Human Immunodeficiency Virus - Essay Example

Human Immunodeficiency Virus INTRODUCTION: HIV stands for human immunodeficiency virus. It belongs to the retrovirus family of viruses. It is an infectious agent that is responsible causing for AIDS. AIDS stands for acquired immunodeficiency syndrome, a disease that leaves the victim vulnerable to life threatening infections by destroying the innate human immune system. Till date two variants of HIV have been identified by virologists—namely HIV-1 and HIV-2. HIV-1 is believed to be the cause of AIDS with world wide distribution. On the other hand the number of victims affected by HIV-2 is mostly localized to selected areas in West African Nations. In 1983 the French Cancer specialist Luc Montagnier and his fellow researchers working at the Pasteur Institute identified a new human retrovirus from patients suffering from AIDS. They named it as Lymphadenopathy virus (LAV). Some eight months later Gallo and his fellow researchers identified and isolated the same virus from AIDS patients and named it as HTLV-III. Later scientists came to an agreement and termed the virus HIV. In 1985 a new virus that had the potency to cause AIDS was identified in some of the West African nations. It was termed as HIV-2. Its close resemblance to HIV-1 and its comparatively lower potency become evident from the remark made by Bartlett (2003), “Named HIV-2, the new virus is closely related to the first HIV, but it appears to be less harmful to cells of the immune system and reproduces more slowly than HIV-1.” On the genetic scale HIV-1 contains Simian immunodeficiency virus (SIV) sequences from chimpanzee where as HIV-2 contains SIV sequences from Macaque/Sooty Mangabey. According to the article “Origin of HIV-1 and HIV-2: Cross species transmission of SIV to human.” (n. d), “This indicates that HIV-1 originated from one event where a virus was transmitted from (presumably) chimpanzees to humans, while HIV-2 originates from a second, independent event where virus was transmitted from (presumably) sooty mangabey to humans.” STRUCTURE OF HIV: When HIV is present outside the human cells it exists in the form of independent particles termed as virions. The surface of these virions is not uniform but is studded with numerous spikes. These spikes help HIV in binding to the membrane of human cells and facilitate its entry. Each virion measures around 0.1 micrometer. The spikes are made up of protein matter namely, the proteins gp120 and gp41. According to "BioAfrica - HIV-1 gp41 (glycoprotein 41) sequence, structure and function information." “The gp120-gp41 complex occurs as a trimer on the surface of the virion. It contains an N-terminal fusogenic domain, which mediates the fusion of viral and cellular membranes. The interaction between gp120 with cellular receptors triggers gp41 to extend (forming a prehairpin intermediate), which interacts with the plasma membrane of the target cell. The extended prehairpin intermediate collapses into a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 extra cellular domain into close proximity bringing the amino- and carboxyl-terminal regions of the extra cellular domain together forces the membranes together in a manner that facilitates membrane fusion.” The outermost layer—the viral envelope is made up of fatty material. The matrix is a layer that is present just beneath the viral envelope and is made of the protein p17. The core or capsid is made up of a protein called p24 and is usually bullet shaped. Inside the core are three enzymes required for HIV replication called reverse transcriptase, integrase and protease. Also held within the core is HIV's genetic material, which consists of two identical strands of RNA (“HIV structure and life cycle” n. d). HIV has in total nine genes. Three among these genes are responsible for storing information for synthesis of structural proteins for new viral particles. These are termed gag, pol and env respectively. The other six proteins contain information for production of proteins that give the virus the ability to infect new cells, replicate or cause disease. These proteins are termed tat, rev, nef, vif, vpr and vpu respectively. INFECTION OF HUMAN CELLS WITH HIV: As the case with viruses, HIV cannot replicate independently and can do so only inside human cells. The infection begins when HIV comes into contact with human cells that have the proteins CD4 and chemokines receptor-5 (CCR5) on their membrane surface. The spikes on the surface of HIV attach with CD4 and CCR5 and this aids in the fusion of the viral envelope with the cellular membrane. Then the internal contents of the HIV particle, chiefly the capsid, are injected into the interior of the cell. In some people the genes responsible for CCR5 are absent and hence HIV cannot cause infection in such cases. Regarding viral entry Spenlehauer et al (2000) say, “Human immunodeficiency virus type 1 (HIV-1) is taken up into cells via a complex process including specific protein-protein interactions and conformational changes. The env-encoded proteins, gp120 and gp41, are key determinants in this process.” The genes present in HIV in particular and all retroviruses in general are made up of RNA and not DNA—which is the genetic material in the rest of the organisms. After the viral contents are injected inside the cell, the enzyme—reverse transcriptase converts the viral RNA into DNA. This is compatible with the human DNA. This viral DNA is then transported into the