The Surprising Facts about HIV - Essay Example

The necessity of detailed study of viral threat 2007 Outline: A) Introduction: general overview. B) General discussion The history of HIV 2) The surprising facts about HIV. 3) Human pappilomavirus 4) The importance of study of mechanisms of viral infection. C) Conclusion. Foreword: This research paper discusses the importance and necessity of studying the mechanisms of penetration and action of DNA-based viruses. Thesis: The effectiveness and eternal probability of mutations of DNA-based viruses needs eternal corresponding scientific solutions. A) Introduction: general overview Virus - in Latin means the toxin or poison. A virus is a sub-microscopic infectious agent that is unable to grow or reproduce outside a host cell. A virus is usually characterised by three features, nucleic acid genome covered by protective protein , can reproduce or multiply only in living cell, and the genome separates from protein sheel for integration. Virus diseases inflict a heavy illness and economic damage on humans and animals and can injure agricultural crops. Each viral particle, called virion, consists of genetic material, DNA or RNA, within a protective protein coat called a capsid. Their shape varies from simple helical and icosahedral (polyhedral or near-spherical) forms, to more complex structures with tails or an envelope. Viruses infect cellular forms of life and are grouped into animal, plant and bacterial viruses. There always been a discussion whether viruses are living organisms. Some consider them non-living as they do not meet the criteria of the definition of life. For example, unlike most organisms, viruses do not have cells. However, viruses have genes and evolve by natural selection. The viruses mutate and compete. They have been described as organisms at the edge of life. The main feature of virus is that it usually destroys or modifies the cell it infects , thus exist as a potential agent that could afflict mankind and cause numerous dieseases as ranging from common cold, rabies, small pox, mumps, polio ,chicken pox , measles, rubella, hemorrhagic fevers to the Acquired Immuno Deficiency syndrome. Viral infections in human as well as animal hosts usually result in an immune response and disease. Often, a virus is completely eliminated by the immune system. Antibiotics have no effect on viruses, but antiviral drugs have been developed to treat life-threatening infections. Vaccines that produce lifelong immunity can prevent virus infections. The main area still now developed in antiviral therapy to stop the viral replication is targeted either on viral replication or the process of polyprotein clevage. Over a long period of known human history terrible epidemics involved humanity. The flu, smallpox, and plague killed millions of people. The epidemics of “Black Death” in the 14th century killed almost one third of Europe’s population. These terrible epidemics left traces in the genome of populations. There appeared a probability to resist diseases. Scientists find new surprising abilities of immunity to resist viral attacks. In this paper I would like to discuss some of the factors that allow viral infection to damage organism and some ways to resist it. B) General discussion; 1) The history of HIV Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). HIV was discovered in 1983 after etiology of AIDS. The first official scientific confirmations of AIDS were two articles about strange illnesses of homosexual men. In 1982 the term AIDS was used to identify this illness. Scientists found AIDS analyzing blood of drug addicts and homosexuals. Scientists made an assumption that AIDS was caused by some kind of infection. The results of research, in which the new retrovirus was separated from tissues of patients, were published on May 20th, 1983. In 1986 the virus received its name Human Immunodeficiency Virus, because close virus was found in blood of some primates. First of all HIV infect cells of immune system (CD4 + T lymphocytes, macrophages, dendritic cells). Infected CD4 + T lymphocytes dies because of several reasons: 1) direct destruction of cells by virus; 2) programmed cellular death; 3) CD4 is killed by CD8+T lymphocytes. Step-by-step population of T-lymphocytes decreases. As a result cellular immunity reduces and after gaining the critical level organism become vulnerable to opportunistic infections. 