Компоненты вируса иммунодефицита человека (ВИЧ)

Components of human immunodeficiency virus
The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of 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." 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.

The complete sequence of the HIV 1 genome, extracted from infectious virions, has been solved to single nucleotide resolution. The HIV genome encodes a small number of viral proteins, invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. HIV is different in structure from other retroviruses. The HIV virion is ~100 nm in diameter. Its innermost region consists of a cone shaped core that includes two copies of the (positive sense) ssRNA genome, the enzymes reverse transcriptase, integrase and protease, some minor proteins, and the major core protein. The genome of human immunodeficiency virus (HIV) encodes 8 viral proteins playing essential roles during the HIV life cycle. The two RNAs are often identical, yet they are not independent, but form a compact dimer within the virion. Several reasons as for why two copies of RNA are packaged rather than just one have been proposed, including probably a combination of these advantages: One advantage is that the two copies of RNA strands are vital in contributing to HIV 1 recombination, which occurs during reverse transcription of viral replication, thus increasing genetic diversity. The RNA component is 9749 nucleotides long and bears a 5’ cap (Gppp), a 3’ poly(A) tail, and many open reading frames (ORFs). Viral structural proteins are encoded by long ORFs, whereas smaller ORFs encode regulators of the viral life cycle: attachment, membrane fusion, replication, and assembly. As the only proteins on the surface of the virus, the envelope glycoproteins (gp120 and gp41) are the major targets for HIV vaccine efforts. Over half of the mass of the trimeric envelope spike is N linked glycans. The density is high as the glycans shield underlying viral protein from neutralisation by antibodies. This is one of the most densely 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. The majority of the glycans are therefore stalled as immature 'high mannose' glycans not normally present on secreted or cell surface human glycoproteins. 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. The molecular structure of the viral spike has now been determined by X ray crystallography and cryo electron microscopy. These advances in structural biology were made possible due to the development of stable recombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline mutation in gp41. 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. 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.

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. 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). In addition to these, HIV encodes for proteins which have certain regulatory and auxiliary functions as well. 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. pol codes for viral enzymes reverse transcriptase (RT) and RNase H, integrase (IN), and HIV protease (PR). env (for "envelope") codes for gp160, which is cleaved by a host protease, furin, within the endoplasmic reticulum of the host cell. The post translational processing produces a surface glycoprotein, 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.

Several conserved secondary structure elements have been identified within the HIV RNA genome. The HIV viral RNA structures regulates the progression of reverse transcription. The 5'UTR structure consists of series of stem loop structures connected by small linkers. 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 third variable loop or V3 loop is a part or region of the Human Immunodeficiency Virus. The V3 loop of the viron's envelope glycoprotein, 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. 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.