HIV structure and genome
Encyclopedia
The 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.
HIV is different in structure from other retrovirus
es. It is around 120 nm in diameter (around 60 times smaller than a red blood cell
) and roughly spherical.
HIV-1 is composed of two copies of single-stranded RNA
enclosed by a conical capsid
comprising the viral protein p24
, typical of lentivirus
es (Figure 1). The RNA component is 9749 nucleotides long. This is in turn surrounded by a plasma membrane
of host-cell origin. The single-strand RNA is tightly bound to the nucleocapsid proteins, p6, p7 and enzymes that are indispensable for the development of the virion, such as reverse transcriptase
and integrase
. The nucleocapsid (p7 and p6) associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by nuclease
s. A matrix composed of an association of the viral protein p17 surrounds the capsid, ensuring the integrity of the virion particle. Also enclosed within the virion particle are Vif
, Vpr
, Nef
, p7 and viral Protease (Figure 1). The envelope is formed when the capsid buds from the host cell, taking some of the host-cell membrane with it. The envelope includes the glycoproteins gp120
and gp41
.
As a result of its role in virus-cell attachment, the structure of the virus envelope spike, consisting of gp120 and gp41, is of particular importance. It is hoped that determining the envelope spike's structure will contribute to scientific understanding of the virus and its replication cycle, and help in the creation of a cure. The first model of its structure was compiled in 2006 using cryo-electron microscopy
and suggested that three copies of gp120-gp41 heterodimers are thought to form a trimer as the envelope spike. However, published shortly after was evidence for a single-stalk "mushroom" model, with a head consisting of a trimer gp120s and a gp41 stem, which appears as a compact structure with no obvious separation between the three monomers, anchoring it to the envelope. There are various possibilities as to the source of this difference, as it is unlikely that the viruses imaged by the two groups were structurally different. More recently, further evidence backing up the heterodimer trimer-based model has been found.
HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. The gag gene provides the basic physical infrastructure of the virus, and pol provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. Though they may be altered by mutation, all of these genes except tev exist in all known variants of HIV; see Genetic variability of HIV.
elements have been identified within the HIV RNA genome
. These include the trans-activating responsive (TAR) element located within the 5' end of the genome and the HIV Rev response element
(RRE) within the env gene. Another RNA structure that has been identified is gag stem loop 3 (GSL3)
, thought to be involved in viral packaging. RNA secondary structures have been proposed to affect the HIV life cycle by altering the function of HIV protease
and reverse transcriptase
, although not all elements identified have been assigned a function.
An RNA secondary structure determined by SHAPE analysis has shown to contain three stem loops and is located between the HIV protease and reverse transcriptase genes. This cis regulatory RNA has been shown to be conserved throughout the HIV family and is thought to influence the viral life cycle.
The complete structure of an HIV-1 genome, extracted from infectious virions, has been solved to single-nucleotide resolution.
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
and proteins of 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...
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
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es. It is around 120 nm in diameter (around 60 times smaller than a red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
) and roughly spherical.
HIV-1 is composed of two copies of single-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
enclosed by a conical capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
comprising the viral protein p24
P24 capsid protein
p24 is a component of the HIV particle capsid. There are approximately 2000 molecules per virus particle, or at a molecule weight of 24 kDa, about 10^4 virus particles per picogram of p24.-References:...
, typical of lentivirus
Lentivirus
Lentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period...
es (Figure 1). The RNA component is 9749 nucleotides long. This is in turn surrounded by a plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of host-cell origin. The single-strand RNA is tightly bound to the nucleocapsid proteins, p6, p7 and enzymes that are indispensable for the development of the virion, such as reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
and integrase
Integrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
. The nucleocapsid (p7 and p6) associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by nuclease
Nuclease
A nuclease is an enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids. Older publications may use terms such as "polynucleotidase" or "nucleodepolymerase"....
s. A matrix composed of an association of the viral protein p17 surrounds the capsid, ensuring the integrity of the virion particle. Also enclosed within the virion particle are Vif
Viral infectivity factor
Viral infectivity factor, or Vif, is a protein found in HIV and other retroviruses. Its role is to disrupt the antiviral activity of the human enzyme APOBEC by targeting it for ubiquitination and cellular degradation. APOBEC is a cytidine deaminase enzyme that mutates viral nucleic acids.Vif is a...
, Vpr
Vpr
Vpr is a HIV gene.It stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing cells such as macrophages...
, Nef
Nef (protein)
Nef is a protein expressed by primate lentiviruses. These include human immunodeficiency viruses and simian immunodeficiency virus . Nef is one of many pathogen-expressed proteins, known as virulence factors, which function to manipulate the host's cellular machinery and thus allow infection,...
, p7 and viral Protease (Figure 1). The envelope is formed when the capsid buds from the host cell, taking some of the host-cell membrane with it. The envelope includes the glycoproteins gp120
Gp120
Envelope glycoprotein 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...
and 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...
.
