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90-404: The human immunodeficiency viruses ( HIV ) are two species of Lentivirus (a subgroup of retrovirus ) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, the average survival time after infection with HIV

180-492: A 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 . The term viral tropism refers to

270-666: A transgene , and low immunogenicity. Lentiviruses have also been successfully used for transduction of diabetic mice with the gene encoding PDGF (platelet-derived growth factor), a therapy being considered for use in humans. Finally, lentiviruses have been also used to elicit an immune response against tumor antigens. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases. Virulence Virulence

360-533: A cell by a virion can be called "cell-free spread" to distinguish it from a more recently recognized process called "cell-to-cell spread". In cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or extracellular fluid and then infect another T cell following a chance encounter. HIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described. Firstly, an infected T cell can transmit virus directly to

450-477: A cell surface. 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 cryogenic electron microscopy . These advances in structural biology were made possible due to

540-413: A few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate, when the window period is taken into consideration. A single screening test is correct more than 99% of the time. The chance of a false-positive result in a standard two-step testing protocol

630-448: 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 known as glycoprotein (gp) 120 , and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope. The envelope protein, encoded by

720-572: 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

810-443: A model system. Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophilia is corrected by expressing wild-type platelet- factor VIII , the gene that is mutated in human hemophilia. Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of

900-612: A more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing. RNA can also be processed to produce mature messenger RNAs (mRNAs). In most cases, this processing involves RNA splicing to produce mRNAs that are shorter than the full-length genome. Which part of the RNA is removed during RNA splicing determines which of

990-441: A number of mechanisms, including pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4 T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4 T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to

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1080-457: A resistant host. Virulence can also be transferred using a plasmid . The noun virulence ( Latin noun virulentia ) derives from the adjective virulent , meaning disease severity. The word virulent derives from the Latin word virulentus , meaning "a poisoned wound" or "full of poison". The term virulence does not only apply to viruses. From an ecological standpoint, virulence

1170-461: A strain of SIV found in sooty mangabees. Since HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm. Many HIV-positive people are unaware that they are infected with the virus. For example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion

1260-554: A target T cell via a virological synapse . Secondly, an antigen-presenting cell (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells). Whichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread. A number of factors contribute to this increased efficiency, including polarised virus budding towards

1350-421: Is a pathogen 's or microorganism 's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host . The pathogenicity of an organism—its ability to cause disease —is determined by its virulence factors . In the specific context of gene for gene systems, often in plants, virulence refers to a pathogen's ability to infect

1440-460: Is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit. The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi apparatus where it is cleaved by furin resulting in

1530-512: 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 more stable two-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

1620-487: Is estimated to be 9 to 11 years, depending on the HIV subtype . In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood , pre-ejaculate , semen , and vaginal fluids . Non-sexual transmission can occur from an infected mother to her infant during pregnancy , during childbirth by exposure to her blood or vaginal fluid, and through breast milk . Within these bodily fluids, HIV

1710-522: Is estimated to be about 1 in 250,000 in a low risk population. Testing post-exposure is recommended immediately and then at six weeks, three months, and six months. Lentivirus Lentiviruses can integrate a significant amount of viral complementary DNA into the DNA of the host cell and can efficiently infect nondividing cells, so they are one of the most efficient methods of gene delivery . They can become endogenous , integrating their genome into

1800-420: Is even lower in rural populations. Furthermore, in 2001 only 0.5% of pregnant women attending urban health facilities were counselled, tested or received their test results. Again, this proportion is even lower in rural health facilities. Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV. HIV-1 testing

1890-462: 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. 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

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1980-411: Is initially done using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen

2070-443: Is largely confined to West Africa . HIV is similar in structure to other retroviruses. It is roughly spherical with a diameter of about 120  nm , around 100,000 times smaller in volume than a red blood cell . It is composed of two copies of positive- sense single-stranded RNA that codes for the virus' nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24 . The single-stranded RNA

2160-608: Is more likely, leading to immunodeficiency. Three groups of HIV-1 have been identified on the basis of differences in the envelope ( env ) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or clades ), based on the whole genome, which are geographically distinct. The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in

2250-556: Is present as both free virus particles and virus within infected immune cells . Research has shown (for both same-sex and opposite-sex couples) that HIV is not contagious during sexual intercourse without a condom if the HIV-positive partner has a consistently undetectable viral load . HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4 T cells), macrophages , and dendritic cells . HIV infection leads to low levels of CD4 T cells through

2340-435: Is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats. Conversely, lentivirus are also used to stably over-express certain genes, thus allowing researchers to examine the effect of increased gene expression in

2430-659: Is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a polymerase chain reaction (PCR), western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person. HIV deaths in 2014 excluding

2520-401: Is the loss of fitness induced by a parasite upon its host. Virulence can be understood in terms of proximate causes —those specific traits of the pathogen that help make the host ill—and ultimate causes —the evolutionary pressures that lead to virulent traits occurring in a pathogen strain. The ability of bacteria to cause disease is described in terms of the number of infecting bacteria,

2610-411: 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. This is, in turn, surrounded by the viral envelope , that is composed of the lipid bilayer taken from the membrane of

