What Proteins Come Packaged In The Virus Hiv

We Already Know Lots About Coronavirus Biology

Federal government ‘didn’t want to hear’ about the concerns of HIV protein in vaccine

by John Timmer – Mar 20, 2020 5:05 pm UTC

A coronavirus vaccine may not arrive for at least a yearso what are the chances of finding a useful therapy that could stave off the worst effects of the virus in the meantime?

Earlier coronavirus outbreaks like SARS and MERS raised warning flags for public health officials. Fortunately, they also alerted the biological research community that this large family of viruses was worth studying in more detail. Recent research has built on a large body of knowledge about coronaviruses that have long caused significant diseases in livestock, and so SARS-CoV-2 does not arrive as a total unknown. Indeed, we are actually in a decent position to understand what might make a good potential therapy.

While some of the therapies being tested may seem randomwe’re trying chloroquine, an antimalarial drug?there’s serious biology behind what’s being done.

The Process Of Reverse Transcription

Like many other DNA polymerases, RT needs both a primer and a template. Genomic RNA is plus-stranded , and the primer for the synthesis of the first DNA strand is a host tRNA whose 3 end is base paired to a complementary sequence near the 5 end of the viral RNA called the primer binding site . Different retroviruses use different host tRNAs as primers. HIV-1 uses Lys3. It would appear, based on in vitro experiments, that the addition of the first few nucleotides is slow and difficult. DNA synthesis speeds up considerably once the first five to six deoxyribonucleotides have been added to the 3 end of the tRNA primer . In HIV-1, the pbs is approximately 180 nucleotides from the 5 end of genomic RNA. DNA synthesis creates an RNADNA duplex, which is a substrate for RNase H. There are perhaps 50 RTs in an HIV-1 virion it is unclear whether the same RT that synthesizes the DNA plays a significant role in degrading the RNA. This is not a requirementretroviruses can replicate with a mixture of RTs, some of which have only polymerase activity and some that have only RNase H activity . Moreover, in in vitro assays, little or no RNase H cleavage is detected while RT is actively synthesizing DNA instead, cleavages occur at sites where DNA synthesis pauses . Whatever the exact mechanism, RNase H degradation removes the 5 end of the viral RNA, exposing the newly synthesized minus-strand DNA .

Mechanisms Of Exosomal Packaging Of Hiv Elements

While the Trojan Exosome Hypothesis remains a subject of discussion and debate, research by the original proponents of the hypothesis was foundational in uncovering some of the mechanistic elements behind the secretion of viral proteins, particularly Gag, into extracellular vesicles, if not specifically exosomes. Fang et al. demonstrated that higher-order oligomerization, i.e. oligomerization of multiple Gag peptides, at the plasma membrane contributes to vesicular export of the polypeptide by an apparently sequence-independent process. There has been very little research regarding how higher-order oligomerization affects protein loading into the MVB or canonical exosomes, however, so the relevance and implications of this phenomenon with regard to exosomal transport of host or viral proteins are not yet understood.

A similar phenomenon may also occur with lipid rafts. Lipid rafts are regions of the membrane that are rich in cholesterol and unsaturated fats. Much like TEMs, lipid rafts serve as sites of viral assembly and budding . There are also some reports that lipid rafts may be preferentially endocytosed and exported via exosomes . There is also evidence, as reported by Hogue et al. and others from the same group, that Gag can induce overlap of lipid rafts and TEMs to enhance viral assembly and budding, though the implications for exosome formation and packaging are not clear at this time .

Table 1 HIV elements packaged within exosomes and their effects

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Severity And Course Of The Disease

The course of an HIV infection is always chronic, ending fatally without antiretroviral therapy. CD4 cell disintegration and clinical symptoms can be decelerated or suppressed by antiretroviral therapy for decades . In untreated HIV-1 infections, AIDS-defining symptoms appear after a mean of about 10 years, with a range of 2-25 years. HIV-2-induced AIDS becomes apparent after a mean of approximately 15 years . With antiviral therapy it is possible to extend the phase without or with only slight symptoms for many years .