As a result of its role in virus-cell attachment, the structure of the virus envelope spike, consisting of gp120 and gp41, is of particular importance. It is hoped that determining the envelope spike's structure will contribute to scientific understanding of the virus and its replication cycle, and help in the creation of a cure. The first model of its structure was compiled in 2006 using cryo-electron microscopy
Cryo-electron microscopy
Cryo-electron microscopy , or electron cryomicroscopy, is a form of transmission electron microscopy where the sample is studied at cryogenic temperatures...
and suggested that three copies of gp120-gp41 heterodimers are thought to form a trimer as the envelope spike. However, published shortly after was evidence for a single-stalk "mushroom" model, with a head consisting of a trimer gp120s and a gp41 stem, which appears as a compact structure with no obvious separation between the three monomers, anchoring it to the envelope. There are various possibilities as to the source of this difference, as it is unlikely that the viruses imaged by the two groups were structurally different. More recently, further evidence backing up the heterodimer trimer-based model has been found.
Genome organization
- gag (group-specific antigenGroup-specific antigenGroup-specific antigen is the genetic material that codes for the core structural proteins of a retrovirus.It comprises part of the gag-onc fusion protein.-Gag in HIV:...
): codes for the Gag polyprotein, which is processed during maturation to MA (matrix protein, p17); CA (capsid protein, p24P24 capsid proteinp24 is a component of the HIV particle capsid. There are approximately 2000 molecules per virus particle, or at a molecule weight of 24 kDa, about 10^4 virus particles per picogram of p24.-References:...
); SP1 (spacer peptide 1, p2); NC (nucleocapsid protein, p7); SP2 (spacer peptide 2, p1) and p6P6P6, P-6, or P.6 may refer to:* P-6 Hawk, a 1927 American single-engine biplane fighter* p6 protein, a protein of HIV* HAT-P-6, a star in the constellation Andromeda* Integrated Truss Structure#P6, S6 trusses on the International Space Station...
.
- polPol (HIV)Pol refers to a gene in retroviruses, or the protein produced by that gene.Products of pol include:-Reverse transcriptase:Common to all retroviruses, this enzyme transcribes the viral RNA into double-stranded DNA.-Integrase:...
: codes for viral enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s reverse transcriptaseReverse transcriptaseIn the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, integraseIntegraseRetroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
, and HIV protease.
- envEnv (gene)-Env in HIV:The env gene does not actually code for gp120 and gp41, but for a precursor to both, gp160. During HIV reproduction, the host cell's own enzymes cleave gp160 into gp120 and gp41. The host cell protease that cleaves Env into gp120 and gp41 is Furin...
(for "envelope"): codes for gp160, the precursor to gp120Gp120Envelope glycoprotein 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...
and gp41Gp41gp41 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...
, proteins embedded in the viral envelope which enable the virus to attach to and fuse with target cells.
- Transactivators: tatTat (HIV)Tat is an HIV gene.Tat stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.-Function:...
, rev, vprVprVpr is a HIV gene.It stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing cells such as macrophages...
- Other regulators: vifViral infectivity factorViral infectivity factor, or Vif, is a protein found in HIV and other retroviruses. Its role is to disrupt the antiviral activity of the human enzyme APOBEC by targeting it for ubiquitination and cellular degradation. APOBEC is a cytidine deaminase enzyme that mutates viral nucleic acids.Vif is a...
, nefNef (protein)Nef is a protein expressed by primate lentiviruses. These include human immunodeficiency viruses and simian immunodeficiency virus . Nef is one of many pathogen-expressed proteins, known as virulence factors, which function to manipulate the host's cellular machinery and thus allow infection,...
, vpuVpuVpu is a HIV gene.Vpu stands for "Viral Protein U". Vpu is involved in viral budding, enhancing virion release from the cell by counteracting BST2 . In the absence of vpu, tetherin binds to the viral envelope and ties it to the cell membrane and other viral particles, impeding release of the viral...
- tev: This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the tat, env, and rev genes, and codes for a protein with some of the properties of tatTat (HIV)Tat is an HIV gene.Tat stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.-Function:...
, but little or none of the properties of rev.
RNA secondary structure
Several conserved secondary structureSecondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
elements have been identified within the HIV RNA genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. These include the trans-activating responsive (TAR) element located within the 5' end of the genome and the HIV Rev response element
HIV Rev response element
The HIV-1 Rev response element is a highly structured, ~350 nucleotide RNA segment present in the Env coding region of unspliced and partially spliced viral mRNAs...
(RRE) within the env gene. Another RNA structure that has been identified is gag stem loop 3 (GSL3)
HIV gag stem loop 3 (GSL3)
HIV gag stem loop 3 is an RNA element that is known to direct specific packaging of HIV-1 genomic RNA. Deletion of GSL3 leads to decreases in both viral RNA packaging and dimerisation....
, thought to be involved in viral packaging. RNA secondary structures have been proposed to affect the HIV life cycle by altering the function of HIV protease
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
and reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, although not all elements identified have been assigned a function.
An RNA secondary structure determined by SHAPE analysis has shown to contain three stem loops and is located between the HIV protease and reverse transcriptase genes. This cis regulatory RNA has been shown to be conserved throughout the HIV family and is thought to influence the viral life cycle.
The complete structure of an HIV-1 genome, extracted from infectious virions, has been solved to single-nucleotide resolution.