HIV I

how does HIV store its DNA? what is the DNA template it makes called?
enveloped RNA, the DNA template copy is called a “provirus” that enters nucleus and integrates. it is the template for mRNA and RNA genome
what genus is HIV?
HIV is a member of the lentiviruses, (slow viruses)
what strain of HIV is responsible for most strains of HIV in the US? where is it derived from?
HIV-1, which is related to SIV – simian immunodeficiency virus (SIV), a chimpanzee strains
where does HIV-2 derive from?
sooty mangabey strains
what are the 3 subgroups of HIV-1? how do subgroups arise? what are subtypes/clades? what is a CRF?
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)
what clade of group M predominates in the US?
clade B
where is group O seen?
group O is seen in africa and india, not so much in the US
what is group N a result of?
group N is the result of a recombination between SIV and HIV-1
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?
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
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?
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
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?
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.
what happens when T cell trophic/X4 viruses adapt to binding to the CXCR4 chemokine receptor?
they gain the ability to replicate in CD4+ T cell lines, but lose the ability to replicate in monocytes/macrophages
what does the core of HIV contain?
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
what is the matrix protein/p17 involved in? where is it located?
assembly. the matrix protein is located right inside the envelope
what two components is the envelope glycoprotein composed of?
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*
what are the three essential retrovirus genes?
gag, pol, and env
what does the gag gene encode?
it encodes the matrix protein (p17), capsid protein (p24), and nucleocapsid protein (p7). (gag stands for “group antigens”)
what does the env gene encode?
the surface subunit (gp120) and the transmembrane subunit (gp41)
what does the pol gene encode?
the pol gene encodes proteins needed for viral replication: protease, RT, RNase, and integrase
what is the result of the gag and pol genes overlapping?
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
how is the env gene translated?
the env gene is translated as gp 160 and then that polyprotein is cleaved into gp120 (SU) and gp41 (TM)
what are the HIV regulatory genes? what do they do?
tat, rev, nef, vif, vpu, and vpr all add to the virulence and pathogenicity of HIV
what does tat do?
tat transactivates transcription of HIV
what does rev do?
rev regulates RNA splicing and promotes export of mRNA into the cytoplasm
what does nef do?
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
what does vif do?
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)
what does vpu do?
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
what does vpr do?
vpr transports cDNA to the nucleus, interrupting the cell cycle and can target DNA repair enzymes for degradation
what do the long terminal repeats (LTRs) contain?
HIV LTRs contain promoters, enhancers & sequences used as binding sites for transcription factors.
how does an activated cell, such as a T cell behave differently in terms of LTR interaction once the cell is activated?
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
what are the host cell co-receptors HIV has affinity for?
CD4 and chemokine receptors (CCR-5 or CXCR-4)
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?
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)
what is the sequence of HIV binding to cells, and what proteins are involved?
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
what kind of fusion does gp41 mediate?
pH-independent fusion
what kinds of infection can HIV produce?
HIV can infect cells and cause productive or latent infections, (of which there are 2 kinds: pre-integration/post-integration latency)
what happens durng a productive HIV infection?
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
what happens durng a pre-integration latent HIV infection?
the cDNA provirus is made, but it remains inactive in the cell
what happens durng a post-integration latent HIV infection?
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)
what is brought together at the HIV assembly step? how does the new virus bud out?
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
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?
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.
how does the function of HIV’s reverse transcription affect it’s variability? can the host immune system/drug therapy affect this?
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.
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?
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.
what are advantages of HIV genetic variability?
genetic variability allows the virus to escape immune recognitio and evolve to resist antiretroviral therapy (why no HIV is just given one drug)
what do mutations in gp120 allow HIV viruses to do?
mutations in gp120 allow HIV viruses to go from infecting R5 viruses to X4 viruses
what do mutations in gp41 allow HIV viruses to do?
mutations in gp41 allow the virus to alter fusogenicity of the cells it infects: nonsyncytia-inducing -> syncytia-inducing
what is the evolution of the HIV virus in a host during the early stages of infection?
R5 (macrophage tropic viruses) bind CCR-5 and infect in a non-cytopathic, non-syncytia-inducing manner
what is the evolution of the HIV virus in a host during the late stages of infection?
X4 viruses (T cell tropic viruses) bind CXCR-4 and infect cells in a cytopathic, syncytia-inducing manner
what receptors do CD4+ primary T cells express, which HIV cell-tropic viruses cen infect them?
CD4+ T lymphocytes both express CCR-5 and CXCR-4, therefore they can be infected by both R5/X4 viruses
what cells can T-cell tropic X4 viruses infect?
all T-cell lines and CD4+ lymphocytes, b/c they express the CXCR-4 chemokine receptor
what cells can macrophage tropic R5 viruses infect?
monocytes and CD4+ T lymphocytes, b/c they both express the CCR-5 chemokine receptor
can an HIV virus have affinity for both CXCR-4 and CCR-5 chemokine receptors?
yes, these are referred to as “dual-trophic”
what are the different kinds of antiretrovirals (5 classes)?
nucleoside reverse transcriptase inhibitors (NRTIs); nucleoside analogues, non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, attachment/entry inhibitors (fusion, CCR5 inhibitors), and integrase inhibitors
what steps of the HIV viral cycle are not yet targeted by antivirals?
transcription, translation
how do NRTIs work? can they affect cells other than those virally infected?
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.
what is an example of viral resistance to NRTIs? what gene encodes this resistance? is there an NRTI for every nucleotide?
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.
how do NNRTIs work? do they work on all kinds of HIV? can resistance be developed to NNTRIs?
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
how do protease inhibitors work?
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
how is resistance developed to protease inhibitors? can cross resistance occur?
the pol gene can mutate, causing the protease to be resistant to inhibition. cross resistance between proteast inhibitors is common.
how do fusion inhibitors work?
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.
how does the CCR5 inhibitor work? what is significant about it?
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.
what are mechanisms of resistance for CCR5 inhibitors such as maraviroc?
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
are there drugs being developed to block HIV binding to both T cells and macrophages?
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
what is PRO 140? vicriviroc?
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
what is raltegravir? what does it inhibit?
an integrase inhibitor which binds to integrase > preventing integration of DNA provirus
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