cellular nucleus and inculcated into the nucleus with the aid of the enzyme—integrase. At this stage it is termed as provirus. The status of provirus depends upon the cellular activity. It will lie in dormant state if the cell does so but if the cell gets activated the provirus gets the same treatment as the human genes. Messenger RNA is formed from the provirus with the help of human enzymes. This may then be carried outside the cell and it acts as a template for producing new HIV proteins and enzymes. The messenger RNA molecules thus produced contain copies of entire HIV genetic material. These combine with HIV proteins and enzymes to form new viral particles. These are then released from the cell and infect other cells. There they begin the replication process all over again. In this way the complete human body is infected by HIV. Once a person is infected HIV enter the body fluids and spread to new hosts when close contact with body fluids takes place. The role of CD4+T cells is of importance which becomes clear from a remark made by Liou et al (2002), “Analyses of patients treated with drugs that effectively block HIV-1 replication in vivo have revealed that infected CD4+T cells produce the majority (>90%) of virus during the prolonged infection period before the onset of AIDS” IMMUNOLOGICAL RESPONSE OF HUMAN CELLS AFTER HIV INFECTION: HIV1 infection is basically an infection to the human immune system. This is evident from the quote made by Walker (2004), “Infection is associated with the progressive and relentless destruction of the immune system in the majority of infected persons, but some persons appear able to successfully contain the virus for prolonged periods of time in the absence of antiviral therapy.” There have been some infection cases since 1970s wherein the levels of viremia have remained substantially lower even in the absence antiviral drug administration. This shows that the human immune system has the capability to restrict HIV infection. This becomes evident from the quote made by Walker, “The existence of persons with long-term non-progressing HIV-1 infection indicates that the host immune response can successfully contain this virus…” The immune response to HIV infection is at both cellular as well as humoral level. The independent contribution levels to contain HIV infection have not been established till now but emerging data shows that both to be of equal importance. As soon as HIV infection is detected Cytotoxic T-Lymphocytes (CTL) are generated. CTL stops viral replication by two mechanisms. The first mechanism involves direct destruction of infected cells. Cells infected with HIV have HIV related proteins on their membrane. This is recognized by the CTL and results in subsequent destruction of the cell. Regarding this Walker says, “The presence of a viral protein (usually 9-10 amino acids in length) within the peptide-binding cleft of a class I molecule is a signal to the immune system that a foreign invader is present within that cell. This then triggers CTL to kill the infected cell through a direct recognition mediated by the T-cell receptor (TCR) on the CTL.” The second mechanism involves soluble antiviral factors. CTL also releases soluble antiviral factors like beta chemokines which are capable of inhibiting infection by any progeny virions that might have already been produced. At this stage the virus is uncoated and is hence vulnerable. This is expressed by Walker, “If the infected cell is lysed before progeny are produced, then the virus will be eliminated.” Some of the chemokines that have been isolated so far are RANTES, MIP-1 alpha, MIP-1 beta. Other groups of soluble factors are grouped as “defensins”. RANTES, MIP-1 alpha and MIP-1 beta inhibit HIV infection of new cells by competing with the virus for binding to certain coreceptors present on the cellular membrane surface that are necessary for the entry of virus. In addition to CTL cellular immune response also includes the generation of virus specific T-helper cells. The role of T-helper cells is the maintenance of CTL in many chronic viral infections. Antigen presenting cells (APC) take up viral proteins into their lysosomes and process them into smaller peptides. These are presented to the cellular surface within the peptide-binding groove of class II molecule. The presence of viral peptide in class II groove of the cell membrane causes activation of T-helper cells. This is mediated by CD4+ cells which become activated to trigger an active immune response. How exactly T-helper cells and CD4+ cells interact with each other to bring about active viral combat is not yet fully understood but direct cell to cell interaction and release of cytokines which act at a distance may be the mechanisms that are involved. Most of the antibodies secreted during HIV infection do not exhibit an antiviral effect because they are directed more towards virions’ debris rather that towards conformational epitopes on intact viral surface. In some studies conducted on animals involving acute HIV infection, when CD4+ cell levels were decreased no delay in the initial viremia level was observed. This shows that these responses do not play a major role in determining the viral set point. Neutralizing antibodies that are directed towards a number of viral epitopes have also been detected in HIV infection. Theses antibodies include V3 loop antibodies and CD4-binding site antibodies. V3 loop antibodies are directed against portions of protein