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122 Cards in this Set
- Front
- Back
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AIDS stats: # cases of living ppl with AIDS? WW? place with most AIDS? predictions by 2010?
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1.2 mil. 40 mil. sub saharan africa ~ 25 mil. 105 million cases, 25 million orphans, 100 million children have only one parent.
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two biggest groups with AIDS and their percentages?
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MSM (60%), IV drugs (25%)
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HIV 1 M is divided into how many subtypes and why? what subtype is usually seen in US?
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9 (A,B,C,D,F,G,H,J,K) based on variation in the envelope protein. note that some of these clades can form recombinant forms as well. Subtype B
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three major groups of HIV 1?
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M (main cause of pandemic),O (outlier some seen in africa),N (new group which is a combo with more simian virus)
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origination of the virus?
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pan troglodytes (chimp) for HIV1 and sootey mangabey monkeys for HIV2
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what is a major problem in vaccine development?
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recombination between subtypes due to strand switching during reverse transcription and copackaging of two different RNAs into one virion.
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genetic differences bw HIV 1 and HIV 2?
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1 has VPU gene while 2 has VPX gene.
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describe cells infected by HIV1.
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mainly CD4 lymphocytes, cells of lymph nodes, macs, monocytes, endothelial cells, and CNS (microglial) cells. lymphocytes in the gut are the early target
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cells infected by HIV2?
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CD4s
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describe the virion.
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L type virus, enveloped with trimeric peplomers, wedge shaped core, matrix
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describe the peplomer.
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trimer of gp120 (SU) and gp41 (TM) that are cleaved from gp160 ENV protein by a cellular golgi protease
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aspects of the gp120 protein?
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attachment protein, determines host range (tropism), determines MON group, binds CD4 on cell surface and the co-receptor for a mac (beta chemokine) or a T cell (alpha chemokine). it does this via a V3 loop that is very important and can also bind DC sign molecule on surface of the dendritic cell
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after the initial clinical phase and during the period of clinical latency (8 to 10 years in untreated) how many virions are made daily and why?
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a billion bc even though circulating blood may not have as much virus, lymphoid tissue and underlying organs are infected and virus is being actively made there, will go back to blood during ARC - aids related complex
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describe the cleavage and role of the glycoprotein
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gp160 is cleaved to gp120 and gp41 in the golgi by a cellular protease. Gp120 is the attachment protein - attaches to CD4 and co receptor, gp41 has 3 domains: an internal domain, a transmembrane domain, and an ectodomain which mediates fusion and syncytium formation. Gp160 traps cellular CD4 molecules in the ER. gp120 SU protein determines HIV1 group (MON) and subgroup/clade - high mutation rate of 1 NT change per 1000 per yr. gp160/gp120 induce apoptosis
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describe the capsid and proteins of the virion.
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made from GAG. Has matrix (MA), CA which is major compnent of capsid and the NC nucleocapsid core protein that binds the genome via the psi sequence of RNA
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describe the proteins made from GAG-PRO-POL and their functions.
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pol portion yields RT, RNAse-H, endonuclease, and pro yields protease. Protease, aspartyl protease, is essential to cleave rest of polyprotein, without it virion is noninfectious. RT copies RNA to (-)DNA then makes dsDNA, high error rate. RNAse H digests vRNA, INT is the endonuclease that integrates provirus.
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what serves as the primer for (-) DNA synth? (+) DNA synth?
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tRNA that PBS. PPT is the primer for +DNA
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what is the HIV genome?
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5' cap-R-U5-PBS-psi-ten genes-ppt-U3-R-poly A tail-3'
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what are the LTR sequences and what do they each do?
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U3-R-U5 at each end. U3 has cis regulatory factors for plus strand synth of vDNA, R is the molecular jump sequences, U5 has regulatory elements and is needed for minus strand synth
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3 activities of the RT?