Infection And Infectious Diseases

Viremia: Definition, causes, and symptoms

HIV is able to enter the body via intact mucous membranes, eczematous or injured skin or mucosa and by parenteral inoculation. When transmitted by sexual contact, HIV attaches first to dendritic cells or macrophages/monocytes HIV using CCR-5 as a co-receptor is then preferentially replicated . HIV is taken up by macrophages and replicated as shown for M cells in the mucosa . HIV exposure to blood cells can result in the direct infection of T helper cells and the transmission of R5 and X4 viruses . As mentioned above, 1 HID is equivalent to approximately 500-1,000 HIV particles, with a higher dose required for infection via mucous membranes compared to infection via the bloodstream, e.g. by needle stick injury. The majority of new HIV infections are still transmitted sexually. Another epidemiologically relevant route is parenteral administration of drugs and also snorting of drugs with epistaxis.

Transmission of HIV via blood or transplanted organs, including bone, is possible from about days 5-6 after infection of the donor. Mother-to-child transmission has been demonstrated from the 12th week of gestation, but transmission occurs predominantly in the final trimester and particularly shortly before or during birth . HIV can be transmitted via breast milk .

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Tip4: Role In Gag Localization And Env Incorporation

TIP47 is an essential protein for endosome-to-TGN retrograde transport of mannose-6-phosphate receptors, has been shown to form a ternary complex by bridging between the Env and Gag proteins . The interaction between Gag and TIP47 is mediated by the MA domain. Mutations in the MA domain of Gag that abrogate TIP47 binding were found to inhibit Env incorporation, EnvGag colocalization, and virus infectivity . Silencing of TIP47 was found to impair Env incorporation and infectivity and abolished co-immunoprecipitation of Gag and Env. Based on these findings, it was suggested that TIP47 acts as a connector between Gag and Env during assembly . Interestingly, several point mutations and deletions within the first 23 residues of MA resulted in loss of TIP47 binding and thus Env incorporation. Among these mutations were W16A and E17A. Mutations in helix I of MA have been shown to block Env incorporation , which led to the suggestion that MA interacts directly with the Env protein. Altogether, studies on TIP47 suggest a functional role of this protein in Env incorporation and colocalization of Gag and Env. However, role of TIP47 in HIV biology remains unclear as studies conducted in other laboratories have failed to support any role of TIP47 in particle production or virus replication .

Fancy Break In: Viralentry

To infect a cell, a membrane-enveloped virus such as HIV must transfer its genome across both the viral and cellular membranesnot a trivial task given the inherent stability of biological membranes. Enveloped viruses accomplish this feat by encoding and expressing on their surface integral membrane proteins that, under the right conditions, undergo conformational changes that cause the viral and cellular membranes to fuse with one another, providing a portal of entry . The entry process can be divided into three components: attachment of the virus to the cell surface, involving recognition and binding to specific cell surface receptors a triggering event that causes the viral fusion protein to undergo conformational changes and the membrane fusion reaction itself. The presence or absence of molecules on the cell surface necessary for attachment and triggering greatly influences viral tropism: the ability of a given virus to infect only specific cell types.

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Introduction To Human Retroviruses

The family Retroviridae comprises a large group of ubiquitous single-stranded RNA viruses that infect all classes of vertebrates. A defining feature of retroviruses is the integration of the reverse-transcribed viral cDNA into the host cell’s genome to establish a persistent, life-long infection. The integrated viral cDNA, termed the provirus, serves as the template for viral replication. The genetic relatedness of retroviruses can be ascertained from the amino acid sequence similarities in the reverse transcriptase enzyme of these retroviruses . Human immunodeficiency viruses type-1 and -2 are two of the six recognized exogenous retroviruses that infect humans. Only three retroviruses from two of the seven retrovirus genera produce well-defined clinical disease: namely, the deltaretrovirus, primate T-lymphotropic virus type-I and the lentiviruses, HIV-1 and -2. Neither PTLV nor the spumavirus, human foamy virus , have been associated with well-defined human disease.1,2 The recent but controversial discovery of a novel gammaretrovirus, xenotropic murine leukemia virus-related virus , in tumor tissue from a subset of men with prostate cancer and from some patients with chronic fatigue syndrome, raises intriguing questions about whether XMRV has a causal association in these and perhaps other human diseases.35

Origins of HIV

HIV structure

HIV replication

How Much Does The Test Cost

The Fight Against HIV/AIDS | HIV vaccine development

The cost of an HIV test is usually covered by insurance without a copay, although specific costs depend on a persons insurance coverage and where the test is performed. Check with your health plan and health care provider for specific cost details.