envelops that aid in the viral entry into the cell while CD4-binding site antibodies are directed against proteins helping in CD4 binding. HOW HIV EVADES THE IMMUNE SYSTEM: Though large scale immune response is observed after HIV infection, a large number of HIV particles avoid this response and succeed in causing AIDS. Regarding this phenomenon Esser et al (2001) say, “Like many viruses that have evolved to evade or suppress the host immune response, several lines of evidence suggest that HIV has evolved countermeasures to foil the immune system” In chronic viral infections CD4+T cells are required to check the infection levels, but in HIV infected patients only few anti-CD4+T cells proliferate when exposed to viral proteins. The absence of proliferate T-cell responses is either due to destruction of specific CD+4 cells or due to inactivation by HIV (NIH news. 2001). According to Poznansky et al a protein called SDF-1 which is known to attract immune cells repels T-cells when present in elevated quantities. According to “Study finds HIV protein can drive immune cells away” (2004), “SDF-1 is a chemokine, a protein normally produced to summon immune cells to the site of an injury or infection. The molecule is known to interact with a T cell receptor called CXCR4 which also is used by HIV when it binds to and enters T helper cells.” CURE BASED ON IMMUNE RESPONSE: In an experiment conducted on simian immunodeficiency virus infected macaques, evidence was found which demonstrated that CTL response is involved in maintaining viral set point. Since increased levels of CTL means lowered HIV levels, it may be possible to affect a cure by means of increasing CTL levels. HIV levels can be controlled which means a cure to AIDS. This becomes evident from a quote made by Lassen et al (2004), “The advent of highly active antiretroviral therapy to treat human immunodeficiency virus type 1 (HIV-1) infection has allowed the suppression of plasma virus levels in adherent patients to below the limit of detection” Other methods of control involve blocking the binding sites or by usage of compounds like Azidothymidine (AZT) that is known to suppress HIV. TIAS injections also have shown some results by stopping the proliferation of HIV. Efforts are on to produce a vaccine which would give the immune system capability to resist HIV at entry level itself. BIBLIOGRAPHY: Bartlett J. G. (2003): Acquired Immunodeficiency syndrome. Retrieved September 18, 2005 from Microsoft Encarta 2003. BioAfrica - HIV-1 gp41 (glycoprotein 41) sequence, structure and function information.(n. d). Retrieved September 18, 2005 from http://www.bioafrica.net/proteomics/ENV-GP41prot.html Cortese J. (n. d): How AIDS and the HIV works. Retrieved September 18, 2005 from http://www.io.com/~wwwomen/aids/aids1.html. Esser et al. 75. "Partial Activation and Induction of Apoptosis in CD4+ and CD8+ T Lymphocytes by Conformationally Authentic Noninfectious Human Immunodeficiency Virus Type 1 (3): 1152 -- The Journal of Virology." Retrieved September 18, 2005 from http://jvi.asm.org/cgi/content/full/75/3/1152?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=mechanism+of+hiv+infection&searchid=1127044860567_558&stored_search=&FIRSTINDEX=0&journalcode=jvi HIV Infection and AIDS. (n. d). Retrieved September 18, 2005 from http://www.cellsalive.com/hiv0.htm HIV Infection: Attachment and RNA Entry.(n. d) Retrieved September 18, 2005 from http://www.cellsalive.com/hiv1.htm HIV structure and life cycle (n. d).Retrieved September 18, 2005 from http://www.avert.org/virus.htm Lassen et al. (2004)."Analysis of Human Immunodeficiency Virus Type 1 Transcriptional Elongation in Resting CD4+ T Cells In Vivo 78 (17): 9105 -- The Journal of Virology." Retrieved September 18, 2005 from http://jvi.asm.org/cgi/content/full/78/17/9105?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=mechanism+of+hiv+infection&searchid=1127044860567_558&stored_search=&FIRSTINDEX=0&journalcode=jvi Liou L. Y et al (2002). "Transient Induction of Cyclin T1 during Human Macrophage Differentiation Regulates Human Immunodeficiency Virus Type 1 Tat Transactivation Function 76 (21): 10579 -- The Journal of Virology." Retrieved September 18, 2005 from http://jvi.asm.org/cgi/content/full/76/21/10579?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=mechanism+of+hiv+infection&searchid=1127044860567_558&stored_search=&FIRSTINDEX=0&journalcode=jvi NIH news: (2001). Retrieved September 18, 2005 from http://www3.niaid.nih.gov/news/newsreleases/2001/highhiv.htm Origin of HIV1 and HIV2: Cross species transmission of SIV to human.(n. d). Retrieved September 18, 2005 from http://www.cbs.dtu.dk/dtucourse/cookbooks/gorm/msc.5.phylogeny/HIV-phylogeny.php Spenlehauer C. et al (2000). Antibody-Mediated Neutralization of Primary Human Immunodeficiency Virus Type 1 Isolates: Investigation of the Mechanism of Inhibition 75 (5): 2235 -- The Journal of Virology. Retrieved September 18, 2005 from http://jvi.asm.org/cgi/content/full/75/5/2235?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=mechanism Study find HIV can drive immune cells away. (2004). Retrieved September 18, 2005 from http://www.eurekalert.org/pub_releases/2004-05/mgh-sfh050304.php The History of HIV.(n. d) Retrieved September 18, 2005 from http://aids.about.com/cs/aidsfactsheets/a/hivhis.htm Walker B. D (2003): Immunopathogenesis and Immune response in HIV infection CME. Retrieved September 18, 2005 from http://www.medscape.com/viewprogram/2434_pnt Read More