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RNA directed DNA polymerization, Rnase H, DNA directed DNA synthesis
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what is the mechanism for antigenic variance?
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antigenic drift in ENV
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role of VIF protein?
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a factor in tropism and efficient replication in non permissive cells. It blocks incorporation of cellular cytidine deaminase which would mutates the provirus unless VIF were there.
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role of NEF protein?
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very important for pathogenicity but not essential for replication. Major effects are impairment of CD4 functions. Down regulates CD4 Ig receptor, IL-2R, MHC1 and2. also has stuff like release of NFKB and stimulation of MACs to activate the LTR in the provirus to cause replication/txn of HIV in the CD4 cell.
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role of the TAT protein?
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trans activator txn protein. Essential for HIV replication. Many functions. Anti terminator of HIV txn by binding to TAR, which is a cis acting regulatory stem/loop sequence on HIV mRNA that would stop txn if it was not for TAT. Binds CD26 protein that blocks immune memory recall. IS neurotoxic. promotes angiogenesis thus a stimulator of tumor cell growth in kaposis sarcoma patients. stimulates collagenase IV which promotes spread of tumor cells. upregulates the LTR and HIV expression. Blocks IFN functions. Causes immune stimulation of neighboring cells. makes uninfected quiescent T cells more permisive for HIV1 replication. can induce apoptosis. NOTE is a new target for new drugs
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role of the REV protein?
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essential in replication. Binds some viral mRNAs and promotes their transport from the nucleus to the cytoplasm to be tslned. Is the transition from early to late phase. Binds to a sequence called the rev response element. Mediates exportation of mRNAs encoding GAG, GAG-POL, ENV, VIF, VPU and VPR so that virions may be assembled. note mRNAs for REV, TAT, and NEF are multiply spliced thus the rev response element is not retained and these are tslned early to facilitate the switch to the late structural genes
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role of VPR protein?
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allows viral replication in nondividng macs/monocytes. VPR and MA transport viral genome/core into the nucleus but is multifunctional and complex. Blocks cell cycle at G2/M phase then induces apoptosis (can induce apoptosis in neurons) and uses NFKB to activate provirus
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role of VPU protein?
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from bicistronic ENV RNA, not required for replication but enhances it and has role in assembly. Seen in HIV1. integral membrane protein in golgi and PM. Enhances release of virion at PM and induces degradation of CD4 protein in ER that is held there by gp160.
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3 proteins that destroy the CD4 proteins?
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ENV, VPU, and NEF
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what are the 4 cells that HIV can attack ad how?
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they need a CD4 protein and a coreceptor (alpha chemokine receptor in CD4 or B chemokin receptor seen in macs/monos). Thus infects CD4 T cells, macs, and monocytes. It can also attach to dendritic cells via surface protein DC-sign but it does not infect, it does get transported to the lymph node with the dendritic cell though
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what part of the gp120 interacts with the coreceptor?
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the VP3 loop
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when are the HIV cells MAC trophic? T cell trophic?
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M trophic at the beginning and T cell tropic more towards end of disease
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what type of chemokine receptor is the alpha receptor? Beta?
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alpha is CXCR4 for T cells and is syncytial inducing and thus emerge with disease. Beta is CCR5, found on macs and is not syncytial inducing
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what cells are important in viral latency?
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the macs, virus is M tropic at first and during latency stays in these fellas
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what persons are immune to infection?
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ppl with a mutated CCR5 and thus the virus cannot infect macs, ~10% of caucasions in US have this
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how do the new anti fusion drugs work?
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D peptides that bind to pocket on surface of trimeric gp41 and prevent fusion
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where does the provirus integrate in the host?
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random place
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describe the process of integration.
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viral integrase removes 2 or 3 nts from provirus ends, then makes staggered cut in cell DNA to have 5' ends overhang. 3' recessed ends of provirus join the 5' ends of cell DNA. Cellular repair system repairs the gap. Integrated proviruse is flanked by a 5 bp direct repeat and terminates with TG at 5' ends and CA at 3' ends
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where is TAR located?
