asn-X-Thr motifs. Different retroviruses vary widely in N-linked glycosylation sites: HIV-1 can have as many as 30 sites glycosylated, 25 of which reside in gp120 . At the other end of the spectrum, MMTV ( Mouse Mammary Tumor Virus has only 4 sites for oligosaccharide addition (two on gp52 and two on gp37). The addition of oligosaccharides

754-528: A receptor on the target cell surface, which triggers a conformational change , allowing for binding of the fusion protein . The fusion peptide inserts itself in the host cell membrane and brings the host cell membrane very close to the viral membrane to facilitate membrane fusion. While there are significant differences in sequence of the env gene between retroviruses , the gene is always located downstream of gag , pro , and pol . The env mRNA must be spliced for expression. The mature product of

812-468: A trimer. The virus cannot infect cells before the processing of the envelope precursor protein is completed. For the virus to penetrate the cytosol of a host cell, a low pH is necessary. The env gene of Murine Leukemia Virus (MLV) codes for the 71,000-dalton glycoprotein, gp71. This membrane receptor was isolated from Rauscher murine leukemia virus (R-MuLV). The retroviral protein env has been captured multiple times during mammalian evolution and

870-432: A trimeric structure of heterodimers. It is believed that the intracellular transport of the nascent protein depends, to some extent, on the oligomerization of Env precursors, which allows hydrophobic sequences to be buried inside the protein structure. This oligomerization has also been implicated in fusion initiation with the membrane of the target cell. Env can be modified by the addition of mannose-rich oligosaccharides,

928-519: Is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells. Env (gene) Env is a viral gene that encodes the protein forming the viral envelope . The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane . Analysis of the structure and sequence of several different env genes suggests that Env proteins are type 1 fusion machines . Type 1 fusion machines initially bind

986-504: 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

1044-444: Is believed to play a role in the proper folding of Env, presumably by stabilizing the protein structure. Without proper folding, protein transport and function can be severely compromised. The importance of glycosylation of Env in HIV-1 was ascertained by synthesizing the glycoprotein in the presence of a glycosylation inhibitor, tunicamycin . The synthesized protein was incorrectly folded and incapable of binding CD4 . Receptor binding

1102-661: Is cleaved to yield the surface (SU) and transmembrane (TM) Env products. Gp52 is the SU subunit in MMTV and gp36 is the TM subunit. Gp52 is a 52,000-dalton glycoprotein and gp36 is a 36,000-dalton glycoprotein. MMTV Env is of particular interest to researchers because of the discovery that it encodes an immunoreceptor tyrosine-based activation motif (I TAM ) that has been shown to transform human and murine mammary cell in culture. This ITAM depolarizes epithelial acinar structures, thereby changing

1160-422: Is expressed in placental tissue, where it facilitates fusion of fetal and maternal cells. The protein is called syncytin in mammals. HIV-1 The subtypes of HIV include two main subtypes, known as HIV type 1 (HIV-1) and HIV type 2 (HIV-2). These subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. HIV-1 exhibits

1218-400: Is inefficient, and virions often are released with inactive, uncleaved gp160. Because of the high prevalence of these inactive forms, the immune system often produces antibodies which target inactive gp160, rather than active forms of the envelope protein. See Replication cycle of HIV . Env expression is regulated by the gene product of rev . Experimental deletion of rev resulted in

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1276-418: Is proposed that these mutations induce conformational changes in gp120 that allow the virus to directly interact with the co-receptor. Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. These efforts have been hampered by the fusion mechanism used by HIV, which makes neutralization by antibodies extremely difficult. Prior to binding

1334-529: Is referred to as co-infection. HIV-2 seems to have lower mortality rates, less severe symptoms and slower progression to AIDS than HIV-1 alone or the co-infection. In co-infection, however, this is largely dependent on which virus was contracted first. HIV-1 tends to out compete HIV-2 for disease progression. Co-infection seems to be a growing problem globally as time progresses, with most cases being identified in West African countries, as well as some cases in

1392-540: The endoplasmic reticulum after the translation of the glycosylated Env precursor. The arrangement of these heterodimers determines the 3D structure of the knobbed spike on the viral surface. The Env proteins of the Avian Sarcoma and Leukosis virus ( ASLV ) and the Murine Leukemia Virus ( MLV ) are both trimers of SU-TM heterodimers. The Env protein of Human Immunodeficiency Virus ( HIV ) also has

1450-483: The env gene is the viral spike protein, which has two main parts: the surface protein (SU) and the transmembrane protein (TM). The tropism of the virus is determined by the SU protein domain because it is responsible for the receptor-binding function of the virus. The SU domain therefore determines the specificity of the virus for a single receptor molecule. The retroviral glycoproteins are oligomeric complexes that are composed of SU-TM heterodimers , which are made in

