Human Immunodeficiency Virus, HIV is a retrovirus, which is a unique virus family consisting of RNA as the genetic material instead of DNA. This genetic material is surrounded by an envelope of lipoprotein. HIV differs structurally from other members of the family retrovirus. It is roughly spherical and has a diameter of around 120 nm.
Human Immunodeficiency Virus comprises of two copies of non-covalently joined positive single-stranded RNA enveloped by a conical capsid that consist of the p24 viral protein, which is typical of lentiviruses. Lysine tRNA is reverse transcriptase that is magnesium dependent and is involved in the packaging of both copies of the positive strands, 5'guanosine-capped, unspliced, and the 3'-polyadenylated RNA genome. The 3'-polyadenylated RNA genome is used in the recombination that is strand-transfer-mediated and enables the virus to evolve quickly under stress or pressure from the surrounding environment (McLellan et al., 2011). This explains why the reason as to why HIV possesses two copies of genomic RNA, a feature that is not found in other retroviruses. The components of the RNA are composed of a length of 9749 nucleotides long RNA genome has a 3’ poly (A) tail, 5’ cap (Gppp), and a lot of open reading frames (ORFs). The structural proteins of the virus are encoded by the long ORFs, and the small ORFs are involved in encoding regulator molecules that regulate the viral life cycle. These regulators include components involved with membrane fusion, attachment, replication, as well as assembly (Briggs & Kräusslich, 2011).
The structural proteins and the genome are then surrounded by an envelope that originates from the cell of the host. The single-strand RNA is bound to the nucleocapsid proteins, which are protein p6 and p7, and to the enzymes necessary for the development of the virion. These enzymes include reverse transcriptase as well as integrase. The nucleocapsid proteins associate with the RNA genome where one molecule is associated with one hexamer and works to protect the RNA against nucleases digestion. A matrix made up of viral protein p17 association surrounds the capsid and ensures the unity of the virion particle is not compromised. Other molecules that are enclosed inside the virion particle include Vpr, Vif, Nef, p7 as well as viral Protease. The envelope is usually made when there is capsid budding from the host cell and thus carries a host cell membrane's portion.. Some of the molecules included in the envelope are the glycoprotein gp120 and gp41 (Zhu et al., 2008).
The structure of the envelope spike with the gp120 and gp41 plays an important part in virus attachment to the cell. Understanding the structure of the envelope spike has been the focus with an aim of understanding the virus as well as the replication cycle (Panceraa et al., 2011). This understanding of the structure may also help in the generation of a cure for the disease (Zhu et al., 2008).
Envelope glycoprotein GP120 denoted as gp120 refers to a glycoprotein that is presented on the surface of the envelope of the HIV. The number 120 linked to the name is derived from the molecular weight of the glycoprotein which is 120 kilodaltons (Teixeiraa et al., 2011). Gp120 is of paramount importance essence for entry of the virus into cells since it plays a crucial role in attachment to specific receptors on the cell surface. These receptors are Heparan Sulfate Proteoglycan (de Witte et al., 2007), DC-SIGN, as well as a specific interaction with the CD4 receptor, especially on helper T-cells. Binding to CD4 induces the beginning of a flow of conformational alterations in gp41 and gp120, which causes the union of the viral component with the cell membrane of the host. Binding to CD4 is primarily electrostatic even though there exist van der Waals interactions, as well as, hydrogen bonds.
The HIV env gene codes for Gp120 consisting of around 850 amino acids. The main product from the env gene is the protein gp160, which then undergoes cleavage in the endoplasmatic reticulum using a cellular protease called furin to produce gp120 and gp41. From the crystal structure that makes the core gp120 there is an indication of an organization with an inner domain, an outer domain with respect to a bridging sheet and its termini. The anchoring of the Gp120 to the viral envelope, or membrane occurs through non-covalent bonds with the glycoprotein gp41 that transverse the membrane. Three molecules of gp120s and other three molecules of gp41s combine in a trimer making up heterodimers that then lead to the formation of the envelope spike. The envelope spikes then enhance the virus attachment to the host as well as their entry (Zhu et al., 2008).