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the R-U5 portion of the LTR
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fates of primary transcript?
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forms dimer, binds tRNA and becomes a daughter genome. GAG made. GAG-POL made. Spliced 1X to yield ENV, VPU,; some VIF and VPR. Spliced 2X to yield TAT, REV, and NEF; some VIF and VPR
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how can some Ab be enhancing to infection?
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some will bind the ENV protein on a virion but fail to neutralize it and then the FC receptor will allow it to be endocytozed by the cell it wants to infect
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when does cleavage of GAG and GAG-POL finish?
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after L type particle has been released
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what are the direct means of T cell killing? Indirect means?
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envelope mediated apoptosis, disruption of cell membrane, VPR induced G2 arrest and apoptosis, syncytium formation, accumulation of unintegrated vDNA. Cytolysis by HIV specefic CD8 T cells or NK cells, auto immune rxns of a humoral or cellular nature, incorporation into syncytia by neighboring infected cells, triggering apoptosis upon cell activation or cross linking of CD4 by gp120, apoptosis following interaction with nearby infected antigen presenting cell.
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what proteins are neurotoxic?
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gp120 and TAT
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how can CD8 cells be killed by HIV infection?
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CXCR4 induces macs to make TNF alpha and CD8 cells to make TNF alpha receptor, this leads to mac/CD8 interaction and thus killing of the CD8 T cell
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what immune related proteins can suppress infection?
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chemokines by binding to the co receptors on T cells to prevent infection
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importance of B cells in HIV?
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can infect B lymphocyts and stimulate them to replicate thus producing more IL6 and TNF which activates HIV provirus. Lymph nodes will swell and some cells in rectum and vagina are susceptable and important in sexual transmission of HIV
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how are "innocent bystander" CD4 cells killed?
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pick up an ENV protein, express it on MHC and are killed by CD8 or NK cell OR are induced to form syncytium by infected CD4 cell via the gp120/gp41
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what is responsible for clearing the early viremia in a typical case of AIDS?
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Ab to env proteins + complement OR CD8 killing of infected cells
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how can calmodulin play a role in pathogenesis?
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ENV cytoplasmic domain binds calmodulin and blocks lymphocyte development
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immunologic abnormalities seen in AIDS?
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depletion of CD4 from day one, decreased response to T and B cell antigens, decreased IFN gamma response, polyclonal B cell response, lymphopenia, decreased IL2 and IL2R, decreased CD8 cells and CTL responses, decreased NK function, decreased monocyte chemotaxis, decreased MHCI and MHCII presentation, induction of apoptosis
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T/F: TAT enters infected cell and alters trafficking in the cell.
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False it will enter the UNINFECTED cell and do this
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what cells serve as carriers for the virus to the brain?
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macs and monos
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what is the major target of the virus in the acute phase?
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T cells in the GALT which hold a lot of latency cells
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why is HIV replication restricted to a low percentage of T cells during chronic/latent infection?
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probly due to fact that virus needs a co receptor plus CD4 and replicate best in memory T cells (already stimulated by antigen) .
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in acute infection, how many T cells disappear in about 4 days.
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about 1/2
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describe the typical progressors.
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70 to 80% of cases. Primary infection includes viremia, flu sxs, rash, etc. Clinical latency is asympto or slight sxs, virus made daily, reduced viremia and lasts 8 to 10 yrs. Loss of FDC (?) and inability to control daily virus production leads to late disease. increase viremia, CD4 drops below 400 then below 200. onset of ARC, then 12 to 24 mos later, FRANK AIDS
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how are you designated as ARC?
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2 clinical sxs or 2 lab abnormalities
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what is the eclipse period? Window period?
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time from infection to PCR detection (10 to 15 days). Time from infection to serological detection (weeks)
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big lab finding in intial, acute infection.
