hiv vs aids. can we prevent hiv transformation into aids?
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HIV VS AIDS. Can we prevent HIV
transformation into AIDS?Dmitri Popov MD (Russia), PhD (Russia-Canada)Advanced Medical Technology and Systems Inc.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Research Proposal:
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Dmitri Popov• Full-text · Research Proposal · Feb 2015• Add resources• File name: HIVAIDS.pptx
DOI: 10.13140/RG.2.1.4421.8008
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of
retrovirus) that causes HIV infection.• Human immunodeficiency virus infection and acquired immune
deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV).[5][6][7] Following initial infection, a person may not notice any symptoms or may experience a brief period of influenza-like illness.[8] Typically, this is followed by a prolonged period with no symptoms.[9] As the infection progresses, it interferes more with the immune system, increasing the risk of common infections liketuberculosis, as well as other opportunistic infections, and tumors that rarely affect people who have working immune systems.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Acquired immunodeficiency syndrome (AIDS) is a disease caused by human
immunodeficiency virus (HIV)-mediated destruction of CD4+ T lymphocytes (Barre-Sinoussi et al. 1983 ; Gallo et al. 1983 )
• http://download.springer.com/static/pdf/574/chp%253A10.1007%252F978-1-4614-0980-9_10.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Fchapter%2F10.1007%2F978-1-4614-0980-9_10&token2=exp=1458336334~acl=%2Fstatic%2Fpdf%2F574%2Fchp%25253A10.1007%25252F978-1-4614-0980-9_10.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Fchapter%252F10.1007%252F978-1-4614-0980-9_10*~hmac=df5b2c2477c404d85d40dcdd6ed4b4c06460b3d80f89502c1638fc831eae9fd2
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• In molecular biology, CD4 (cluster of differentiation 4) is a
glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984.• In humans, the CD4 protein is encoded by the CD4 gene.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• CD4+ T helper cells are white blood cells that are an essential part of
the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• HIV infection leads to a progressive reduction in the number of
T cells expressing CD4. Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection. Normal blood values are usually expressed as the number of cells per microliter (or cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500-1200 cells/mm3.
• https://en.wikipedia.org/wiki/CD4#HIV_infection
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• A CD4 count measures the number of T cells expressing CD4. While
CD4 counts are not a direct HIV test—e.g. they do not check the presence of viral DNA, or specific antibodies against HIV—they are used to assess the immune system of a patient. Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500cpm in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. The newest National Institute of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• J Immunol. 1992 Jan 1;148(1):55-62.• Multiple cytolytic mechanisms displayed by activated human peripheral blood T cell
subsets.• Smyth MJ1, Norihisa Y, Ortaldo JR.• Despite both CD4+ and CD8+ T cell subsets expressing granzymes, pore-forming protein,
TNF-beta, and TNF-alpha, these T cell subsets displayed distinct pathways of antibody-redirected lysis against TNF-sensitive and TNF-resistant targets, even in the presence of anti-TNF antibodies. In addition, these same effector T cell subsets were also directly cytotoxic (in the absence of heteroconjugated antibody) against TNF-sensitive targets in an 18-h assay. Indeed, this direct cytotoxicity was completely abrogated by anti-TNF-alpha antibody and was sensitive to the metabolic inhibitors (cyclosporin A, CT, cycloheximide, and actinomycin D), all of which blocked CD4+/CD8+ T cell TNF-alpha production.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Despite both CD4+ and CD8+ T cell subsets expressing granzymes,
pore-forming protein, TNF-beta, and TNF-alpha, these T cell subsets displayed distinct pathways of antibody-redirected lysis against TNF-sensitive and TNF-resistant targets, even in the presence of anti-TNF antibodies. In addition, these same effector T cell subsets were also directly cytotoxic (in the absence of heteroconjugated antibody) against TNF-sensitive targets in an 18-h assay. Indeed, this direct cytotoxicity was completely abrogated by anti-TNF-alpha antibody and was sensitive to the metabolic inhibitors (cyclosporin A, CT, cycloheximide, and actinomycin D), all of which blocked CD4+/CD8+ T cell TNF-alpha production. http://www.ncbi.nlm.nih.gov/pubmed/1345790
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Advances in understanding the HIV entry pathway have directly led to
the development of specifi c and effective antiviral agents that prevent virus entry, including the fi rst antiviral agent that targets a host cell molecule needed for virus infection. This provides proof of principle that virus entry in general, including the viral membrane fusion machines, can be targeted. Currently, two small molecule HIV entry inhibitors, the fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc , are FDA approved for the treatment of HIV, while others are currently under various stages of development (Dwyer et al. 2007 ; He et al. 2008a, b ; Schurmann et al. 2007 ; Strizki et al. 2005 ; Tilton and Doms 2010 )