1508-405: The helper T-cell . Strains of HIV-1 have been isolated that are able to enter host cells that are CD4 negative. This CD4-independence is associated with spontaneous mutation in the env gene. The presence of a co-receptor , CXCR 4 , is sufficient for this mutant strain to infect human cells. The strain with this phenotype was found to have seven mutations in the sequence coding for gp120 and it

1566-507: 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

1624-514: The Ivory Coast. Each of these HIV-2 strains, for which humans are probably dead-end hosts , is most closely related to SIVsmm strains from sooty mangabeys living in the same country where the human infection was found. HIV-2 diagnosis can be made when a patient has no symptoms but positive blood work indicating the individual has HIV. The Multispot HIV-1/HIV-2 Rapid Test is currently the only FDA approved method for such differentiation between

1682-470: 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

1740-467: The USA. A study found that individuals who contract HIV-2 before HIV-1 tend to have a slower rate of disease progression, suggesting that the immune response to HIV-2 may limit the proliferation of HIV-1. If a pregnant mother is exposed, screening is performed as normal. If HIV-2 is present, a number of perinatal ART drugs may be given as a prophylactic to lower the risk of mother-to-child transmission. After

1798-623: The United States was in 1987. The first confirmed case of HIV-2 was a Portuguese man who was treated at the London Hospital for Tropical Diseases and later died in 1987. He was believed to have been exposed to the disease in Guinea-Bissau where he lived between 1956 and 1966. His pathological diagnosis at the time was cryptosporidiosis and enterovirus infection , but an analysis of his stored serum in 1987 found that he

Envelope glycoprotein GP120 - Misplaced Pages Continue

1856-608: The YBF380 variant reacted with an viral envelope antigen from SIVcpz rather than with those of Group M or Group O, indicating it was indeed a novel strain of HIV-1. As of 2015 , fewer than 20 Group N infections have been recorded. The O ("Outlier") group has infected about 100,000 individuals located in West-Central Africa and is not usually seen outside of that area. It is reportedly most common in Cameroon, where

1914-447: The above listed therapies are being looked into as well, also showing variable effect depending on the types of therapies combined. While the mechanisms are not clearly understood for HIV-1 and HIV-2, it is known that they use different pathways and patterns, making the algorithms used to evaluate HIV-1 resistance-associated mutations irrelevant to HIV-2. Each virus can be contracted individually, or they can be contracted together in what

1972-410: The addition of CCR5 co-receptor antagonists and fusion inhibitors . Choice of initial and/or second-line therapy for HIV-2 has not yet been defined. HIV-2 appears to be resistant to NNRTIs intrinsically, but may be sensitive to NRTIs, though the mechanism is poorly understood. Protease inhibitors have shown variable effect, while integrase inhibitors are also being evaluated. Combination regimens of

2030-503: 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

2088-409: The cell. It is originally buried within the viral envelope, but when gp120 binds to a CD4 receptor, gp120 changes its conformation causing gp41 to become exposed, where it can assist in fusion with the host cell. Fusion inhibitor drugs such as enfuvirtide block the fusion process by binding to gp41. The Mouse Mammary Tumor Virus ( MMTV ) env gene codes for a polyprotein gp70 ( P10259 ) that

2146-410: 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

2204-415: The child is born, a standard six-week regimen of these prophylactics should be initiated. Breast milk may also contain viral particles of HIV-2; therefore, breastfeeding is strictly advised against. The rapid evolution of HIV can be attributed to its high mutation rate. During the early stages of mutation, evolution appears to be neutral due to the absence of an evolutionary response. However, when examining

2262-531: The early stages of infection. This preference of the virus to transmit its stored genome copies explains why HIV evolves more quickly within the host than between hosts. HIV is evolving toward a milder form, but it is still "an awfully long way" from no longer being deadly, with severe variants still appearing. Isolates of HIV-1 and HIV-2 with resistance to antiretroviral drugs arise through natural selection and genetic mutations, which have been tracked and analyzed. The Stanford HIV Drug Resistance Database and

2320-408: 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

2378-406: The global AIDS pandemic . Group M can be further subdivided into subtypes based on genetic sequence data. Certain subtypes are known for their increased virulence or drug resistance to different medications used to treat HIV. HIV-2 viruses are generally considered to be less virulent and less transmissible than HIV-1 M group viruses, although HIV-2 is also known to still cause AIDS. One of

Envelope glycoprotein GP120 - Misplaced Pages Continue

2436-424: 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 the neuronal cells, and it