2) The surprising facts about HIV The surprising fact about HIV would be a review of the existing studies done in that fiels that would be organized chronologically. Kaiser etal, 2007 did a interesting study based on an established fact that primate genome has considerably more immunity than human species. On analysis the primate genome is found to contain a large number of endogenous retrovirus that codes eventually for dynamic proteins that provide inbuilt immunity to retroviral infections. In the study they found that resurrection of a core protein 4 million, which on human variation , TRIM 5aalpha was found to prevent viral infection. But they report that due to the years of variation this immunity could have been lost. For this study , they selected chimpanzee and Gorilla genome of Pan troglodytes endogenous retrovirus (PtERV1), which is absent in human genome. This study came with a finding that resistance to one viral might reduce the immunity towards others as here resistance to PtERV1 comes at a cost reduced resistance to other retroviruses, such as HIV-1. What is the origin of the HIV? What caused the AIDS pandemic? Several findings provide a clear picture of HIV origin. SIVcpz, the ancestor of HIV-1, appeared as a recombinant of ancestors of SIV lineages presently infecting red-capped mangabeys and Cercopithecus monkeys in west-central Africa. Chimpanzees were infected by this recombinant virus, or its ancestors, by cross-species transmission some time after the split of P. t. verus and P. t. vellerosus from the other subspecies but possibly before the divergence of P. t. schweinfurthii from P. t. troglodytes. This explains the absence of SIVcpz infection in present-day P. t. verus and P. t. vellerosus apes, and the presence of SIVcpz infection in P. t. troglodytes and P. t. schweinfurthii apes, and the phylogenetic separation of SIVcpzPtt from SIVcpzPts viruses HIV-1 groups M, N, and O each resulted from independent cross-species transmissions of SIVcpzPtt from P. t. troglodytes to humans early in the 20th century. SIVcpzPtt strain that gave rise to HIV-1 group M belonged to a viral lineage that persists today in P. t. troglodytes apes in southeastern Cameroon. That virus was probably transmitted locally. From there it appears to have made its way via the Sangha River (or other tributaries) south to the Congo River and on to Kinshasa where the group M pandemic was probably spawned . HIV-1 group N, which has been identified in only a small number of AIDS patients from Cameroon , derived from a second SIVcpzPtt lineage in south central Cameroon and remained geographically more restricted. The source of HIV-1 group O remains unknown but will probably yield to further study of wild ape populations not yet sampled. Given the extensive genetic diversity and phylogeographic clustering of SIVcpz now recognized, and the vast areas of west central Africa not yet sampled , it is quite possible that still other SIVcpz lineages exist that could pose risks of human infection and prove problematic for HIV diagnostics and vaccines.(Keele 2006). This study was carried out by employing methods that detect the SIVcpz antibodies and nucleic acids present in the fecal sample and then an sequence analysis of the endemic strain, SIVcpz. Also they hasd been deduced using a technique to amplify host mitochondrial DNA and genomic markers as micro satellite loci .For the analysis, a 498 bp mt DNA was fragment was selected and assayed for antibodies using a immunoblot assay. Thus this study explains in detail about the molecular tools and non invasive diagnosis. HIV is extremely effective virus. His ability to integrate the chromosomes enables to establish a permanent reservoir that can be therapeutically suppressed but not eradicated. One of the co-factors for HIV integration is p75 factor. The study of this factor found that HIV viral infection is attributable to p75. P75 helps the productive replication of virus. The mechansim involves the action of p75 as a molecular tether between the chromatin and the integrase enzyme, which was initiated even in minute fraction of p75 This study obviously implies that , perturbing the p75-intergrase interaction may have therapeutic potential. (Llano 2006). • Studying X-linked form of muscular dystrophy, caused by mutation of emerin gene, scientists made very important discovery. It seems that people who suffer from X-linked Emery–Dreifuss muscular dystrophy are resistant to HIV infection. The DNA of HIV, contacting with chromatin, interacts with emerin in order to enter the nucleus. The emerin silencing impairs the infection of cells by HIV cDNA Of course, this silencing does not stop the integration of HIV DNA into cellular DNA, but it seems that the research of small molecules that antagonize the ability of the virus to engage emerin, will be a step towards promotion of abortive HIV infection of the cells. (Jacque and other 2006). • One of the collateral, but very dangerous effects of HIV, is its