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Despite the tremendous advances in understanding HIV entry, many
questions remain unanswered. To penetrate cells, enveloped viruses must fuse with cells either directly at the plasma membrane or in intracellular compartments ( Marsh and Helenius 2006 ) . Historically, many have assumed that HIV fuses at the plasma membrane due to early studies demonstrating that Env can mediate cell–cell fusion both in vitro and in vivo, and because HIV entry can be augmented, but not inhibited, by lysomotropic agents (Maddon et al. 1988 ; McClure et al. 1988 )
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• CD4 is an immunoglobulin superfamily member that contains four
extracellular immunoglobulin domains (D1–D4), a single transmembrane domain, and a short intracellular cytoplasmic tail. CD4 plays a key signaling role that assists the T-cell receptor in activating cells in response to immunologic stimuli. It is expressed on macrophages, dendritic cells, and the eponymous CD4+ T cells, which include naive, central, and effector memory subtypes. Depletion of CD4+ T cells, and in particular the memory subsets, is indicative of disease progression and a poor clinical outcome.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• The major mechanism for CD4+ T cell depletion is programmed cell death
(apoptosis), which can be induced by HIV through multiple pathways. Death of HIV-infected cells can result from the propensity of infected lymphocytes to form short-lived syncytia or from an increased susceptibility of the cells to death. However, the apoptotic cells appear to be primarily uninfected bystander cells and are eradicated by two different mechanisms: either a Fas-mediated mechanism during activation-induced cell death (AICD), or as a result of HIV proteins (Tat, gp120, Nef, Vpu) released from infected cells stimulating apoptosis in uninfected bystander cells. There is also evidence that as AIDS progresses cytokine dysregulation occurs, and the overproduction of type-2 cytokines (IL-4, IL-10) increases susceptibility to AICD whereas type-1 cytokines (IL-12, IFN-c) may be protective. Clearly there are multiple causes of CD4+ T lymphocyte apoptosis in AIDS and therapies that block or decrease that death could have significant clinical benefit.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• All viruses, and some bacteria, multiply in the cytoplasm of infected
cells; indeed, the virus is a highly sophisticated parasite that has no biosynthetic or metabolic apparatus of its own and, in consequence, can replicate only inside cells. Once inside cells, these pathogens are not accessible to antibodies and can be eliminated only by the destruction or modification of the infected cells on which they depend. This role in host defense is fulfilled by cytotoxic CD8 T cells.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Cells can die in either of two ways. Physical or chemical injury, such as
the deprivation of oxygen that occurs in heart muscle during a heart attack, or membrane damage with antibody and complement, leads to cell disintegration or necrosis. The dead or necrotic tissue is taken up and degraded by phagocytic cells, which eventually clear the damaged tissue and heal the wound. The other form of cell death is known as programmed cell death or apoptosis. Apoptosis is a normal cellular response that is crucial in the tissue remodeling that occurs during development and metamorphosis in all multicellular animals.• http://www.ncbi.nlm.nih.gov/books/NBK27101/
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• “Granule-mediated cytolysis is undoubtedly the most important
effector function of CD8þ T cells and natural killer (NK) cells. After a killer cell recognizes its target, the cytotoxic granules move to the immunological synapse, where their membranes fuse with the killer cell plasma membrane, and they release their contents to induce target cell apoptosis.”
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Granule-mediated cytolysis is possible and the most important
effector function of CD8þ T cells and natural killer (NK) cells possible mechanism of CD 4 T cells.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• The principal death effectors are the serine proteases (called
granzymes, for granule enzyme) and the membrane perturbing proteins, perforin and granulysin. These are bound to a proteoglycan matrix. Although killer cells can also destroy their targets by engaging death receptors such as fas, studies using perforin knockout mice have clearly shown the importance of the granuleexocytosis pathway for controlling viral infection and tumors
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• J Immunol. 2006 Oct 15;177(8):5668-75.• Human CD4+ T cells lyse target cells via granzyme/perforin upon
circumvention of MHC class II restriction by an antibody-like immunoreceptor.• Hombach A1, Köhler H, Rappl G, Abken H.
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Human CD4+ T cells lyse target cells via granzyme/perforin.• Can CD +4 T cells lyse CD +4 T cells as a target cells?• Granule-mediated cytolysis is possible and the most important
effector function of CD8þ T cells and natural killer (NK) cells possible mechanism of CD 4 T cells.• Can CD +8 T cells lyse CD +4 cells as a target cells?
HIV VS AIDS. Can we prevent HIV transformation into AIDS?• Blocking Monoclonal Antibodies to Granzyme and Perforin can be
potentially important therapy for prevention development of CD4 lymphocytes depletion at HIV and transformation to AIDS.