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HIV I
cmbm exam V
64
Chemistry
Graduate
02/11/2010

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Term
how does HIV store its DNA? what is the DNA template it makes called?
Definition
enveloped RNA, the DNA template copy is called a "provirus" that enters nucleus and integrates. it is the template for mRNA and RNA genome
Term
what genus is HIV?
Definition
HIV is a member of the lentiviruses, (slow viruses)
Term
what strain of HIV is responsible for most strains of HIV in the US? where is it derived from?
Definition
HIV-1, which is related to SIV - simian immunodeficiency virus (SIV), a chimpanzee strains
Term
where does HIV-2 derive from?
Definition
sooty mangabey strains
Term
what are the 3 subgroups of HIV-1? how do subgroups arise? what are subtypes/clades? what is a CRF?
Definition
groups M, O, N; which are results of the virus crossing the species barrier 3x. subtypes or clades are classifications of HIV that share more than 25% of their genome. a CRF is a circulating recombinant form, where crossing over occurs between clades (clade BC is a CRF of clades B and C)
Term
what clade of group M predominates in the US?
Definition
clade B
Term
where is group O seen?
Definition
group O is seen in africa and india, not so much in the US
Term
what is group N a result of?
Definition
group N is the result of a recombination between SIV and HIV-1
Term
where is HIV-2 prevalent? how does it compare it HIV-1 in terms of virulence? how many clades does it have? how does an HIV-2 infection affect HIV-1 infections?
Definition
west africa, it is less virulent than HIV-1. it has 5 clades and infection with HIV-2 will provide some resistance against HIV-1
Term
what is the macrophage trophic/R5 virus? what kind of cells do they form? where do they replicate? what chemokine receptor do macrophage trophic/R5 viruses use?
Definition
this version of HIV (seen across subtypes), is isolated in early stages of infection and is responsible for most cases of transmission. it tends to be non-syncytia forming, (giant multinucleated cells resulting from cell-to-cell fusion b/c of viral protein). R5 viruses replicate in monocytes and primary T cells, but not CD4+ T cell lines. macrophage trophic/R5 viruses use CCR5 chemokine receptors
Term
when are T cell trophic/X4 viruses isolated? what cells do they replicate in? do they induce syncytia? what chemokine receptor do they have affinity for?
Definition
T cell trophic/X4 viruses are isolated in the late stages of infection and replicate in CD4+ T cell lines as well as primary T cells. they induce syncytia (due to cell-cell fusion), and are more cytopathic than R5 viruses. T cell trophic/X4 viruses have an affinity for CXCR4 chemokine receptors, which allows them to replicate in CD4+ T cell lines.
Term
what happens when T cell trophic/X4 viruses adapt to binding to the CXCR4 chemokine receptor?
Definition
they gain the ability to replicate in CD4+ T cell lines, but lose the ability to replicate in monocytes/macrophages
Term
what does the core of HIV contain?
Definition
the core of the HIV virus contains 2 copies of the RNA genome (surrounded by nucleocapsid protein p7), along with the reverse transcriptase polymerase which is all surrounded by the capsid protein/p24
Term
what is the matrix protein/p17 involved in? where is it located?
Definition
assembly. the matrix protein is located right inside the envelope
Term
what two components is the envelope glycoprotein composed of?
Definition
gp120: globular head of the protein in the envelope, which is the outermost protein responsible for attachment* and is also referred to as a surface unit (SU). gp41 is the transmembrane (TM) portion of the protein that mediates viral-cell fusion*
Term
what are the three essential retrovirus genes?
Definition
gag, pol, and env
Term
what does the gag gene encode?
Definition
it encodes the matrix protein (p17), capsid protein (p24), and nucleocapsid protein (p7). (gag stands for "group antigens")
Term
what does the env gene encode?
Definition
the surface subunit (gp120) and the transmembrane subunit (gp41)
Term
what does the pol gene encode?
Definition
the pol gene encodes proteins needed for viral replication: protease, RT, RNase, and integrase
Term
what is the result of the gag and pol genes overlapping?
Definition
there are 2 difference mRNA transcripts, the gag mRNA that runs the length of gag and becomes p17, p24, and p7 and the gag-pol mRNA that runs the length of gag and pol, which is translated to a different polyprotein, (of which protease is a part of, which frees itself and cleaves the other individual proteins from the polyproteins
Term
how is the env gene translated?
Definition
the env gene is translated as gp 160 and then that polyprotein is cleaved into gp120 (SU) and gp41 (TM)
Term
what are the HIV regulatory genes? what do they do?
Definition
tat, rev, nef, vif, vpu, and vpr all add to the virulence and pathogenicity of HIV
Term
what does tat do?