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2nd week, the CD4/CD8 ratio will invert and stay inverted
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4 mechanisms that reduce initial viremia in typical progressors?
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Ab to virus and complement, CD8 cells, NK cells, FDC (follicular dendritic complex) of lymph nodes traps virus to reduce virus load
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describe the 3 parts to the clinical latency period.
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early stage occurs after initial viremia is cleared, effective FDC, duration of years. Intermediate stage lasts for several to many years, CD4 count drops, FDC begins to involute. Late stage disease is involution of lymphoid tissues, low CD4 count, ARC begins and viremia starts to increase.
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what can opportunistic infections in late stage disease do in terms of HIV production?
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tissue macs produce large amounts of virus at this point bc CD4's are depleted. Opportunistic infections increase the ability of tissue macs to produce HIV 1 in late stage.
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describe rapid progressors.
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develop Frank AIDS in 2 to 3 years after primary infection. 10 to 15% of cases. Viremia is not reduced and they may not have clinical latency.
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describe the long term non progressors.
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less than 5% of cases. Stable and normal T cell count. Essentially asympto, low virus load. Preservation of the architecture of the lymphoid tissues. Do not know why… maybe chemokines?
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describe long term survivors.
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very small percent of cases. Deletion in coreceptor gene and possible high levels of chemokines. 10% of caucasions have this deletion in CCR5 gene
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what cell is largely responsible for infection if HIV comes in contact with mucosal tissues (like rectum, vagina, uterus, etc)?
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dendritic cells
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what are the only body fluids with infective virus?
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blood and genital fluids, saliva has little virus : less than one infectious particle per mL
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how can HIV be transmitted to a newborn?
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either congenitally og perinataly
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how do you diagnose an infant?
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difficult bc they have antibodies from mom, do RT PCR, antigen test and a culture, need a specialized lab
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signs and sxs of ARC and AIDS.
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fever over 100, weight loss (probly from TNF - cachexia), adenopathy in two lymph node chains, severe fatigue, night sweats, dementia.
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what are the non specefic lab abnormalities in ARC?
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cytopenias, depressed CD4 lymphocyte to CD8 lymphocyte ratio, depressed CD4 cells, depressed lymphocyte blastogenesis response to mutagen, elevated Ig from polyclonal B cell activation, cutaneous anergy to multiple skin tests (decreases delayed type hypersensitivity)
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CDC classification of disease?
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group I is acute infection, group II is the latent, asympto infection, group III is latent infection with persistent generalized lymphadenopathy, group IV is symptomatic HIV infection
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80% of cases get this opportunistic infection that predicts serious disease to follow.
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oral candidias
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what infections can cause GI issues?
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HIV itself bc it likes the GALT, CMV is common, many others, note 85% have enteric infection
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organ systems that have major involvement?
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GI, endocrine, kidneys, heart, lungs, hematologic, ocular, and CNS
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what can cause CNS involvement?
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HIV itself or opportunistic infections.
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describe HIV associated dementia (AIDS encephalopathy).
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slowly progressive dementing neurologic CNS syndrome. Cognitive, motor, and behavioral issues. Macs, microglial cells, and derived cells involved bc of HIV infection. Neurons, oligos, and astrocytes are not infected but show cytopath with dysfuncion. neuro sxs may be present at initial dx. meningitis and vacuolar spinal cord degeneration may occur. 70 to 80% show neuropath at autopsy. once HAD begins, mean survival time is 6 mos. late phase shows ataxia, hypertonia, weakness, tremor, incontinence, and psychiatric disturbances. infants develop progressive encephalopathy and abnormalities seen as loss of developmental milestones.
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how can HIV cause brain cytopathology?
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HIV neurotropism via macs/monocytes. Infected endothelial cells may alter BBB. Induction of cytokines by infected cells (cytokines alter CNS function). Toxic effects of HIV proteins on CNS cells (TAT, gp120, gp41, NEF). Autoimmune and immunologic Dos. otherviruses in the CNS like herpes, papovirus.
