HIV
HIV Classification
| Species | Virulence | Infectivity | Prevalence | Inferred origin |
|---|---|---|---|---|
| HIV-1 | High | High | Global | Common chimpanzee |
| HIV-2 | Lower | Low | West Africa | Sooty mangabey |
HIV is a member of the genus Lentivirus,[12] part of the family Retroviridae.[13]Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period.[14] Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded enzyme, integrase, and host co-factors.[15] Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system, for an indiscriminate amount of time.[16] The HIV virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms. Alternatively, the integrated viral DNA may be transcribed, producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew.
Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV (Lymphadenopathy Associated Virus) and HTLV-III (Human T cell Lymphotropic Virus III). HIV-1 is more virulent and more infective than HIV-2,[17]and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.[18]
Structure and genome
HIV is different in structure from other retroviruses. It is roughly spherical[19] with a diameter of about 120 nm, around 60 times smaller than a red blood cell.[20] It is composed of two copies of positive-sense single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24.[21] The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.[21]
This is, in turn, surrounded by the viral envelope, that is composed of the lipid bilayer taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV Envelope protein,[21] which consists of a cap made of three molecules known as glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope.[22][23] The Envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target cell's membrane releasing the viral contents into the cell and initiating the infectious cycle.[22]
As the sole viral protein on the surface of the virus, the Envelope protein is a major target for HIV vaccine efforts.[24] Over half of the mass of the trimeric envelope spike is N-linked glycans. The density is high as the glycans shield the 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 and Golgi apparatus.[25][26] The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.[27] 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.[28]
The molecular structure of the viral spike has now been determined by X-ray crystallography[29] and cryo-electron microscopy.[30] 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.[31] 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.[32] 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.[33]
The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.[21] For example, envcodes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.[21]
The two Tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes ERCC1 and IER3.[34][35] The Rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif protein (p23) prevents the action of APOBEC3G (a cellular protein that deaminates Cytidine to Uridine in the single stranded viral DNA and/or interferes with reverse transcription[36]). The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class IImolecules.[37][38][39]
Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new virus particles from infected cells.[21] The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by Gag and Rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the Gag-Pol reading frame required to make functional Pol.[21]
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