Definition
tat transactivates transcription of HIV
Term
what does rev do?
Definition
rev regulates RNA splicing and promotes export of mRNA into the cytoplasm
Term
what does nef do?
Definition
nef contributes to HIV's virulence by reducing MHC class I/CD4 cell surface expression, alters T cell signaling pathways, maintains high viral loads, alters actin organization, disrupts cell motility -> inhibits T cells ability to migrate toward chemokines = all essential for progression to AIDs
Term
what does vif do?
Definition
vif promotes assembly by blocking cellular antiviral proteins that produce hypermutations during cDNA transcription, (antiviral protein encourages polymerase to incorporate the wrong base, leading to defective viral particles)
Term
what does vpu do?
Definition
vpu facilitates the release of the virus by inhibiting the cellular retroviral protein (tetherin) that tethers virions to the infected cell and allows them to enter endosomes. it also decreases cell surface CD4
Term
what does vpr do?
Definition
vpr transports cDNA to the nucleus, interrupting the cell cycle and can target DNA repair enzymes for degradation
Term
what do the long terminal repeats (LTRs) contain?
Definition
HIV LTRs contain promoters, enhancers & sequences used as binding sites for transcription factors.
Term
how does an activated cell, such as a T cell behave differently in terms of LTR interaction once the cell is activated?
Definition
activated T cells produce more virus than resting T cells b/c activated cells produce more transcription factors that bind LTR & activate transcription of viral genes
Term
what are the host cell co-receptors HIV has affinity for?
Definition
CD4 and chemokine receptors (CCR-5 or CXCR-4)
Term
what viral protein is it's attachment mediated by? what is a this a target for and what is a problem with targeting it? what part of it specifically interacts with the chemokine receptors?
Definition
gp120 mediates viral attachment, which can be targeted by neutralizing antibodies; stopping the spread of infection (gp120 is however highly variable and thus producing antibodies for it can be difficult). the gp120 V3 loop interacts with the chemokine receptors, and it as well is variable (R5 -> X4 affinity)
Term
what is the sequence of HIV binding to cells, and what proteins are involved?
Definition
the gp120 binds to CD4, causing a conformational change that allows the CCR5 to bind to the V3 loop, causing a conformational change that allows gp41's fusion peptide to interact with the cells plasma membrane and initiate fusion (can be before or after endocytosis, pH-independent fusion) and the capsid is released
Term
what kind of fusion does gp41 mediate?
Definition
pH-independent fusion
Term
what kinds of infection can HIV produce?
Definition
HIV can infect cells and cause productive or latent infections, (of which there are 2 kinds: pre-integration/post-integration latency)
Term
what happens durng a productive HIV infection?
Definition
reverse transcriptase makes a cDNA provirus which then integrates into the host chromosome, leading to production of genomic RNA/mRNA as well as structural proteins and viral particles
Term
what happens durng a pre-integration latent HIV infection?
Definition
the cDNA provirus is made, but it remains inactive in the cell
Term
what happens durng a post-integration latent HIV infection?
Definition
the viral cDNA is integrated into host chromosomes and becomes latent. this is responsible for long term reservoir in memory T cells and causes chronic infection, (can be managed but not eradicated with antiretrovirals)
Term
what is brought together at the HIV assembly step? how does the new virus bud out?
Definition
the gag & pol polyprotein precursors and the viral genome are gathered in the HIV assembly step. it picks up lipid bilayer from the host cell via gp120/gp41 and buds off
Term
how does HIV mature in its final stage of release? is it infectious if this step does not take place? can this step be targeted with antiviral drugs?
Definition
HIV protease cleaves the gag-pol polyproteins into individual proteins in the maturation step, which once carried out, creates a mature, infectious HIV virus. if protease inhibitors interfere with this step, the virus will not be infectious.
Term
how does the function of HIV's reverse transcription affect it's variability? can the host immune system/drug therapy affect this?
Definition
the HIV reverse transcriptase makes many mistakes leading to mutations and the host's immune response/antiretroviral therapy (ARV) can provide selection of the most resistant mutations.
Term
what is a virulence factor of HIV related to its high variability within one particular infected individual? how does it happen? what does this lead to?
Definition
HIV generates different quasispecies within an infected individual. this can be a result of inconsistent RT activity, exposure to various clades and subsequent mutuation accumuation, and immune system/drug selection. this variability allows HIV to change its antigenicity and resist antimicrobials.
Term
what are advantages of HIV genetic variability?
Definition
genetic variability allows the virus to escape immune recognitio and evolve to resist antiretroviral therapy (why no HIV is just given one drug)
Term
what do mutations in gp120 allow HIV viruses to do?
Definition
mutations in gp120 allow HIV viruses to go from infecting R5 viruses to X4 viruses
Term
what do mutations in gp41 allow HIV viruses to do?