influence on central nervous system. It leads to HIVHIV-associated dementia (HAD) in a substantial subset of infected individuals. The mechanism of this infection is well-known. HIV-infected immune cells migrate into the brain and cause neuronal injury through the release of viral proteins and immunomodulators with secondary neuronal toxicity. The tumor suppressor transcription factor p53 is an apical mediator of neuronal apoptosis following a variety of injurious stimuli. The scientists decided to study whether p53 participates in degeneration process. Their findings demonstrated that p53 protein accumulates in the nuclei of neurons and glia in patients with HAD. It seems that p53is required for gp120-mediated neuronal apoptosis. P53 is also required for gp120-exposed microglia to create a neurotoxic milieu. P53 activation by HIV proteins is a novel component of the molecular phenotype of HIV. The further study of p53-dependent injures will help to prevent neurodegeneration. (Garden 2004). It is known fact that , the HIV infection in certain people are found to initiate Dementia. In an experiment done by Kaul and Lipton, 1999, they found that the glycoprotein present in the envelope oh HIV – 1 is found to induce neuropathological symptoms similar to that seen in AIDS affected patient’s brain. On invitro and invivo analysis with gp 120 it was found that it induces injury and apoptosis both in rodents and human neuron. Further study showed that gpl20 binds, respectively, to macrophages and T cells via the chemokine receptors CCRS and CXCR4, which, in addition to CD4, function as coreceptors for HIV-1.CCRS and CXCR4, as well as other chemokine receptors . thus it was futher substantiated that both due to direct interaction of gp 120 to chemokine receptor and activation on G protein Signalli8ng , the damage is initiated., as seen in gilial and neuron culture. Most people are extremely vulnerable to infection with HIV. But there are some individuals who remain uninfected by HIV. The laboratory experiments showed that T lymphocytes and macrophages of these individuals are resistant to HIV viruses. The high doses of virus caused infection of several cells, but they didn’t replicate. The scientist found that these individuals are homozygous for a defect in the gene encoding CKR-5, a major co-receptor for macrophage-tropic HIV-1 isolates. Both examples of resistance have identical CKR-5 alleles, which contain a 32bp deletion in a region of the gene corresponding to the second extracellular loop. The CKR-5 allele is critical for HIV transmission. It plays very important role in the early phase of infection. CKR-5 is very useful in determining of the progression of infection. Some atypical accidents show that some infected individuals remain asymptomatic, with very law viral burdens for unusually long periods of time. It is of course very important to understand whether these individuals are heterozygous for deleted CKR-5. If an individual have law level of functional CKR-5, they can be responsible for the law viral burdens. Another factor is that the individuals can have CKR-5 with reduced ability to mediate viral entry. When the CKR-5 allele is deleted it is probably compensated by another chemokine receptor. The surprisingly high percentage of unrelated individuals of western Europe have deleted CKR-5 (20% heterozygotes). From the other side much lower frequency of individuals from Venezuela have this deletion. The frequency of CKR-5-deleted homozygotes is about 1% in the general population of persons with western European heritage. The CKR-5 allele status of HIV-1 infected individuals remains to be determined. Presumably, infected individuals who are homozygous for deleted CKR-5 are extremely rare. If transmission through a CKR-5-independent route occurs infrequently, homozygous individuals would not be completely protected. A large-scale analysis to determine the frequency of the deleted CKR-5 allele among HIV-1 infected individuals continually generates these alleles in the population. It is difficult to estimate when this deletion first occurred; however, its restricted distribution and the absence of secondary mutations in the gene suggest a rather recent evolutionary origin. The selection pressure of HIV is not a reason to explain the high frequency of heterozygotes among individuals of western European ancestry. HIV-1 has only recently become endemic to this population. However, it is possible that in areas where HIV-1 has been endemic for considerably longer periods of time, a selective advantage would be provided to individuals heterozygous or homozygous for this or similarCKR-5 alleles that may be present in these populations. Precedence