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describe HIV induced neuropathology aside from HIV associated dementia.
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myelopathy of spinal cor. Peripheral neuropathy. Cerebral tumors and vascular lesions. PML from JC virus
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what HIV protein contributes to Kaposi sarcoma?
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TAT promotes growth of endothelial cells and causes an increase in angiogenic factor
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what are the most common opportunistic infections in AIDS patients?
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pneumocystis carinii pneumonia, esophageal candidiasis, CMV retinitis, disseminated mycobacterium avium intracellulare, mucocutaneous herpes simplex, cryptococcal meningitis, cerebral toxoplasmosis, and enteric cryptosporidiosis.
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three ways that CD8 cells specefic for HIV, fight HIV.
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make a factor that retards HIV1 replication (non cytocidal mechanism), release B chemokines to tie up coreceptor for M tropic HIV (noncytocidal), and cytocidal mechanisms
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what is the lab diagnosis protocol?
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three steps: EIA, if pos, another EIA, if pos, western blot to confirm - via capsid, gp41, or gp120/160 proteins
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methods to monitor patient?
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RT PCR to measure HIV RNA and thus viral load, check P24 core antigen, if it comes back after viremia, no good
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properties of NRTIs
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compete for RT and lead to chain termination - AZT or zidovudine
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describe the NNRTIs.
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bind to RT at a site distant from the active site, thus change confirmation of the RT and thereby inactivate the enzymatic activity
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what are the two classes of drugs that do not act on the RT?
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blockers of protease activity and the fusion blockers
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describe HAART and results.
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3 drugs and high doses. Usually 1 NNRTI and 2 NRTI together or 1 or 2 Pis and 2 NRTIs together. Must monitor CD4 and viral load.
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if elimination were possible via HAART, how long would it take? How many resting CD4 cells per million actives harbor latent HIV 1 as a source of future infection if HAART is stopped?
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10 to 70 years due to latently infected cells. 0.2 to 16 resting CD4 cells per million active CD4 cells
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potential benefits of early therapy? Risks?
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earlier suppression of viral replication, preserve immune function, prolong disease free survival, less risk of drug resistance if virus is suppressed, might decreasse risk of transmission. Early side effects, early resistance if suboptimal suppression as well as transmission of drug resistant strain, limits future options.
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potential benefits of late therapy? Risks?
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avoid negative effects on quality of life, preserve further treatment options, delay development of drug resistance. Risk irreversible immune system compromise, greater difficulty in viral suppression, increased risk of HIV transmission
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what are the indications for initiating HAART for the chronically infected HIV patient?
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if they are symptomatic, you always treat. If they are asympto with a CD4 under 200, treat. If they are asympto with a CD4 bw 200 and 350 offer treatment. If they are asympto with CD4 over 350 and HIV RNA is over 55,000 you can start therapy - some physicians do nc risk for AIDS in 3 yrs if untreated is over 30%. if they are asympto with CD4 over 350 and HIV RNA less than 55,000 then most defer therapy but monitor CD4 bc 3 yr risk for AIDS in untreated is less than 15%
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does the risk for viral transmission still exist with HAART?
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YES
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when would you use a triple NRTI regiment?
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when NNRTI based or protease inhibitor based regimen cannot be used
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special populations that do not get HAART?
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NONE, treat everyone, even pregnant women and children with HAART, note some of the actual drugs may be different but the principles are the same
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describe the timeline from beginning of HAART treatment with types of T cells repopulated.
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memory cells released from the lymphatics are the T cells that first appear in early weeks of treatment. After 3 wks or so, newly made T cells account for the bulk of replenished T cells which is about 75 million per day. It takes about 1 y for CD4 cells to repopulate the lymphatic tissues to normal levels
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what is a practice that is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%?
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male circumcision
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who should be tested for HIV?
