2-3-10 HIV-1: Basic Virology and Pathobiology 1. Recognize HIV as a zoonosis from chimpanzees.

HIV is a zoonosis from chimpanzees !his "as decided #pon based on genome organization$ phylogenetic relatdness$ I%ing in the nat#ral host$ geographic coincidence$ and loo&ing at possible transmission ro#tes 'rosso(er to h#mans is belie(ed to be aro#nd 1)30 2. Describe HIV structure. !he o#termost coating of the (ir#s is a lipid bilayer that contains GP120 in trimer formation *the trimers are the acti(e attachment prod#ct !he inner coat is the capsid$ "hich contains P24 mar&ers +ithin the capsid are two sing e!stran"e" R#$s and three (ir#s specific enzymes *proteinase$ re%erse transcriptase$ and integrase, &. Describe the ife c'c e of HIV inc u"ing( Receptors on target ce s)*D4 an" **R+s !here are three different combinations of receptors on HIV$ "hich gi(es the (ir#s selective target cell tropism *different chemo&ine receptors target different cell types,: '%- . ''/0 -> binds macrophages '%- . '1'/- -> binds , ce s '%- . '1'/- or ''/0 -> binds , ce s !hese normal s#rface glycoproteins *'%-$ ''/23s$ and %'-4I56, are re7#ired for the f#nction of the ! cells and macrophages8 !h#s$ host cells are complicit in HIV infection Virus!specific enz'me functions)re%erse transcriptase- integrase- protease /e(erse transcriptase mediates the synthesis of pro(iral %69 from the HIV ss/69 genome Integrase integrates that pro(ir#s into the host cell genome Protease clea(es polyproteins into indi(id#al f#nctional HIV proteins and enzymes :or e;ample$ it clea(es en( polyprotein gp1<0 into en(elope glycoproteins gp120 and gp-1 Virus!specific regu ator' proteins $P./0*&: family of n#cleic acid editing enzymes that deaminates '= in retro(iral c%69 and ind#ces fatal m#tations HIV Vif binds and inhibits $P./0*& in humans ,RI123 is a cytoplasmic body component that restricts HIV infection in other primates$ pre(enting capsid shedding and release of (iral %69 ,etherin 4*D&156 inhibits HIV release from infected cells$ "hile HIV Vp# inhibits tethering acti(ity !heternin-mediated HIV retention refers to the ability of b#dded HIV (ir#s to be ta&en #p by the host cell again 4. .ut ine HIV rep ication "'namics an" its re ationship to the persistence of infection an" the emergence of "rug resistance.

HIV replication dynamics: 9c#te phase Imm#ne competence drops rapidly "ith primary infection to near the disease threshold !hen the platea#-phase infection *chronic phase, happens 'hronic phase 9bo#t 10 million (ir#s particles are made per day$ b#t most are eliminated !he half life of free (ir#s in plasma is less than 2 ho#rs and can be eliminated in 2 "ee&s In addition$ abo#t 1 billion '%-> ! cells are eliminated daily$ b#t most are resplaced 9cti(ated '%-> ! cells are the primary so#rce and target of free (ir#s ?Prod#cti(ely-infected@ cells ha(e a half life of 2 days and can be eliminated in 1 month If a retarded doctor *or non-compliant patient, administers a single dr#g treatment$ "ild type (ir#s con(erts to dr#g-resistant (ir#s after A#st 1- days8 !here are also ?long-li(ed@ infected ! cells that ha(e a 1-- "ee& half-life$ and ta&e 2-0 years to eliminate Bastly$ there are resting '%-> !-cells that ha(e half-li(es of months$ and ta&e decades to eliminate Cmergence of dr#g resistance: 4pontaneo#s n#cleic acid m#tation arises d#ring (iral replication and res#lts in 99 s#bstit#tions in (iral proteins !he extraordinary replication rate and lack of nucleic acid repair res#lts in a high m#tation rate !he res#ltant 99 s#bstit#tions target enzyme a(idity for indi(id#al dr#g inhibitors of enzyme f#nction !h#s$ complete s#ppression of (iral replication is re7#ired to pre(ent resistance 2. I"entif' properties of HIV that are associate" with immune e%asion an" immune "eficienc'. 6ot all HIV3s are e7#al$ d#e to their high mutation rate and mar&ed genomic (ariability HIV imm#ne e(asion: Preferential infection of HIV specific '%- ! cells /ed#ction in '%- ! cell f#nction Dacrophages archi(e HIV (irions HIV ma&es reg#latory gene prod#cts thatE Vpr: s#ppresses IB-12 prod#ction from macrophages Vif: inhibits 9PFBC'3 #ef: red#ces '%- e;pression and bloc&s apoptosis Vpu: inhibits tethering and 6G! cell acti(ation 7. Describe current concepts of HIV "isease pathogenesis. HIV-ind#ced Imm#ne %eficiency /apid early destr#ction of 00H of m#cosal memorty ! cells888

'%-> ! cells are depleted by "irect c'toto8icit'$ s'nc'tia formation$ and innocent b'stan"er effects %ecreased BD prod#ction of lymphoid prec#rsors %ecreased thymic o#tp#t of ne" ! cells *"ill see disr#pted thymic and lymph node architect#re, Carly se7#estration of '%-> ! cells in B63s Bater destr#ction of B6 architect#reimpaired clonal e;pansion 6H399 of gp-1 interferes "ith lipid rafts and ! cell acti(ation

!he pathophysiology of HIV can be simplified to as follo"s: HIV ca#ses cell deficiencyIdysf#nctionopport#nistic infections HIV infects '64 Dicrogliane#roencephalopathy InappropriateI#ncontrolled imm#ne acti(ationproliferati(e disorders *BIP*lymphocytic interstitial pne#monia,$ adenopathy$ hepatosplenomegaly, and systemic cyto&ine effects *fatig#e$ "asting,