HIV and Bacteria (Week 2) Flashcards
Essential parts of HIV virion
1) 2 identical ssRNA pieces (diploid)
2) Nucleocapsid (NC) proteins
3) 3 essential enzymes: protease, reverse transcriptase, integrase
4) Capsid proteins (CA) of which major one is p24 (forms icosahedral capsid)
5) Matrix proteins under envelope (like influenza)
6) Surface glycoproteins: gp120, gp41
HIV genome
1) Long terminal repeats (LTRs) at two ends: sticky ends used by integrase for insertion into host DNA and promoter/enhancer once incorporated into host DNA
2) Gag: major structural proteins like nucleocapsid (NC), p24 (capsid), matrix (MA)
3) Pol: protease, integrase and reverse transcriptase
4) Env: envelope proteins that form gp120 and gp41 once glycosylated
5) Tat: viral transactivator protein that activates transcription
6) Rev: binds env gene to decrease splicing in order to REV up reading of gag, pol, and env to produce more virions (also produces vif, vpu, vpr)
7) Nef: unclear, can both positively and negatively regulate HIV expression
Where is there a high concentration of hypervariable regions?
1) gp120 (within the env gene; specifically the V3 loop): this is why it is so hard to make a vaccine, because envelope constantly changing
2) Gene for reverse transcriptase: this is why RT inhibitors don’t work well either
Progression to AIDS in 3 stages
1) Acute viral illness like mononucleosis (fever, lymphadenopathy, pharyngitis, etc) about 1 month after initial exposure; viremia, viruses spread to infect lymph nodes and macrophages, then HIV-specific immune response arises resulting in decreased viremia and resolution of symptoms; HIV replication still continues in lymph nodes and peripheral blood
2) Clinical latency for 8 years where no symptoms (other than maybe lymphadenopathy) but HIV continues to replicate and destroy CD4 T cells; then begin to get bacterial and skin infections and constitutional symptoms (fever, weight loss, night sweats)
3) AIDS (CD4 T cells < 200 and/or AIDS-defining opportunistic infection) for 2 years before death
Mechanisms of T-cell death caused by HIV
1) When virion budding, gp160 binds adjacent CD4 receptors on same T cell and tear membrane
2) Infected cell to noninfected cell fusion via gp160 causing multinucleated giant cells (as many as 500 cells can fuse!)
3) GP160 marks T cell as “non-self” to cause autoimmune destruction by CD8 T cells
As CD4 T cells are lost during HIV infection, what happens to other parts of immune system?
1) Multinucleated giant cells form and allow virus to pass from cell to cell protected from circulating antibodies
2) HIV doesn’t infect B cells but there is somehow polyclonal activation of B cells causing outpouring of immunoglobulins –> hypergammaglobulinemia causes immune complex formation and autoantibody production –> also diminished ability to produce antibodies in response to new antigens
3) HIV infects monocytes and macrophages and doesn’t kill them but (1) creates reservoir of HIV to replicate, and (2) causes carries HIV across BBB to cause brain disease
Diseases seen in AIDS
Neurologic: AIDS dementia complex, aseptic meningitis
Malignancies: B cell lymphoma, Kaposi’s sarcoma
Opportunistic infections: mycobacterium tuberculosis, mycobacterium avium-intracellulare (MAI), candida albicans (thrush), cryptococcus neoformans, histoplasma capsulatum, coccidioides immitis, herpes zoster, oral hairy leukoplakia, herpes simplex, CMV (retinitis), pneumocystic carinii pneumonia (PCP), toxoplasm gondii, cryptosporidium, microsporidia, isospora belli
Fuzeon (enfuvirtide)
Drug that prevents fusion of HIV and cell membrane (prevents 6-helix bundle from forming)
Maraviroc (Selzentry)
Drug that binds allosterically to CCR5 to inhibit it, so can no longer bind gp120 so HIV cannot enter cell
Note: before giving this, should check to make sure patient actually has CCR5 virus (M-tropic) because this drug won’t help if patient has CXCR4 virus!
Ibalizumab
Drug that binds CD4 (anti-CD4 monoclonal antibody) so HIV cannot get into cell
Tropism of HIV
M-tropic: macrophages contain only CCR5; in early stage of HIV, viruses grow in macrophages
T-tropic: T cells (mature?) contain only CXCR4; in later stage of HIV, viruses grow in T cells
Note: primary T cells contain both CCR5 and CXCR4
What does it mean if someone has a CXCR4-using HIV virus?
Bad prognostic sign
Doesn’t mean CXCR4-using virus is the cause of disease progression –> CXCR4-using virus may actually be LESS fit, and thus arise late in disease when immune system is damaged
What mutations result in a person being very resistant to HIV infection?
delta32ccr5
Deletion 32 in the CCR5 coreceptor gene
Homozygous for deletion confers resistance to HIV infection
Heterozygous for deletion means will progress to AIDS slower
Nucleotide reverse transcriptase inhibitors (NRTI)
Drugs that are nucleotide analogues that are chain terminators
Azidothymidine (AZT) and lamivudine (3TC) used together because if you become resistant to one you become susceptible to the other
Non-nucleotide reverse transcriptase inhibitors (NNRTI)
Drugs that are not nucleotide analogues, but actually bind allosterically to reverse transcriptase protein to inactivate it
RNaseH
Degrades RNA strand of an RNA-DNA hybrid, which is necessary as RNA –> dsDNA
Integrase inhibitors
Drug that inhibits integrase (which is an enzyme that allows HIV to integrate into terminally differentiated cells and not just dividing cells like other viruses)
Ex: Raltegravir
Protease inhibitors
Prevent viral assembly because can’t process structural proteins –> no virus budding
Note: probably do more than just inhibit proteases
Ex: Saquinavir
4 steps that HIV drugs target
1) Entry: enfuvirtide (Fuzeon) blocks fusion, maraviroc (Selzentry) blocks CCR5
2) Reverse transcription: NRTIs and NNRTIs
3) Integrating genetic info into cell: raltegravir (Isentress)
4) Proteases allow virus to be put together and bud: protease inhibitors
Our host cell’s intrinsic immunity that fights off HIV and the HIV mechanisms that have evolved to fight back
1) APOBEC3G in host cell is a cytosine deaminase that causes hypermutation to try to kill virus, but HIV has vif that destroys APOBEC3G
2) The TRIM5-alpha that humans have is bad and has one mutation that prevents it from doing its original job which was to prevent HIV uncoating (monkey TRIM5-alpha DOES prevent HIV uncoating!)
3) Tetherin in host cell prevents (enveloped) viruses from leaving the cell. HIV’s vpu gene binds and degrades tetherin
Window period
Don’t yet have antibodies to HIV, but do have very high viral load
Note: usually you develop antibodies within the first few days of infection, but with HIV don’t develop antibodies until 6 weeks later