for selective pressure to lose expression of a chemokine receptor is provided by the example of the erythrocyte chemokine receptor, DARC. A mutant DARC allele that cannot be expressed in erythrocytes provides resistance to Plasmodium vivax . Individuals carrying this allele may have a selective advantage in areas where the parasite is endemic. Whether there is an advantage to heterozygosity for deleted CKR-5 is not clear. While heterozygous cells had a somewhat reduced ability to replicate HIV-1, it is not clear whether this magnitude of decrease would offer significant protection against sexual transmission. Whether there is any protection offered to heterozygotes could be determined by comparing the frequency of the deleted allele in HIV-infected, HIV-exposed but uninfected, and none exposed individuals. Such an advantage has been described in the case of b-globin mutations. The erythrocytes of individuals heterozygous for a mutation in b-globin are resistant to Plasmodium falciparum. As a result, the frequency of the mutant allele is high in Saharan Africa . Selection for the CKR-5 allele, or for other yet unknown CKR-5 polymorphisms might be most evident in areas of Africa that have a high incidence of HIV-1 infection. (Liu and other 1996). It is very important to develop therapeutic agents, directed against HIV and CKR-5 cooperation. Eva Poveda etal.,2006, in their paper analyzed that, Within the last few years, the interest in HIV tropism has resurged mainly due to the appearance of promising new anti-HIV molecules that target CCR5 and CXCR4 receptors. With their mechanism of action known ,the clinical development of these compounds could be plausible with a prior knowledge of viral tropism in a given HIV-infected individual. However, clinical determination of HIV-1 co-receptor usage is difficult since only a few methods exist, which are complicated and less available. In this review they summarize the molecular basis of viral tropism and its impact on HIV disease progression. Furthermore, we discuss the tools currently available for determining HIV co-receptor usage in the era of HIV co-receptor antagonists. A study by Erica check in 2006 throws light on the H5N1 avian flu virus in bird, on which now the US government is concerned. The sea ducks Eiders are migratory birds seen along the Bering sea.feces sample from the cloaca of the birds are analyzed to check for the viral trace as a part of a massive effort to track the possible entry of H5N1 into the United States. This virus is been the cause of death of more than 200 million birds, and also with reports that 132 people are affected because of it . it is feared that if it masteres the art of transmission from birds to human , millions of life could be at risk. The H5N1 strain was found all over Asia, Russia, Europe, Africa etc. genetic studies are undertaken to solve the rissle of where from it has originated, has it infected poultry or the strain was originated from poultry etc. 3) Human pappilomavirus Another group of DNA-based viruses are papillomaviruses. They infect both animals and humans. More than 100 human papillomaviruses are known today. The relations between HPV and cervical cancer were first assumed more than 30 years ago. Since that time DNA of HPV has been detected in all cervical cancer biopsies. It seems that HPV is the main factor of cervical cancer. The main question is how can we prevent and treatment this virus? The cervical cancer is the second most frequent gynecological disease in the world. 12% of all women cancer cases are carcinomas of the anogenital tract. The main reason of this type of cancer is human papillomavirus infection. It also causes almost 25% of oral cancers. The first HPV examples were found in cancer biopsies of the cervix. During the next several years the role of HPV was explained. The specific HPV genes were found in cervical cancer cell lines. The papillomavirus life cycle differs from any virus family. The HPV infection requires the presence of mucosal and epidermal epithelial cells. These should be able to proliferate. In these cells viral gene is extremely suppressed. The HPV types that are found preferentially in cervical and other anogenital cancers have been designated as ‘high-risk’ types. From the other side, the viruses found primarily in genital warts and non-malignant lesions were considered as low-risk types. Subsequently, it was shown that only the E6 and E7 genes of high-risk types were able to immortalize human cells in tissue culture.High-risk HPV types are widespread within all human populations. Infection is commonly transmitted by sexual contact and results initially in inconspicuous squamous intraepithelial lesions (SIL) in women Most of these lesions are cleared 6–12 months after appearance, probably due to immunological intervention. A small percentage, however, persists, progresses to high-grade SIL, carcinoma in situ and, without surgical interference, to squamous-cell carcinoma or adenocarcinoma of the cervix. The immune system is important in the control of HPV infections. This can be indirectly deduced from the increased incidence and prolonged persistence of SIL in immune suppressed women. There is also evidence for T-helper-cell involvement in regressing lesions, and a concomitant detectable humoral and cellular immune response against HPV antigens during the course of regression. The escape of high-grade SIL and carcinomata in situ from immunological control seems to be based on different modifications of the cellular antigen-presenting system, which might involve the proteasome transportation system, the HLA receptors and the cellular recognition system for presented oligopeptides. The escape from immune-surveillance mechanisms emerges as one important step in the progression of HPV-linked tumours. In addition, two other modes of control exist in proliferating cells that are infected by HPV to protect them against malignant transformation: one involves inhibition of viral oncoprotein function, the other involves transcriptional control . The evidence that host cells can impair the function of viral oncoproteins is still indirect and, so far, exists only for the E6 oncoprotein in cells that have been immortalized by E6 alone. In cell lines that have been transected with E6 DNA, the CDKN2A gene — which encodes INK4A — is commonly inactivated by methylation, mutation or deletion. INK4A inactivates cyclin D1–CDK4 or cyclin D1–CDK6 complexes, which prevents expression of cyclin E and, therefore, progression through the cell cycle. Another pathway — which involves blocking the transcription of HPV DNA and is known as the cellular interference factor (CIF) concept — has been analysed in more detail. It is triggered by paracrine stimulation of cervical epithelial cells by macrophages and tumour increasing necrosis factor-α (TNF-α), and causes several effects in HPV-immortalized cells. These include a modification of the transcription factor AP1, which is essential for HPV gene expression, and the induction of endogenous synthesis of the antiviral interferon-β57. It is suspected that the change in AP1 composition mediates the suppression of high-risk HPV transcription58. These pathways do not function in cervical carcinoma cells, indicating that the TNF-α-mediated signaling cascade is interrupted during malignant transformation. High-risk HPV infections result in progression to cervical cancer in only a small percentage of infected women, after a long latency period (reviewed in REF. A high percentage of infected women clear the infection by immunological mechanisms. Lasting immunosuppressant represents a risk factor for viral DNA persistence and lesional progression, but the factors that determine viral persistence in other women are not completely defined. Some result from modifications of cellular genes that influence antigen presentation, or from signaling cascades that are engaged in the suppression of viral oncogene transcription or viral oncoprotein function. Other factors directly affect the persisting viral DNA; for example, by upregulating viral oncogene transcription, by modifying the viral promoter region or by amplifying the persisting viral genomes. The most visible benefit from HPV research is prevention of cervical cancer.A very early benefit originated from the recognition by clinicians that cervical, vulvar, vaginal and perianal squamous intraepithelial lesions are of infectious origin and produce large quantities of infectious virus Conversely, the mechanical prevention of anogenital HPV infections that are transmitted by sexual contact is impractical. HPV infections are highly prevalent within the sexually active population and the use of condoms offers only limited protection in view of the common presence of virus-infected cells at external genital sites. It is widely accepted that in most cases, HPV infection is cleared by immunological intervention. Spontaneous regression of LSILs, or even HSILs, is commonly accompanied by homoral and cellular immune responses against virus-specific antigens. Although the surface localization of most viral antigens does not sufficiently stimulate the immune system, vaccination with viral structural proteins in animal systems and in humans regularly leads to the induction of an effective immune response.