L#23 & #24: HIV/AIDS and Immunity to Infections.
L#23 & #24: HIV/AIDS and Immunity to Infections. 0530
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This 4 page Class Notes was uploaded by Denise Croote on Saturday January 23, 2016. The Class Notes belongs to 0530 at Brown University taught by Dr. Richard Bungiro in Fall 2013. Since its upload, it has received 31 views. For similar materials see Principles of Immunology in Biology at Brown University.
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Date Created: 01/23/16
Lecture Twenty Three: HIV/AIDS Retroviruses contain 2 identical RNA strands and replicate with reverse transcriptase (turns RNA into DNA) A provirus is the DNA copy of the viral RNA and it integrates randomly into the host cell Retroviruses share three structural genes: gag, pol, env. Pol encodes enzymes required for the life cycle (reverse transcriptase, integrase, and proteases) During reverse transcriptase the promoter is duplicated and put upstream in the genome, you need a second promoter so that the virus that is created to infect other cells has a promoter Steps for Infection: 1. HIV binds to the target cell (with the viral spike proteins on its envelope)) 2. Nucleocapsid containing viral genome and enzymes enter cells 3. Viral reverse transcriptase creates the HIV dsDNA provirus 4. Provirus is translocated and integrated into the host chromosomal DNA by viral integrase enzymes 5. Transcription of proviral DNA into mRNA 6. Viral mRNA is exported to the cytoplasm where ribosomes synthesize viral precursors 7. Viral protease cleaves precursors into viral proteins 8. Viral proteins assemble under the membrane, bud out, and are released from the cell HIV entry into the cell: o Gp120 on HIV binds to CD4 on T cells (why T cells are primarily affected) o Monocytes/macrophages also express CD4 and can be affected o Cell entry also requires interaction between gp41 on HIV and a co-receptor on the host cell 1. CXCR4 is the coreceptor on the CD4 T cells 2. CCR5 is a coreceptor on monocytes/macrophages Individuals with homozygouse CCR5 deletions are resistant to HIV Individuals with heterozygous individuals appear to progress less rapidly to AIDS RNA viruses lack proofreading steps, and acquire many cellular genes that give rise to highly oncogenic retroviruses (hard to make vaccines when the viral genome is constantly changing ) The first human retrovirus discovered was HTLV1 and was isolated from a patient with adult T cell lymphoma HIV/AIDs and its course: o Acute Phase: CD4 T cell count decreases as the viral load increases, lasts about 8 weeks o Seroconversion: appearance of anti-HIV antibodies in the blood (can take months to develop o Chronic Phase: asymptomatic, can last up to 8 years, viral load and CD4 T cell count have decreased but are holding steady o AIDS: 8-11 years after infection, viral load launches upward and CD4 T cell count decreases, leads to other infections Regulatory genes of HIV are tat and rev. o Tat lengthens the transcript and enhances viral transcription o Rev allows for RNA to be exported before any splicing cuts out the vital proteins Accessory genes are dispensable for growth but helpful in other ways… o Nef and Vpu downregulate CD4 o Vpu increases viral release by downregulating tetherin o Vpr arrests cells in the G2 phase o APOBEC3 is a human enzyme that prevents replication of retroviruses, accessory protein vif in HIV excludes APOBEC3 HIV Vaccine Approaches o Cannot use a whole inactivated virus or a live attenuated virus o Vaccinate with antigen-recombinant protein o DNA vaccine o Live recombinant vectors expressing HIV DNA o Synthetic peptides Chemotherapy has shown some success in treating HIV Antiretroviral drugs target multiple stages in the virus life cycle o Inhibit fusion with the cell, reverse transcriptase, integrase, and protease Study conducted where a baby was rapidly treated with antiviral drugs after birth and the number of anti-HIV antibodies in the baby 30 months later were undetectable Early treatment with antivirals can help reduce the spread of the disease to the partner Lecture Twenty Four: Immunity to Infections The major categories of infectious diseases are virus, bacterium, fungus, and parasites Still do not have vaccines to some of the more serious diseases, like HIV, Malaria, and parasite diseases Resistance to drugs is becoming a problem Vaccines offer protective immunity to stop a person from being infected with a disease if they are ever exposed o Viral infections are intracellular o Bacteria and protozoal infections are intracellular or extracellular o Parasitic worm infections are almost always extracellular Antibody Mediated Effector Responses Include: o Neutralization of the toxin or whole pathogen o Opsonization of antigens for phagocytosis or lysis o Complement activation leading to the lysis of cells or enveloped viruses by MAC, and opsonization o ADCC o Mast cell degranulation (by IgE) Cell Mediated Effector Responses o Phagocytosis by neutrophils and macrophages o Cytotoxic T cells o Natural Killers o Delayed Type Hypersensitivity – (macrophage activation) o ADCC Viral Infections o Viruses must bind to and invade host pathogens before they can replicate and infect o Viruses are typically acquired by ingestion or