The entry processes of HIV into the cell of the host also need the involvement of a number of cell surface proteins, which usually play a part as chemokine receptors. Chemokines are molecules that hormone like mediators and are involved in the attraction of the immune system cells to particular locations in the body. These receptors occur on the T cells and are described as co-receptors because they function in tandem with CD4 in allowing the entry of HIV into the cells. Some of the chemokine receptors that function as co-receptors of Human Immunodeficiency Virus include chemokine [C-C motif] receptor, CCR5 and chemokine [C-X-C motif] receptor 4, CXCR4.
The two kinds of receptors are categorized as G protein-coupled receptors. The gp120binding to CD4 displays an area of gp120 that has an interaction with the chemokine receptors. This interaction induces a conformational alteration, which displays an area of the viral envelope protein gp41 that puts itself into the cell membrane of the host so that it links the viral envelope and the membrane of the cell. An extra conformational alteration in gp41 draws these two membranes together, permitting union to happen (Zhu et al., 2008). After union, the genetic information of the virus can penetrate the cell of the host. Both CXCR4 and CCR5 have raised interest as a drug development target. This is from agents that can bind to and block the receptors may inhibit the entry of HIV into cells.
After the virus has infected a T cell, the Human Immunodeficiency Virus makes many copies of its RNA through a process called reverse transcription. This process leads to double-stranded DNA from the viral RNA using the enzyme called reverse transcriptase. The process is known as reverse transcription since it violates the normal way through which transcription of genetic information is done. Lack of prove-reading mechanisms by the reverse transcriptase causes the transcription process to have many mutations, and this affects the way the immune system combats the virus. These mutations permit the rapid evolution of the virus, which is approximated to be one million times more than the human genome undergoes evolution (Zhu et al., 2008).
This fast evolution permits the virus to evade antiretroviral drugs as well as antiviral immune responses. The virus then integrates the genome into the DNA in the host cell. Integration takes place at essentially any reachable site in the genome of the host and leads to the permanent viral genes acquisition by the cell of the host. Under suitable conditions, these genes are transcribed into molecules of viral RNA. A number of viral RNA molecules are integrated into new viral particles as others are utilized as messenger RNA for the synthesis of new viral proteins.
These viral proteins gather at the plasma membrane in combination with the genomic viral RNA to produce a virus particle budding from the infected cell’s surface, carrying with it a number of the host cell membrane that acts as the envelope of the virus. The gp120/gp41 complexes are embedded in this envelope, and they permit helper T cells attachment in the next infection. A majority of infected cells die fast. The helper T cells’ numbers that are lost via direct infection or other mechanisms surpass the number of new cells synthesized by the immune system, at last leading to a reduction in the helper T cells’ number. The disease course is usually followed by determination of the count of helper T cells, CD4+ cells, in the blood. This assessment, known as the CD4 count, offers a good sign of the immune system status. The amount of virus in the bloodstream, which offers an indication of the speed at which the virus is replicate and destroy helper T cells is also measured (Zhu et al., 2008).
Untreated HIV disease is identified by a slow worsening of immune function. Most significantly, the CD4+ T-cells undergo disruption and destruction during the typical path of HIV infection. The CD4+ T-cells, T-helper cells have a role in the immune response, signaling other immune system cells to carry out their specific roles. Fundamentally, a healthy person who is HIV-negative usually has 800 to 1, 200 CD4+ T-cells per mm3 of blood. Throughout the infection of untreated HIV, the number of these cells in the blood of a person progressively reduces (Zhu et al., 2008).
When the count of CD4+ T-cell goes below 200/mm3, a person tends to be mainly vulnerable to the opportunistic infections, which are related to AIDS. It is believed that HIV leads to AIDS through induction of the CD4+ T-cells death or interference with the normal function of CD4+ T-cells. HIV also leads to AIDS by inducing other events that make an individual’s immune system weak. For instance, the signaling molecules’ network that usually regulates an individual’s immune response is disrupted during HIV disease, causing impairment of the individual’s ability to resist other infections. The destruction of lymph nodes as well as related immunological organs that are mediated by HIV also takes a key part in leading to the immuno-suppression observed in HIV infected people (Imamichi et al., 2012).
There are a number of mechanisms that explain how CD4 T-cells are destroyed by HIV. Syncytium formation is among the mechanisms whereby some HIV-infected CD4 T-cells may form a clump of fused cells. HIV strains present in the late phases of infection are likely to be able to cause syncytium formation. The cytokine interleukin-15 may have a vital role in the non-syncytium inducing conversion to syncytium inducing strains of the virus. The syncytium inducing strains have the ability to replicate more than the non-syncytium inducing strains, and the actual viral turnover might be the CD4 T-cells killing mechanism rather than syncytium formation itself.
