Project?Summary?? ? Viruses? exploit? cell? surface? receptors? to? gain? access? to? the? interior? of? host? cells.? These? receptors? are? now? appreciated?as?major?obstacles?to?virus?spillover,?a?process?by?which?animal?viruses?move?from?one?host?species? into?another.?In?the?many?documented?examples?of?spillover,?viruses?typically?use?the?same?entry?receptor?in?the? old? and? new? host,? but? need? to? acquire? mutations? to? make? them? compatible? with? the? specific? ortholog? of? that? receptor? found? in? the? new? host.? Diverse? viruses? such? as? avian? influenza? viruses,? rodent? arenaviruses,? MERS? coronavirus,?and?possibly?SARS?and?Ebola?viruses?all?overcame?receptor?barriers?in?humans?as?they?transmitted? from? their? animal? hosts.? Here,? we? explore? the? following? hypothesis? of? disease? emergence:? viruses? can? more? easily? overcome? receptor? barriers? when? host? individuals? of? specific? receptor? genotypes? come? into? contact.?We?use?the?simian?immunodeficiency?virus?(SIV)?reservoir?in?African?primates?as?a?model?for?this,?and? investigate?the?role?that?the?SIV/HIV?receptors,?CD4?and?CCR5,?play?in?limiting?spillover?of?these?viruses.?Primate? lentiviruses?(SIV/HIV)?are?an?excellent?model?because?the?HIV/SIV?receptors?CD4?and?CCR5?serve?as?significant? host?barriers?to?the?spillover?of?these?viruses?between?primate?species.?We?and?others?have?shown?that?(1)?CD4? and?CCR5?vary?from?one?species?to?the?next?in?their?ability?to?serve?as?receptors?for?HIV/SIV,?and?(2)?different? individuals? within? primate? populations? have? different? virus? susceptibilities? because? of? receptor? polymorphisms.? We?leverage?genetic?data?and?biomaterials?from?approximately?1,300?primates?representing?15?different?species,? and? a? broad? array? of? different? HIV? and? SIV? variants,? to? test? the? idea? that? certain? individuals? within? populations? are?better?poised?to?transmit?or?receive?infection?during?spillover?scenarios.?The?main?innovation?of?the?proposal? is? to? define? the? role? of? host? genetic? variation? in? disease? emergence,? beyond? a? strict? focus? on? the? evolutionary? properties? of? viruses.? The? project? will? aid? in? our? understanding? of? the? evolutionary? processes? leading? to? the? emergence?of?new?diseases.?It?is?significant?because?the?work?here?will?be?widely?applicable?to?diverse?viruses? beyond?lentiviruses,?and?to?host?barriers?beyond?receptor?blocks.? ? ? ?

R01AI137011

2018-01-10

2022-12-31