inhalation o All viruses have an outer coat containing multiple copies of a protein required to bind to the host cell receptor and an inner core containing DNA or RNA o Bind to CD4 receptors on cells (HIV) or ICAM1 receptors (rhinovirus) Immune Responses Against Viruses: Antibodies surround virus and block target binding C’ mediated lysis of the viral envelope Phagocytosis NK cell attack Cytokine production of IL2 and IFNy promote an antiviral state CTL recognize virally infected host cells How do viruses defend themselves? Inhibit antigen presentation Inhibit MHC expression of viral proteins by downregulating class I MHC Interfere with complement activation Antigenic variation of viruses changes their identifiers, making it hard for memory B cells and T cells to activate and attack Downregulate Th1 response Antigenic drift – generates variants within the sub-types, leading to regular seasonal epidemics. Antigenic drift is a process during which several point mutation result in structural changes in coat proteins over time and these changes weaken the ability of the Abs to bind and effectively recognize Antigenic shift – may lead to pandemics as a new sub-type emerges or re-emerges, could result from the combination of human influenza and swine influenza, entire ssRNA strands from animal and human viruses infecting the same cell pair to make a new virus o Influenza is hard to vaccinate against because the HA and NA surface proteins have a lot of variability o 2009 H1N1 virus was an example of mixing segments of different viruses to create an whole new virus o H1N1 was actually more deadly to young people (rather than older people) because the young people had never seen anything like it before and the older people were alive for a virus like it several years ago Bacterial Infections o Bacteria are unicellular organisms with proteins and a cell wall o They can infect intracellulary or extracellulary (extracellular infections are easier to combat) Immune Responses: Extracellular Infections: bacterial agglutination, Abs block attachment to cells, toxin neutralization, complement activated lysis, C3a/C5a mediated mast cell degranulation, neutrophil/macrophage chemotaxis because of complement activation Intracellular Infections: NK Death stimulated by cytokines and DTH ( macrophage activation via IFNy produced by Th1 cells) How do bacteria defend themselves? Increase their adhesion to the host cell with a structure called pilli Inhibit complement or phagocytosis Antigenic variation and shift to avoid memory recognition Survival within the phagocytic cells (like the acidic environment) o Defending against bacteria can get dangerous if you overproduce inflammatory mediators leading to septic shock and food poisoning or chronically activate CD4 T cells leading to the accumulation of macrophages and the formation of granulomas o Diptheria is a bacterial infection that forms a pseudomembrane that interferes with breathing and ultimately leads to suffocation The pathology is mediated by a secreted exotoxin (a single toxin is strong enough to kill a cell) Infection is treated with an antitoxin – usually a toxoid that retains the protective epitopes but cannot cause disease o Tuberculosis (TB) – 90% of those that are infected mount an effective CD4 response while 10% develop chronic TB. Those that develop chronic TB have pulmonary lesions, right now TB strains have developed to multidrug resistance Protozoan Infections o Unicellular organisms with a plasma membrane and a nucleus o Malaria is an example, multiples within cells o Have a complicated life cycle with an intermediate in which they display different forms with new antigens o If the infection is extracellular the immune response is antibody mediated, if the infection is intracellular the response is cell mediated o Malaria: Causes 1 million death per year No vaccine yet o Frequently antigenic shift causing new structures to be placed in the expression site Parasite Infections o An example is Leishmania – a single celled parasite that infects macrophages o Causes cutaneous and visceral lesions o Worms are parasitic infections – worms are too big to phagocytize and are often resistant to digestion and immune effector mechanisms Immune Responses to Worms: Immune response are specific to the stage and the place where the infection has occurred CTL responses are not possible and phagocytosis is not possible either Antibody or encapsulation may be effective How do worms defend themselves? Secreting immunoregulatory factors Covering their surface with the host’s proteins o Schistosomiasis is a common worm disease in developing countries, survival does not guarantee immunity. Schistosomiasis is acquired by contact with contaminated water Fungal Diseases o Controlled by the innate immune system mostly (phagocytosis by neutrophils, Pattern recognition, and activation of complement by proteins on fungal cell walls) o Acquire immunity when anti fungal antibodies develop o HIV patients are more susceptible to infection Summary: changing conditions bring back the presence of some disease, for ex.) TB has exploited the HIV/AIDS pandemic, and global climate change has allowed tropical diseases like malaria to expand their range
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