2494-415: The host cell, gp120 remains effectively hidden from antibodies because it is buried in the protein and shielded by sugars. Gp120 is only exposed when in close proximity to a host cell and the space between the viral and host cell membranes is small enough to sterically hinder the binding of antibodies. The glycoprotein gp41 is non- covalently bound to gp120, and provides the second step by which HIV enters

2552-413: 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

2610-461: The inability to detect the Env protein and levels of env mRNA in the cell cytoplasm were significantly diminished. However, when total cellular RNA was analyzed, env RNA totals were not significantly different in the presence and absence of rev coexpression. It was found that without rev expression, there was a marked increase in nuclear env RNA, which suggests that rev plays an important role in

2668-417: 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

2726-466: The nuclear export of env mRNA. The role of rev was further elucidated when it was found that rev acts in trans to target a specific sequence present in the env gene of HIV-1 to initiate export of incompletely spliced HIV-1 RNA from the nucleus. Exposed on the surface of the viral envelope, the glycoprotein gp120 binds to the CD4 receptor on any target cell that has such a receptor, particularly

2784-433: The phenotype of the cells and causing them to become cancerous. Avian Sarcoma and Leukosis Viruses ( ASLV ) have ten subgroups (A through J). The envelope glycoprotein of subgroup A is called EnvA and its env gene codes for precursor protein known as Pr95. This precursor is cleaved by host cell enzymes to yield the surface protein subunit, gp85, and the transmembrane protein subunit, gp37, which heterodimerize and then form

2842-408: The prevailing challenges in the pursuit of effective management of HIV is the virus's pronounced genetic variability and rapid viral evolution . HIV-1 is the most common and most pathogenic strain of the virus. As of 2022 , approximately 1.3 million such infections occur annually. Scientists divide HIV-1 into a major group (group M) and two or more minor groups, namely groups N, O and possibly

2900-488: 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

2958-448: The two viruses. Recommendations for the screening and diagnosis of HIV has always been to use enzyme immunoassays that detect HIV-1, HIV-1 group O, and HIV-2. When screening the combination, if the test is positive followed by an indeterminate HIV-1 western blot , a follow-up test, such as amino acid testing, must be performed to distinguish which infection is present. According to the NIH,

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3016-416: 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

3074-406: The virus in several different individuals, convergent mutations can be found appearing in these viral populations independently. HIV evolution within a host influences factors including the virus' set-point viral load . If the virus has a low set-point viral load, the host will live longer, and there is a greater probability that the virus will be transmitted to another individual. If the virus has

3132-457: Was found to be strongly associated with rapid progression to AIDS in Cuba . This is not thought to be a complete or final list, and further types are likely to be found. The 'N' stands for "non-M, non-O". This group was discovered by a Franco-Cameroonian team in 1998, when they identified and isolated the HIV-1 variant strain, YBF380, from a Cameroonian woman who died of AIDS in 1995. When tested,

3190-589: Was infected with HIV-2. Many test kits for HIV-1 will also detect HIV-2. There are eight known HIV-2 groups, designated A to H. Of these, only groups A and B are pandemic . Group A is found mainly in West Africa, but has also spread to Angola, Mozambique, Brazil, India, Europe, and the US. Despite the presence of HIV-2 globally, Group B is mainly confined to West Africa. HIV-2 is closely related to SIV endemic in sooty mangabeys ( Cercocebus atys atys ) (SIVsmm),

3248-492: Was only minimally affected, however, when the secreted env product was enzymatically deglycosylated. The env gene codes for the gp160 protein which forms a homotrimer, and is cleaved into gp120 and gp41 by the host cell protease , furin . To form an active fusion protein, SU gp120 and TM gp41 polypeptides remain non-covalently bound together, but this interaction is often not stable, leading to shed, soluble gp120 and membrane-bound, gp41 'stumps'. Separately, cleavage by furin

3306-704: Was reported to have greater similarity to SIVgor, than SIVcpz. The virus had been isolated from a Cameroonian woman residing in France who was diagnosed with HIV-1 infection in 2004. The scientists reporting this sequence placed it in a proposed Group P "pending the identification of further human cases". HIV-2 is mostly found in Africa, and therefore less recognized elsewhere in the world. The first identification of HIV-2 occurred in 1985 in Senegal by microbiologist Souleymane Mboup and his collaborators. The first case in

3364-780: Was the source of pre-1960 pandemic viruses, originated in the 1920s in Léopoldville , the Belgian Congo , today known as Kinshasa, which is now the capital of the Democratic Republic of Congo (DRC). Its zoonotic origin is the SIVcpz strain, which infects chimpanzees. The M group is subdivided further into clades , called subtypes, that are also given a letter. There are also "circulating recombinant forms" or CRFs derived from genetic recombination between viruses of different subtypes which are in addition each given

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