2700-531: Is unknown how often such mixed packaging occurs under natural conditions. Bonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome. In addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies. This view of

2790-634: The African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus, which is present at high levels in the host's blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans. In contrast, when these strains infect species that have not adapted to SIV ("heterologous" or similar hosts such as rhesus or cynomologus macaques ),

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2880-544: 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. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid , which enables the virus to be transmitted from a male to his sexual partner . The virions can then infect numerous cellular targets and disseminate into

2970-443: 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 (generally either CCR5 or CXCR4 , but others are known to interact) on

3060-420: The gag polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the protease inhibitor class. The various structural components then assemble to produce a mature HIV virion. Only mature virions are then able to infect another cell. The classical process of infection of

3150-513: 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

3240-434: The ovine , caprine , and feline lentiviruses). Antibodies to gags in lions and other large felines indicate the existence of another yet-to-be identified virus related to feline lentivirus and the ovine/caprine lentiviruses. The virions are enveloped viruses 80–100 nm in diameter. They are spherical or pleomorphic , with capsid cores that mature to a cylindrical or conical shape. Projections of envelope make

3330-403: The phylogenetic tree representing the lineage of the M group of HIV-1. Co-infection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and

3420-435: The α -chemokine receptor, CXCR4 , for entry. Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able 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

3510-424: The β -chemokine receptor, CCR5 , for entry and are thus able to replicate in both macrophages and CD4 T cells. This CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4 cells become depleted in

3600-583: 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 not explain viral tropism, as not all 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 constitute a reservoir that maintains infection when CD4 T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV. For example, people with

3690-404: The DIS (dimerization initiation signal) hairpin is exposed. The formation of the gRNA dimer is mediated by a 'kissing' interaction between the DIS hairpin loops of the gRNA monomers. At the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly. The labile gRNA dimer has been also reported to achieve

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3780-417: 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. 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

3870-439: The HIV protein-coding sequences is translated. Mature HIV mRNAs are exported from the nucleus into the cytoplasm , where they are translated to produce HIV proteins, including Rev . As the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus. Some of these full-length RNAs function as mRNAs that are translated to produce

3960-562: The HIV virological synapse in vivo . The many dissemination mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies. HIV differs from many viruses in that it has very high genetic variability . This diversity is a result of its fast replication cycle , with the generation of about 10 virions every day, coupled with a high mutation rate of approximately 3 x 10 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase. This complex scenario leads to

4050-524: 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

4140-431: The U.S.: Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations. In addition,

4230-409: The adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically. On the view that recombination in HIV is a repair process,

4320-421: The advent of AIDS. HIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of HAART therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies. Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be

4410-401: The animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection. Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host. SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to

4500-460: The bound virus then enters the host cell. Virulent viruses such as HIV , which causes AIDS , have mechanisms for evading host defenses. HIV infects T-helper cells , which leads to a reduction of the adaptive immune response of the host and eventually leads to an immunocompromised state. Death results from opportunistic infections secondary to disruption of the immune system caused by AIDS. Some viral virulence factors confer ability to replicate during

4590-591: 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 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

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4680-465: 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 entry 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

4770-455: The collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, 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

4860-408: The defensive inflammation responses of the host such as during virus-induced fever . Many viruses can exist inside a host for long periods during which little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host. The term " neurovirulent " is used for viruses such as rabies and herpes simplex which can invade

4950-444: The development of AIDS. HIV is a member of the genus Lentivirus , part of the family Retroviridae . 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 . Lentiviruses are transmitted as single-stranded , positive- sense , enveloped RNA viruses . Upon entry into

5040-575: The development of stable recombinant 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 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

5130-489: The early stages of genome replication, and include reverse transcriptase and integrase . Reverse transcriptase is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase possesses [RNase H] activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and

5220-428: The envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins . Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon is infrequently based on their antigenic properties. Classed as having class C morphology Lentivirus

5310-430: The generation of many variants of HIV in a single infected patient in the course of one day. This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens,

5400-573: The generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching. HIV-1 infection causes chronic inflammation and production of reactive oxygen species . Thus, the HIV genome may be vulnerable to oxidative damage , including breaks in the single-stranded RNA. For HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species. Thus, Michod et al. suggested that recombination by viruses

5490-550: The genetic information that is transmitted from parental to progeny genomes. Viral recombination produces genetic variation that likely contributes to the evolution of resistance to anti-retroviral therapy . Recombination may also contribute, in principle, to overcoming the immune defenses of the host. Yet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution. It

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5580-469: The host germline genome, so that the virus is henceforth inherited by the host's descendants. Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, domestic cats, and cattle). The primate lentiviruses are distinguished by the use of CD4 protein as a receptor and the absence of dUTPase . Some groups have cross-reactive gags ( group-specific antigens ) (e.g.,

5670-468: The host DNA. It then processes the LTRs before inserting the viral genome into the host DNA. Tat acts as a trans-activator during transcription to enhance initiation and elongation. The Rev responsive element acts post-transcriptionally, regulating mRNA splicing and transport to the cytoplasm. The lentiviral proteome consists of five major structural proteins and three or four non-structural proteins (three in