Definition
mutations in gp41 allow the virus to alter fusogenicity of the cells it infects: nonsyncytia-inducing -> syncytia-inducing
Term
what is the evolution of the HIV virus in a host during the early stages of infection?
Definition
R5 (macrophage tropic viruses) bind CCR-5 and infect in a non-cytopathic, non-syncytia-inducing manner
Term
what is the evolution of the HIV virus in a host during the late stages of infection?
Definition
X4 viruses (T cell tropic viruses) bind CXCR-4 and infect cells in a cytopathic, syncytia-inducing manner
Term
what receptors do CD4+ primary T cells express, which HIV cell-tropic viruses cen infect them?
Definition
CD4+ T lymphocytes both express CCR-5 and CXCR-4, therefore they can be infected by both R5/X4 viruses
Term
what cells can T-cell tropic X4 viruses infect?
Definition
all T-cell lines and CD4+ lymphocytes, b/c they express the CXCR-4 chemokine receptor
Term
what cells can macrophage tropic R5 viruses infect?
Definition
monocytes and CD4+ T lymphocytes, b/c they both express the CCR-5 chemokine receptor
Term
can an HIV virus have affinity for both CXCR-4 and CCR-5 chemokine receptors?
Definition
yes, these are referred to as "dual-trophic"
Term
what are the different kinds of antiretrovirals (5 classes)?
Definition
nucleoside reverse transcriptase inhibitors (NRTIs); nucleoside analogues, non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, attachment/entry inhibitors (fusion, CCR5 inhibitors), and integrase inhibitors
Term
what steps of the HIV viral cycle are not yet targeted by antivirals?
Definition
transcription, translation
Term
how do NRTIs work? can they affect cells other than those virally infected?
Definition
nucleoside reverse transcriptase inhibitors such as zidovudine (azigothymidine/AZT - thymidine analogues) which must be phosphorylated 3x by a cellular kinase to be activated, and once it is, it binds and inhibits the RT. this results in chain termination, b/c the DNA strand cannot accept the next base (no OH). these (and most) antivirals have higher affinity for viral than cellular polymerase and usually only damage infected cells.
Term
what is an example of viral resistance to NRTIs? what gene encodes this resistance? is there an NRTI for every nucleotide?
Definition
the HIV RT can be mutated, keeping the drug from binding in a form of resistance mediated by the pol gene. there is an NRTI for every nucleotide.
Term
how do NNRTIs work? do they work on all kinds of HIV? can resistance be developed to NNTRIs?
Definition
non-nucleoside reverse transcriptase inhibitors such as nevirapine do not require phosphorylation for activation, and bind to the RT at a site distinct from the active site, yet still are inhibitory. NNRTIs only work on HIV-1, not HIV-2. NNRTI resistant mutations can occur, but they are different than mutations that affect NRTIs
Term
how do protease inhibitors work?
Definition
protease inhibitors such as saquinavir are small molecules that bind in the enzymatic pocket of the HIV protease. inhibition of this protease inhibits the maturation of infectious viral particles
Term
how is resistance developed to protease inhibitors? can cross resistance occur?
Definition
the pol gene can mutate, causing the protease to be resistant to inhibition. cross resistance between proteast inhibitors is common.
Term
how do fusion inhibitors work?
Definition
fusion inhibitors such as enfuvirtide (36 AA peptide that binds gp41) block the conformational change that occurs after gp120 binds to CD4, and gp41 is thus unable to mediate fusion between the viral envelope & host cell plasma membrane. this inhibits viral entry.
Term
how does the CCR5 inhibitor work? what is significant about it?
Definition
maraviroc, a CCR5 inhibitor binds CCR5 and alters its conformation - inhibiting HIV binding. it is the only licensed antiretroviral that binds to a host protein.
Term
what are mechanisms of resistance for CCR5 inhibitors such as maraviroc?
Definition
HIV can develop an affinity for CXCR4 chemokine receptors (more pathogenic) or for the drug-bound CCR5 conformation. also, if someone has pre-existing variants that use CXCR4, that population will increase
Term
are there drugs being developed to block HIV binding to both T cells and macrophages?
Definition
TNX-355 is a monoclonal antibody drug in development that is specific for the CD4 receptor, therefore blocking HIV binding to both T cells and macrophages
Term
what is PRO 140? vicriviroc?
Definition
PRO 140 is a monoclonal antibody drug in development that is specific for the CCR5 coreceptor, (acts like maraviroc). vicriviroc is another drug in development that also binds to CCR5
Term
what is raltegravir? what does it inhibit?
Definition
an integrase inhibitor which binds to integrase → preventing integration of DNA provirus
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