At-home HIV tests cost below $50. Health departments and community-based organizations may provide HIV self-test kits for free or at a reduced cost.

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Hiv Exports Viral Protein In Cellular Packages

by University of North Carolina at Chapel Hill School of Medicine

HIV may be able to affect cells it can’t directly infect by packaging a key protein within the host’s cellular mail and sending it out into the body, according to a new study out of a University of North Carolina Lineberger Comprehensive Cancer Center laboratory.

Researchers reported in the journal mBio that the virus uses secreted cellular packages called exosomes to send the viral protein Nef into the body. Researchers are planning to continue to investigate the role of the protein outside of infected immune cells, since they believe it’s being sent out for a purpose.

“This study establishes that an HIV protein called Nef circulates independently of the virus itself,” said UNC Lineberger’s Dirk Dittmer, Ph.D., professor in the UNC School of Medicine Department of Microbiology & Immunology. “This could explain how HIV affects cells that it cannot ordinarily infect, such as endothelial cells of the blood-brain barrier.”

HIV, or the human immunodeficiency virus, attacks a person’s immune system by infecting disease-fighting white blood cells called T-cells or macrophages. While other proteins are involved in the virus’ ability to infect these white blood cells and replicate, researchers say Nef plays a role in preventing reinfection of the same white blood cell by two different HIV viruses, and in preventing recognition of the virus by the immune system.

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How Viruses Replicate

Viruses were first discovered after the development of a porcelain filter, called the Chamberland-Pasteur filter, which could remove all bacteria visible under the microscope from any liquid sample. In 1886, Adolph Meyer demonstrated that a disease of tobacco plants, tobacco mosaic disease, could be transferred from a diseased plant to a healthy one through liquid plant extracts. In 1892, Dmitri Ivanowski showed that this disease could be transmitted in this way even after the Chamberland-Pasteur filter had removed all viable bacteria from the extract. Still, it was many years before it was proven that these âfilterableâ infectious agents were not simply very small bacteria but were a new type of tiny, disease-causing particle.

Virions, single virus particles, are very small, about 20â250 nanometers . These individual virus particles are the infectious form of a virus outside the host cell. Unlike bacteria , we cannot see viruses with a light microscope, with the exception of some large virions of the poxvirus family .

It was not until the development of the electron microscope in the 1940s that scientists got their first good view of the structure of the tobacco mosaic virus and others. The surface structure of virions can be observed by both scanning and transmission electron microscopy, whereas the internal structures of the virus can only be observed in images from a transmission electron microscope .

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The Missing Link: Hiv

Great progress has been made in defining both the viral and cellular determinants of HIV-1 assembly and release . However, the trafficking pathway used by Gag to reach its assembly sites in the infected cell is poorly understood. There is mounting evidence that HIV-1 Gag interacts with several cellular proteins during the replication cycle. These include CaM , the human adaptor protein complexes AP-1, AP-2, and AP-3 , TIP47 , Golgi-localized gammaear containing Arf-binding protein , ADP ribosylation factor , the suppressor of cytokine signaling 1 , a lymphoid specific Src kinase , N-ethylmaleimide-sensitive factor attachment protein receptor , Filamin A , vacuolar protein sorting-associated protein 18 , Mon2 , and Lyric . The majority of these proteins have been implicated in retroviral assembly. Since we are focusing on the MA protein, we will summarize the current understanding of the proposed interactions between the MA domain of Gag and a small selection of the proteins described above including CaM, AP-3, TIP47, SOCS1, and Lyric.

Myristyl Exposure Is Modulated By Ph

Hepatitis B: The creation and destruction of a virus

Figure 2. The imidazole ring of His-89 forms a salt bridge with Glu-12 in HIV-1 myrMA but not in myrMA.

Figure 3. Schematic representation showing multimerization events of Gag and MA proteins as a function of pH. Reprinted with permission from . Copyright American Chemical Society.