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ppl with STDs, IV drug users, ppl who consider themselves at risk, prostitution, high risk sexual partners, transfusion bw 1978 and 1985, person planning marriage, if pt has indicator disease or symptoms of ARC/AIDS. Ppl in correctional system, ppl admitted to hospitals.
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what is a frequent complication that often brings the HIV pt to the doctor?
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pneumocystis carinii pneumonia
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clinical presentation of pneumocystis?
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dyspnea is CC, onset is days to wks, mild cough, white sputm, low fever, low sat O2
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what tests for pneumocystis?
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CXR will show ground glass in both lower lungs but can be variable and completely normal, sputum gram stain will show epi cells and assorted bacs, sputum culture will show normal flora. Definitive dx is silver stain, bronchoscopy with biopsy, broncho alveolar lavage, or induced sputum.
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pneumocystis treatment?
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TMP-sulfa for 3 weeks and start steroid AT SAME TIME
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evaluations for every new HIV patient?
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hx, PE, TB skin test, CBC, blood chemistry profile, RPR (syphillis), toxoplasma Abs, pelvic exam and PAP smear
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when would you order HIV RNA in a new patient instead of EIA and western blot?
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if you suspect acute primary infection bc Abs have not developed yet
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what phases of AIDS should definitely be treated?
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acute infection phase and AIDS phase, steady state/chronic phase is under debate
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according to Dr. Todd when do you treat steady state patients?
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if they are symptomatic, if CD4 is under 350, if HIV RNA is over 100,000, if they are pregnant
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examples of weak regimens?
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single drug therapy and inconsistent medication practices of the patient
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side effects of NRTIs?
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occasional neuropathy, pancreatitis, and myopathy as well as lactic acidosis (usually present with nausea and vomiting), and neutropenia (AZT)
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side effects of NNRTIs?
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rash that can be severe and hepatitis. Efavirenz is highly teratogenic
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side effects of protease inhibitors?
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lipodystrophy, hyperlipidemia, hyperglycemia, nausea, diarrhea
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common regimine for 2 NRTIs and 1 NNRTI
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efavirenz (NNRTI) + ZDV (AZT) or tenofovir + lamivudine (3TC) or emtricitabine
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common regimine for 2 NRTIs and 1 PI
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kaletra (PI) + ZDV (AZT) + lamivudine (3TC) or emtricitabine
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effect of zidovudine and stavudine together?
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antagonism
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effects of stavudine and didanosine together?
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increased risk of lactic acidosis, pancreatitis, and dangers in pregnancy
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effect of tenofovir and didanosine together?
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pancreatitis
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monitoring HIV protocol.
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monitor before starting treatment, before changing treatment, one month after changing treatment, every 3 months in stable patient
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best way to guage effectiveness of treatment?
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HIV RNA levels (ideally under 75)
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what are indicators for treatment failure and what do you do next?
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fail if HIV RNA stays over 500 repeatedly after 6 months on a regimen or if HIV falls under 500 but then comes back up and stays steadily over 500 for 6 months. Check to see if this is pt compliance issue or viral resistance. If viral resistance do viral susceptibility testing. hopefully you can come up with 3 drugs the pt is sensitve to, but this is often impossible but do the best you can
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what drug should you try to include if pt is pregnant? What special circumstances exist?
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zidovudine. Consider IV therapy for mom during delivery, consider treating the infant for 6 weeks
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what drug has a hypersensitivity syndrome?
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abacavir: fever, muscle aches, GI issues.
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describe the lipodystrophy syndrome seen in treatment.
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increased fat deposit to buffalof hump, abdomen, sometimes breast. Wasting in face, butt, and extremities
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protocol if a HCW gets a needle stick.
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test the source pt for HIV if not already known to be infected. Test exposed person at baseline, 6 wks, 12 wks, and 6 months. Do post exposure prophylaxis with AZT + 3TC + indinavir for 4 weeks.
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