Structure and genome of HIV

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The

Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV."[3] Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.[4][5]

Structure

Diagram of HIV
Structure of the immature HIV-1 capsid in intact virus particles
A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide

The complete sequence of the HIV-1 genome, extracted from infectious virions, has been solved to single-nucleotide resolution.[6] The HIV genome encodes a small number of

ssRNA genome, the enzymes reverse transcriptase, integrase and protease, some minor proteins, and the major core protein.[8] The genome of human immunodeficiency virus (HIV) encodes 8 viral proteins playing essential roles during the HIV life cycle.[7]

HIV-1 is composed of two copies of

poly(A) tail, and many open reading frames (ORFs).[15] Viral structural proteins are encoded by long ORFs, whereas smaller ORFs encode regulators of the viral life cycle: attachment, membrane fusion, replication, and assembly.[15]

The single-strand RNA is tightly bound to p7

gp120 and gp41. Env is responsible for binding to its primary host receptor, CD4, and its co-receptor (mainly CCR5 or CXCR4), leading to viral entry into its target cell.[16]

As the only proteins on the surface of the virus, the envelope glycoproteins (gp120 and gp41) are the major targets for

glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic reticulum and Golgi apparatus.[18][19] The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on secreted or cell surface human glycoproteins.[20] The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to or, are adapted to cope with, these envelope glycans.[21]

The molecular structure of the

disulphide bond and an isoleucine to proline mutation in gp41.[24] The so-called SOSIP trimers not only reproduce the antigenic properties of the native viral spike but also display the same degree of immature glycans as presented on the native virus.[25] Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising epitopes than recombinant monomeric gp120 which act to suppress the immune response to target epitopes.[26]

Genome organization

Structure of the RNA genome of HIV-1

HIV has several major genes coding for structural proteins that are found in all retroviruses as well as several nonstructural ("accessory") genes unique to HIV.[27] The HIV genome contains nine genes that encode fifteen viral proteins.[28] These are synthesized as polyproteins which produce proteins for virion interior, called Gag, group specific antigen; the viral enzymes (Pol, polymerase) or the glycoproteins of the virion env (envelope).[29] In addition to these, HIV encodes for proteins which have certain regulatory and auxiliary functions as well.[29] HIV-1 has two important regulatory elements: Tat and Rev and few important accessory proteins such as Nef, Vpr, Vif and Vpu which are not essential for replication in certain tissues.[29] 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.[citation needed]

HIV employs a sophisticated system of differential RNA splicing to obtain nine different gene products from a less than 10kb genome.[30] HIV has a 9.2kb unspliced genomic transcript which encodes for gag and pol precursors; a singly spliced, 4.5 kb encoding for env, Vif, Vpr and Vpu and a multiply spliced, 2 kb mRNA encoding for Tat, Rev and Nef.[30]

Proteins encoded by the HIV genome
Class Gene name Primary protein products Processed protein products
Viral structural proteins gag Gag polyprotein MA, CA, SP1, NC, SP2, P6
pol Pol polyprotein RT, RNase H, IN, PR
env gp160 gp120, gp41
Essential regulatory elements tat Tat
rev Rev
Accessory regulatory proteins nef Nef
vpr Vpr
vif Vif
vpu Vpu

Viral structural proteins

The HIV capsid consists of roughly 200 copies of the p24 protein. The p24 structure is shown in two representations: cartoon (top) and isosurface (bottom)
  • nucleocapsid protein, p7); SP2 (spacer peptide 2, p1) and P6 protein.[31]
  • HIV protease (PR).[29] HIV protease is required to cleave the precursor Gag polyprotein to produce structural proteins, RT is required to transcribe DNA from RNA template, and IN is necessary to integrate the double-stranded viral DNA into the host genome.[27]
  • gp120 or SU, which attaches to the CD4 receptors present on lymphocytes, and gp41 or TM, which embeds in the viral envelope to enable the virus to attach to and fuse with target cells.[27][31]

Essential regulatory elements

Accessory regulatory proteins

RNA secondary structure

HIV pol-1 stem loop
Cis-reg
PDB structuresPDBe

Several conserved

secondary structure elements have been identified within the HIV RNA genome. The HIV viral RNA structures regulates the progression of reverse transcription. [33] The 5'UTR structure consists of series of stem-loop structures connected by small linkers.[10] These stem-loops (5' to 3') include the trans-activation region (TAR) element, the 5' polyadenylation signal [poly(A)], the PBS, the DIS, the major SD and the ψ hairpin structure located within the 5' end of the genome and the HIV Rev response element (RRE) within the env gene.[10][34][35] Another RNA structure that has been identified is gag stem loop 3 (GSL3), thought to be involved in viral packaging.[36][37] 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.[citation needed
]

An RNA secondary structure determined by

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.[38]

V3 loop

The third variable loop or V3 loop is a part or region of the

gp120, allows it to infect human immune cells by binding to a cytokine receptor on the target human immune cell, such as a CCR5 cell or CXCR4 cell, depending on the strain of HIV.[39]
The envelope glycoprotein (Env) gp 120/41 is essential for HIV-1 entry into cells. Env serves as a molecular target of a medicine treating individuals with HIV-1 infection, and a source of immunogen to develop AIDS vaccine. However, the structure of the functional Env trimer has remained elusive.[40]

See also

References

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