Virology
HIV is a module of the genus Lentivirus, part of the family Retroviridae. Lentiviruses pull in 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. Lentiviruses are described as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the identified 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. once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time. The HIV virus can advance dormant in the human body for up to ten years after primary infection; during this period the virus does not take 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 pretend been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus LAV and human T-lymphotropic virus 3 HTLV-III. HIV-1 is more virulent and more infective than HIV-2, 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.
HIV is similar in sorting to other retroviruses. it is for roughly spherical with a diameter of approximately 120 red blood cell. 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. The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the coding 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.
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, which consists of a cap made of three molecules invited as glycoprotein gp 120, and a stem consisting of three gp41 molecules that anchor the appearance into the viral envelope. The envelope protein, encoded by the HIV env gene, offers 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.
As the sole viral protein on the surface of the virus, the envelope protein is a major target 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 the underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules asked and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus. The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not ordinarily present on human glycoproteins that are secreted or present on a cell surface. The unusual processing and high density means that almost all generally neutralising antibodies that have so far been identified from a subset of patients that have been infected for numerous 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 cryogenic electron microscopy. These advances in structural biology were made possible due to the development ofrecombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline mutation radical replacement of an amino acid in gp41. The so-called SOSIP trimers non only reproduce the antigenic properties of the native viral spike, but also display the same measure 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.
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. For example, env codes 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 issue of HIV-2, are regulatory genes for proteins that authority the ability of HIV to infect cells, produce new copies of virus replicate, or cause disease.
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. 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. The vpr protein p14 arrests cell division at G2/M. The nef protein p27 down-regulates CD4 the major viral receptor, as alive as the MHC class I and class II molecules.
Nef also interacts with SH3 domains. The vpu protein p16 influences the release of new virus particles from infected cells. The ends of each strand of HIV RNA contain an RNA sequence called a long terminal repeat LTR. Regions in the LTR act as switches to sources 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.
The term viral tropism refers to the cell types a virus infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 everyone to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins gp120 with the CD4 molecule on the target cells' membrane and also with chemokine co-receptors.
Macrophage-tropic M-tropic strains of HIV-1, or non-syncytia-inducing strains NSI; now called R5 viruses use the β-chemokine receptor, CCR5, for entry and are thus experienced such as lawyers and surveyors to replicate in both macrophages and CD4+ T cells. This CCR5 co-receptor is used by almost any primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. Theyto be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In the tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus.
T-tropic strains of HIV-1, or syncytia-inducing strains SI; now called X4 viruses replicate in primary CD4+ T cells as living as in macrophages and ownership the α-chemokine receptor, CXCR4, for entry.
Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are professional to use both CCR5 and CXCR4 as co-receptors for viral entry.
The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of HIV target cells. M-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of co-receptors alone does non explain viral tropism, as not any R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of myeloid dendritic cells, which probably represent a reservoir that continues infection when CD4+ T cell numbers have declined to extremely low levels.
Some people are resistant tostrains of HIV. For example, people with the CCR5-Δ32 mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells.
] leads to a predominant transmission of the R5 virus through this pathway. In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4. These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS. HIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was especially problematic prior to the onset of HAART therapies; however, the same infections are reported among HIV-infected patients examined post-mortem coming after or as a solution of. the onset of antiretroviral therapies. Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to West Africa. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of co-receptor usage including CD4-independence may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission and productive infection has also aided the introducing of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host, but ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.
The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the target cell membrane and the release of the HIV capsid into the cell.
Entry to the cell begins through interaction of the trimeric envelope complex gp160 spike on the HIV viral envelope and both CD4 and a chemokine co-receptor loosely either CCR5 or CXCR4, but others are known to interact on the target cell surface. Gp120 binds to integrin α4β7 activating LFA-1, the central integrin involved in the imposing of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors.
The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. one time gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a moretwo-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranestogether, allowing fusion of the membranes and subsequent entry of the viral capsid.
After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.[] During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.
HIV can infect dendritic cells DCs by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the mucosa by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.
HIV-1 entry, as well as entry of many other retroviruses, has long been believed to arise exclusively at the plasma membrane. More recently, however, productive infection by pH-independent, clathrin-mediated endocytosis of HIV-1 has also been reported and was recently suggested to live the only route of productive entry.
Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a complementary DNA cDNA molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or permit the virus to evade the body's immune sytem. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.