Microbiology 38 Hiv

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Micro 38: Human Retroviruses

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Micro 38: Human Retroviruses

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associated with leukemia and lymphoma

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HTLV-1

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causes AIDS

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HIV

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HIV binds to

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CD4 molecule found on TH cells and monocytes

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latency of HIV

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usually long ~10 years

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pneumonia associated with end stage AIDS

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Pneumocystis jiroveci

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What makes AIDS unique amongst infectious diseases

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1. uniformly fatal 2. most devistating effects not directly caused by the HIV agent

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retrovivuses are ___________ viruses that contain _____________ enzyme

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RNA viruses, contain reverse transcriptase

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structure of RNA molecule

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small sphrical virion surrounded by lipid envelope

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retrovirus genome

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2 identical RNA molecules

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how does retrovirus RNA resemble eukaryotic RNA

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has a cap at 5' end and poly A sequence at 3' end

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gag gene

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encodes core proteins

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pol gene

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encodes reverse transcriptase (RNA dependent DNA polymerase) and integrase which is required for integration of viral DNA into host genome

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integrase

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required for integration of viral DNA into host genome

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env gene

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encodes gp120 and gp41

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pro gene

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encodes a protease necessary for cleaving and activation Gag and Pol proteins to active forms

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4 genes required for replicaton of retrovirus

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gag, pol, env, pro

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3 major routes of HIV transmission

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sexual contact, IV drug use, vertical (mother to baby)

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accounts for 1/3 HIV transmissions

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heterosexual transmission

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accounts for 1/6 HIV transmissions

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IV drug use

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why are hemophiliacs at higher risk for bloodbourne viruses

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they get factor VIII from plasma pooled from thousands of donors; they are more likely to get hep B/C than HIV because of more rigorous screening for HIV antibodies

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most common form of spread HIV in most countries outside US and europe

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heterosexual transmission

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transmission risk between infected and unifnected spouses

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~0.3%

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transmission rates are higher between spouces when

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when infected partner has higher viral load,

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these men are more suscptable to HIV invfection

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uncircumcised

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sex associated with ___________ more often results in HIV transmission

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trauma

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CCR5 and HIV

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this gene is defective in 10% of europeans. If homozygous defective (~1% of the 10%) ; a strong but not absolute resistance to HIV infection is confered

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heterozygous CCR5 mutants and aids

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have slower progression

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homozygous CCR5 mutants and AIDS

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have high level of resistance to infection

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can interrupt maternofetal transmission of HIV

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antiretroviral drugs

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transmission rate from mother to baby if HIV is untreated

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~25-33% (less than 1% if treated)

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needle stick HIV transmission risk

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~0.3%

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entry of HIV

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poorly understood, may be within infected cells or even as free virus

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spread of HIV to nonsexual contacts (both family and professional, social)

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virtually nonexistant

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major cell types infected by HIV

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helper T lymphocytes and monocytes

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faciltates early HIV binding to CD4 molecule

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gp120

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antibodies to this can prevent HIV infection

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gp120

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after CD4 binding to gp120 what happens

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gp12 engages either CCR5 or CXCR4 for secondary binding

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physiological purpose of CCR5 and CXCR4

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binding site for chemokines

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binding of gp120 to CCR5 or CXCR4 triggers what

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conformational change in gp41

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fusion of viral envelope to cell membrane is facilitated by

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gp41 and target cell membrane

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long terminal repeat

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result of reverse transcriptase converting the ends of viral genomic RNA

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joins ends of LTR to host DNA

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integrase

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provirus

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integrated viral genetic material analagous to a cellular gene

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how is the progeny virus synthesized

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the integrated viral DNA is transcribed and is directed y signals from LTR section. The viral RNA molecules are produced and some are used for synthesis of viral protiens while others are used for genomes of progeny. The new virus gets its enevlope by passing through host membrane

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latent phase

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infected cells contain provirus but do not express viral RNA or proteins

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transactivation

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expression of HIV macromolecules is subject to regulation by viral gene products that operate as soluable elements in trans

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regulates transativation

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tat and rev

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transactivating factors greatly

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enhance expression of viral RNAs and proteins

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Tat protein

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accellerated transcription of viral RNA by host RNA ply

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Rev protein

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enhances transport of some viral RNAs from nucleus to cytoplasm

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Nef protein

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downregulates cell expression of MHC 1 molecules

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Vif protein

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facilitates destruction of ABOBEC 3G which is a cellular protein that is capable of blocking reverse transcription when packaged in the viral particle

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Vpu

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downregulates IFN induced cellular protein tetherin

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tetherin

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inhibits release of viral particles from cell surface

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3 ways HIV persists in host despite antiviral immune response.