When HIV is undergoing replication in CD4 T-cells, there is increased synthesis of HIV proteins that can be discharged into the bloodstream and functions as antigens. Free proteins known as gp120 could get attached to molecules of CD4 on uninfected CD4 cells resulting in an attack on the cell by cytotoxic cells and antibodies. The gp120attachment to CD4, as well, suppresses the CD4 T-cell function (Teixeiraa et al., 2011).
In a normal individual, all cells may be programmed for death if there is a need for them to be replaced or eliminated. This is referred to as apoptosis. Unusually large parts of CD4 T-cells that are either infected or uninfected appear to be programmed for apoptosis in HIV infected people. This involves the free HIV proteins attachment to CD4 cells or because of over-activation of the cell. The HIV antigens serve as super antigens, which can activate a bigger variety of CD4 T-cells than usual and which can lead to increased HIV replication. Alterations in levels of cytokine, like raised decreased interleukin-1 as well as tumor necrosis factor, may also trigger apoptosis. Natural killer cells, B-cells, as well as, CD8 T-cells are also have a tendency to apoptosis in the course of HIV infection.
The homology of major histocompatibility complex and gp120 is also known to be a mechanism used in the destruction of CDA+ T-cells. It has been discovered that components of the HIV envelope protein gp120 are the same as molecules of the major histocompatibility complex, the antigens available on the surfaces of human cell, which signal to the immune system that the cell is of the host. The normal receptor of the T-cell learns to pick out foreign antigens when they are exhibited in association with MHC 'self' molecules. However, free gp120 can also attach to T-cell receptors by mimicking proteins of the major histocompatibility complex. This causes the activation of the T cell that explains the excessive T cells activation in the course of HIV infection (Imamichi et al., 2012).
Among the key controversial theories for death of CD4 T-cell is on the idea that HIV triggers auto-immunity. This theory postulates that the CD4 T-cells of the host are no longer regarded as self but as strange cells that undergo destruction by the immune system. The causes of this are the homology between molecules of non-self MHC and HIV antigens, with HIV antigens on the CD4 T-cells’ surface leading them to be regarded as strange cells. Activated B cells can also give anti-lymphocyte antibodies. One consequence of recognizing cells of the host as foreign might be the activation of the immune system that appears during HIV infection. Conditions typical of auto-immunity are known to materialize during HIV infection, including lowered counts of platelet cell, dermatitis, vasculitis, psoriasis as well as arthritis. It appears possible that genetic factors have an influence on the risk of auto-immunity. These features are the same those that appear when strange material is transplanted into the body, like during an infection or following transplant. The employment of immune suppressant therapies, like corticosteroids, may thus be of advantage in lowering the immune system over-stimulation, and death of CD4 T-cell seen in chronic HIV-infection (Montesano et al., 2010).
The CD8 T-cells have a crucial function in controlling replication of HIV in the early infection phase. HIV-specific CD8 T-cells are aimed at the main viral variant, and their appearance is related to a fast reduction in viral load, prior to the development of a response of antibody (Montesano et al., 2010). A majority of the CD8 T-cells created in primary infection die in a few weeks, leaving a pool of HIV-specific CD8 memory cells that will persevere despite the availability of CD4 helper cells or an antigen. CD8 T-cells seem to act against HIV using two ways in primary infection. These include killing cells that are HIV-infected and by producing chemokines. HIV-specific CD8 T-cells identify a particular HIV genetic sequence and are primed to replicate themselves if this sequence is met again (Imamichi et al., 2012).
In adaptive immunity, it is a basic rule that naive lymphocytes that are antigen-specific are hard to be activated by antigen only. Naive T cells need a co-stimulatory signal from professional antigen-presenting cells. Naive B cells need accessory signals, which can come from an armed helper T cell or, in some instances, directly from constituents of microbes. Responses of antibody to protein antigens need the help of antigen-specific T-cell. B cells can obtain aid from armed helper T cells when antigen that is bound by surface immunoglobulin is interiorized and returned to the surface of the cell as peptides bound to molecules of major histocompatibility complex class II. Armed helper T cells, which identify the peptide, MHC complex then convey activating signals to the B cell. Therefore, protein antigens binding to B cells offer a specific signal to the B cell through cross-linking its antigen receptors and permit the B cell to draw the help of antigen specific T-cell. These antigens are not able to trigger antibody responses in animals or humans who do not have T cells, and they, thus, are referred to as thymus-dependent antigens.