5760-414: 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

5850-521: The integrated DNA provirus is transcribed into RNA. The full-length genomic RNAs (gRNA) can be packaged into new viral particles in a pseudodiploid form. The selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA. The gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG hairpins , responsible for splicing and translation respectively, are sequestered and

5940-449: The molecules. These are all proximate causes of morbidity in the host. Virus virulence factors allow it to replicate, modify host defenses, and spread within the host, and they are toxic to the host. They determine whether infection occurs and how severe the resulting viral disease symptoms are. Viruses often require receptor proteins on host cells to which they specifically bind. Typically, these host cell proteins are endocytosed and

6030-408: 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 well as in macrophages and use

6120-562: The primate lentiviruses). Structural proteins listed by size: The envelope proteins SU and TM are glycosylated in at least some lentiviruses (HIV, SIV), if not all of them. Glycosylation seems to play a structural role in the concealment and variation of antigenic sites necessary for the host to mount an immune system response. Enzymes: Gene regulatory proteins: Accessory proteins: Serological relationships: Antigen determinants are type specific and group specific. Antigen determinants that possess type-specific reactivity are found on

6210-401: The remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes. The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009. The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006. HIV-2's closest relative is SIVsm,

6300-632: The result that host defense mechanisms do damage to host tissues while the infection is being countered (e.g., cytokine storm ). The virulence factors of bacteria are typically proteins or other molecules that are synthesized by enzymes . These proteins are coded for by genes in chromosomal DNA, bacteriophage DNA or plasmids . Certain bacteria employ mobile genetic elements and horizontal gene transfer . Therefore, strategies to combat certain bacterial infections by targeting these specific virulence factors and mobile genetic elements have been proposed. Bacteria use quorum sensing to synchronise release of

6390-423: The reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes. This recombination is most obvious when it occurs between subtypes. The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of

6480-426: The route of entry into the body, the effects of host defense mechanisms, and intrinsic characteristics of the bacteria called virulence factors . Many virulence factors are so-called effector proteins that are injected into the host cells by specialized secretion apparati, such as the type three secretion system . Host-mediated pathogenesis is often important because the host can respond aggressively to infection with

6570-514: 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 well 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

6660-409: The site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase diffusion of virions, and clustering of HIV entry receptors on the target cell towards the contact zone. Cell-to-cell spread is thought to be particularly important in lymphoid tissues , where CD4 T cells are densely packed and likely to interact frequently. Intravital imaging studies have supported the concept of

6750-551: The structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles. HIV-1 and HIV-2 appear to package their RNA differently. HIV-1 will bind to any appropriate RNA. HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. Two RNA genomes are encapsidated in each HIV-1 particle (see Structure and genome of HIV ). Upon infection and replication catalyzed by reverse transcriptase, recombination between

6840-494: 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 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. The two tat proteins (p16 and p14) are transcriptional transactivators for

6930-493: The surface appear rough, or tiny spikes (about 8 nm) may be dispersed evenly over the surface. Lentiviruses contain 2 sense, single-strand RNAs that are bound by nucleocapsid proteins. As with all retroviruses, lentiviruses have gag , pol and env genes, coding for viral proteins in the order: 5´- gag - pol - env -3´. Unlike other retroviruses, however, lentiviruses have two regulatory genes , tat and rev . They may also have additional accessory genes depending on

7020-422: The target cell surface. Gp120 binds to integrin α 4 β 7 activating LFA-1 , the central integrin involved in the establishment 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. Once gp120

7110-412: 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 . Once integrated,

7200-413: The two HIV envelope glycoproteins, gp41 and gp120 . These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. The budded virion is still immature as

7290-482: The two genomes can occur. Recombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA. During reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA. This form of recombination is known as copy-choice. Recombination events may occur throughout the genome. Anywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle

7380-567: The viral DNA into the host cell's genome is carried out by another viral enzyme called integrase . The integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF- κ B (nuclear factor kappa B), which is upregulated when T cells become activated. This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection. During viral replication,

7470-536: The virus (e.g., for HIV-1: vif , vpr , vpu , nef ) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The long terminal repeat (LTR) is about 600 nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long. Retroviruses carry proteins within their capsids , which bind the RNA genome. These proteins are typically involved in

7560-534: 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 establishment 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

7650-423: 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 occur exclusively at the plasma membrane. More recently, however, productive infection by pH -independent, clathrin-mediated endocytosis of HIV-1 has also been reported and

7740-462: 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 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

7830-402: The virus to evade the body's immune system. 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

7920-539: The virus. This virus has also lost a function of the nef gene that is present in most SIVs. For non-pathogenic SIV variants, nef suppresses T cell activation through the CD3 marker. Nef 's function in non-pathogenic forms of SIV is to downregulate expression of inflammatory cytokines , MHC-1 , and signals that affect T cell trafficking. In HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function. Without this function, T cell depletion

8010-470: The whole organism. However, a selection process 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

8100-442: Was recently suggested to constitute 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 allow

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