(Hausen 2002) 4) The importance of study of mechanisms of viral infection. Viruses represent huge danger to mankind. Their simple structure forces many to think of them as about not alive particles. Really, the mechanism owing to which these elementary essences can damage the most complicated organisms amazes. Many people consider viruses as one of the mechanisms created by the nature for the control of overpopulation of kinds. Detailed studying of mechanisms of influence of viruses, especially DNA-based viruses, began only recently. These researches have huge value. Not looking at a seeming omnipotence of viruses their mechanisms have strict operating conditions. The understanding of how the virus influences the organism, what that influence his efficiency, helps us to improve preventive and therapeutic methods of struggle against viruses. With a lot of viral based diseases being found out, it becomes important and need of the hour to study the mechanism of the infection , in order to bring in aremedy.Viruses, as well as other organisms, do not stand on place, they evolve, adapt. Therefore they always will be a threat to mankind, and researches of viruses will be always be on the heel with it.. Materials and Methods: There are various techniques routinely followed to analyze DNA virus as immunoassay and DNA-based diagnostic methods including • Fluorescent antibody tests (FAT) • Enzyme-linked immunosorbent assays (ELISA) ELISA helps to ddetect specific antigen, for which a purified antibody specific for antigen is linked chemically to an enzyme. The samples to be tested are coated onto the surface of plastic wells to which they bind nonspecifically; residual sticky sites on the plastic are blocked by adding irrelevant proteins. The labeled antibody is then added to the wells under conditions where nonspecific binding is prevented, so that only binding to antigen A causes the labeled antibody to be retained on the surface. Unbound labeled antibody is removed from all wells by washing, and bound antibody is detected by an enzyme-dependent color-change reaction • Radioimmunoassay (RIA), in situ hybridization (ISH), • Dot blot hybridization DBH) • Polymerase chain reaction (PCR) amplification techniques- this allows a DNA to be copied million times as the same or even as altered sequence. It includes mixing of DNA template, polymerase, free dNTP’s, DNA template and primer, where with the primer the enzyme synthesizes complementary strand with the template. To denature as first step the mixer is heated up further to which the primer anneal and starts on. Gel electrophoresis- used as a separation technique where DNA , RNA and proteina are separated in a agarose gel field using electricity. Blot technique- Southern (DNA), Northern (RNA )and Western Blot (Protein ), which uses the same technique, for example in northern blot the DNA samples are subjected to restriction enzymes, gel electrophoresced, then blotted to another paper by capillary action which is probed using DNA probes to identify particular piece of DNA. The probes are labelled eithr as radiolabel or as fluorescent tags. (Keith Roberts etal.,2002) Bibliography 1. Llano M, 2006. An essential role for LEDGF/p75 in HIV Integration. Science 314:461 2. Liu R, Paxton WA, Martin SR, Horuk R, Koup RA, Landau NR, 1996. Homozygous defect in HIV-1 coreceptor accounts for resistance of some Multiply-exposed individuals to HIV-1 infection. Cell 86: 367-377. 3. Jacque JN, Stevenson M, 2006. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Nature 441:641 4. Garden GA, 2004. HIV associated neurodegeneration requires p53 in neurons and microglia. The FASEB journal 5. Keele BF, 2006. 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Sheehy AM, 2004. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418: 646. 13. Schiller JT, 2004. Delivering the promise: HPV vaccines and cervical cancer. Nature reviews 2: 343. 14. Shari M. Kaiser,1,2 Harmit S. Malik,3 Michael Emerman2,3*, 2007, Restriction of an Extinct Retrovirus by the Human TRIM5a Antiviral Protein, 22 JUNE 2007 VOL 316 SCIENCE. 15. MARCUSUUL AN D STUARAT . LIPTON*, 1999, Chemokines and activated macrophages in HIV gpl20-induced neuronal apoptosis, Pro(. Natl Acarl. Sci. USA Vol. 96, pp. 8212-8216, July 1999, Neul.obiolog. 16. Eva Poveda; Verónica Briz; Miguel Quiñones-Mateu; Vincent Soriano, 2006, HIV Tropism: Diagnostic Tools and Implications for Disease Progression and Treatment With Entry Inhibitors, AIDS.  2006;20(10):1359-1367. 17. Erica Check,2006, ON BORDER PATROL, NATURE|Vol 442|27 July 2006. 18. Keith Roberts, Martin Raff, Bruce Alberts, Peter Walter, Julian Lewis and Alexander Johnson, Molecular Biology of the Cell , 4th Edition, Routledge, March, 2002, hardcover, 1616 pages, 7.6 pounds, ISBN 0-8153-3218-1 19. Read More