One of the major cells that are targeted for by the HIV-1 infection are the macrophages. The macrophages are involved in the pathogenesis process of the virus. Studies have indicated that the HIV-1 particle morphogenesis pathway is discrete in primary human macrophages. This characteristic is known to have an essential role in the virus persistence, in human. Macrophages have also been shown to form of the HIV-1 in the infected individuals. They also act as a way through which the virus spread from one tissue to the other. HIV-1 has also been found in the macrophages that are located in the intracellular compartment newly identified. It is thus assumed that the HIV can be stored in these invaginations and are thus protected from the antibodies that may neutralize them (Deneka et al., 2007).
The HIV infection is also known to destroy cells such as the macrophages, monocytes, and CD4/T4 lymphocytes. This causes the ability of the body to fight against the invading organisms to be seriously impairing. Once the monocytes, as well as, the macrophages have been destroyed, processes such as phagocytosis and release of cytokine especially those that promote the growth and replication of lymphocyte are highly reduced (Welsch et al., 2007).
Macrophages are infected very early by monocytotropic strains of HIV. They contribute to defense mechanisms of the host and to perpetuation as well as dissemination of the infection. Macrophages that are infected with HIV- have been shown, not just in lymph nodes but also in peripheral organs like the brain and lung, where they release cytotoxic mediators, which contribute to the development of neurologic and pulmonary lesions. Functional destruction of HIV-infected macrophages may take part in the immune deficiency typical of AIDS. Infected macrophages are a sanctuary and a reservoir for the HIV, by virtue of which the virus can evade sensing by the immunologic surveillance system. These features make the HIV-infected macrophage a perfect agent of the perpetuation and propagation of HIV infection (Russo-Marie, 1997).
Reference Lists
Briggs JA. & Kräusslich HG. 2011. The Molecular Architecture of HIV. Journal of Molecular Biology Volume. 410: 491–500.
de Witte L, Bobardt M, Chatterji U, Degeest G, David G, Geijtenbeek TB, Gallay P. 2007. Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1. Proc. Natl. Acad. Sci. U.S.A. 104:19464–19469.
Deneka M, Pelchen-Matthews A, Byland R, Ruiz-Mateos E, Marsh M. 2007. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J Cell Biol. 177: 329-341.
Imamichi H, Lempicki RA, Adelsberger JW, Hasley RB, Rosenberg A, Roby G, Rehm CA. 2012. The CD8+ HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls. Eur J Immunol. 42:2608-2620.
McLellan, JS, Pancera M, Carrico C, Gorman J, Julien JP, Khayat R. 2011. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature. Volume 480:336–343.
Montesano C, Anselmi A, Palma P, Bernardi S, Cicconi R, Mattei M, Castelli-Gattinara G, Ciccozzi M, Colizzi V, Amicosante M. 2010. HIV replicationleads to skewed maturation of CD8-positive T-cell responses in infected children. New Microbiologica. Volume 33:303-309.
Panceraa M, Majeeda S, Banb YA, Chena, L, Huanga C, Konga L, Kwona YD, Stuckeya, J, Zhoua T. 2011. Structure of HIV-1 gp120 with the gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. PNAS. 107:1166–1171.
Russo-Marie F. 1997. HIV and macrophage. Pathol Biol. 45:137-45.
Teixeiraa C, Gomesb JRB, Gomesc P, Maurela F. 2011. Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug. European Journal of Medicinal Chemistry. 46:979–992.
Welsch S, Keppler, OT, Habermann A, Allespach I, Krijnse-Locker, JK, Hans-Georg, 2007. HIV-1 Buds Predominantly at the Plasma Membrane of Primary Human Macrophages. PLoS Pathog. 3:36.
Zhu P, Winkler H, Chertova E, Taylor K, Roux, KH. 2008. Cryoelectron Tomography of HIV-1 Envelope Spikes: Further Evidence for Tripod-Like Legs. PLoS Pathogens. 4 (11).