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1. viral gene products are relatively invisable to immune response 2. viral may change antigenic spcificity 3. virus replicates in lymph follicles where virus directed immune cells cannot migrate freely

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which HIV gene shows much variation ; which are stable

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Env shows many variations, Gag and Pol are fairly stable

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unique and protective (to the virus) features of HIV envelope glycoproteins

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extensive polysaccride coating (less immunogenic) and hypervariable antigenic configurations

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2 groups of retroviruses that cause human disease

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HTLV group and Lentiviruses (HIV1-2)

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HTLV1

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causes T cell leukemias and lymphomas

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HTLV 2

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associated with cases of hairy cell leukemia

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HIV1

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causative agent of aids

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HIV 2

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related to HIV1 causes AIDS in West Africa

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IL-2

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stimulates growth of T lymphocytes in vitro

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other infections (besides leukemia) associated with HTLV1

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progressive spinal cord diseases

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what determines if an acute HIV infection will persist

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if immune response arrives before the first burst of the infection "dies out"

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kills cells infected with HIV1

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Tc cells ; antibody mediated cellular cytotoxicity, or viral replication itself

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immune challenge of fighting HIV

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the cells you are making to combat the virus are the same cells that are fueling it.

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chronic phase is reached when

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relative balance between immune response and viral replication

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99% of HIV replication is said to occur where?

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CD4+ lymphocytes in lymphoid organs

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normal, symptomatic and advanced, late stage HIV T cell counts

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~1000 ; ~500 ; ~200 ; ~50

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why can HIV effect other cell types besides TH cells

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CD4 can be found on cells monocyres NK cells and some macrophages making them sucesceptable to infection

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AIDS conditions are characterized by

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diarrhea, oral candidasis, weight loss, fever

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category A HIV infection

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asymptomatic, primary, or persistant generalized adenopathy

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category B HIV infection

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oropharyngeal candidasis, cervical dysplasica, constitutional symtpoms (diarrhea >1mo); oral hairy leukoplakia, recurrent herpes zoster, ITP, listerosis, PID …etc…

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category C HIV infection

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these are the bad ones; pretty much all disseminated viral/fungal/bacterial infections and more widespread candidasis and cancers such as kaopsi sarcoma, HL, NHL and burkitt will develop

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most common presenting clinical manifestation of AIDS in untreated pt

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P. jiroveci pneumonia (M tuberculosis if in zimbabwe)

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associated with CNS manifestations of AIDS

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T. gondii ; Cryptococcus neoformans

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evidence of HIV infection is based on presense of

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HIV antiviral antibodies

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initial HIV test

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ELISA (enzyme linked immunosorbent assay)

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repeat (conformatory HIV test)

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western blot (immunoblot)

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first approved drug for HIV

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AZT (zidovudine)

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drug class of first antiretroviral drugs

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reverse transcriptase inhibitors

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NNRTIs

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inhibit reverse transcriptase by bining to the enzyme at a site distant from the active site

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dianosine, zalcitabine, stavudine, lamivudine, emtricitabine, tenofovir

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reverse transcripase inhibitors ; cause premature termination of growing strands of viral DNA

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nevirapine, efavirenz, delavirdine

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NNRTIs

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ralegravir

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viral integrase inhibitor

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ritonavir, indinvir, sauinavir, amprenavir, nelfinavir, arunavir, lopinavir

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viral protease inhibitors

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CCR5 inhibitors

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can prevent entry of HIV particle, require susceptable testing

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HIV therapy should include

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3-4 drugs of varying mechanism for greatest outcome