Earlier studies have also shown that mutation of His-89 and other residues in the vicinity led to targeting of Gag to intracellular compartments and severely reduced virus production . We recently found that the internal Gag puncta observed with H89G mutation colocalized extensively with CD63, indicating multivesicular bodies localization . These results indicate that His-89 is essential for proper targeting of Gag to the PM and efficient particle formation in HeLa cells. Structural studies have shown that substitution of His-89 destabilized the tertiary structure, triggering myr exposure, and promoting high-order protein self-association .

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Donor Testing And Significance

In Germany, both HIV antibody and HIV NAT testing are mandatory.

2.3.1 HIV Antibody Testing

Initial testing of a donation is carried out with antibody screening test systems approved in Europe according to the German Medicinal Products Act in connection with the In Vitro Diagnostics Directive . Tests used in Germany recognise antibodies to all known HIV-1 groups and HIV-2. Reactive screening test results must be followed by a serologic confirmation test or a NAT assay. An additional second blood sample has to be investigated for confirmation of an HIV infection . Until the results are clarified, the donation is separated and should be preserved for additional investigations. The donor is deferred until the final results are available . According to current knowledge, the vast majority of reactive HIV antibody screening test results of blood donors are non-specific, i.e. false-positive, and have other causes, e.g., immune complexes in the specimen .

2.3.2 Detecting HIV RNA by NAT

The diagnostic window period, which is between 3 and 6 weeks for antibody screening tests, can be shortened by application of NAT. Depending on the level of viraemia, the sensitivity of the assay used and the infecting HIV, an infection can be detected as early as about 11 days post infection . The HIV NAT enables sensitive detection also of non-HIV-1 M:B. Reference materials for the detection of different HIV-1 genotypes are available .

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Integration Of Viral Dna Into Host Genome

Integration of the viral DNA is mediated by PICs formation. These PICs are capable of performing integration in vitro . Even though specific ) and non-specific could able to restore the activity, but only BAF can restore the native structure of the HIV-1 proteinDNA intasome from salt stripped PICs . HIV-1 integration in host genome is not a random event. In majority of cases, it takes place in AT rich, euchromatin region. Even though PIC formation can protect the DNA and helps in the nuclear transport, it cannot guide the integration in a proper location in the host genome. A host protein called cellular lens epithelium-derived growth factor which binds both chromosomal DNA and HIV integrase , directs the integration to a location where active transcription takes place under its control . The interaction between the integrase and INI1 stimulates the DNA-joining activity of the integrase and helps to target the viral DNA towards active genes . Presence of a Topo II cleavage site in the HIV-1 promoter and also at 180 bp upstream of the HIV-1 integration site and association of these Topo II isoforms with HIV-1 PICs . Based on the available information, it can be derived that, IN alone can carry out the integration reaction but for the selection of the proper location in the host genome for the integration and success full HIV-1 gene transcription, Integrase required the support of the host factors.

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Prevalence And Incidence Of Blood

Prior to the introduction of compulsory testing for HIV antibodies in May and October 1985, about 1,380 haemophiliacs and about 200 transfusion recipients were infected in Germany with HIV by blood donations and plasma derivatives . With the introduction of antibody screening tests and obligatory virus inactivation procedures in the production process of plasma derivatives, the number of HIV and hepatitis virus infections by transfusion declined significantly, especially in the first 2 years. Since 2004, HIV antibody testing and HIV NAT further reduced the potential HIV burden of the source material . Since 1990/1991 no HIV infections have been transmitted by plasma derivatives .

According to reports to the Paul Ehrlich Institute, 2 HIV transmissions by cellular blood components have occurred after the introduction of NAT screening in 2004 . Both transmissions were due to very recent infections and a failure of the NAT systems used. In the case of 2007, presumably a low viral load and mutations in the primer binding region were responsible for the false-negative test results . Regarding the transmission reported in 2009, the HIV-positive donor sample was repeatedly tested negative with the NAT system used .

As recommended for HIV-infected donors, plasma and lymphocytes of the HIV-infected recipient should also be stored in order to possibly clarify the origin of infection and the transmission using molecular methods .

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