CLINICAL IMPLICATIONS OF BASIC RESEARCH Elizabeth G. Phimister, Ph.D., Editor Immunotherapy for HIV Infection Robin A. Weiss, Ph.D.

un#er!stan#in of ho, these mono%$ona$ anti"o#ies "in# to the HI3 enve$ope ,i$$ $ea# to the #esi n of prote%tive immuno ens& This important oa$ has yet to "e rea$i+e#* "ut the ne, stu#ies in#i!%ate that the same mono%$ona$ anti"o#ies %an "e use# therapeuti%a$$y& A rapi# an# profoun# %$ear!an%e of virus from the periphera$ "$oo# of in!fe%te# ma%a1ues after the infusion of one or more mono%$ona$ anti"o#ies ,as o"serve# "y "oth Barou%h et a$&' an# Shin ai et a$&0 A$thou h the virus eventua$$y reappeare# as $eve$s of mono%$ona$ anti"o#ies ,ane# over time* in sev!era$ anima$s vira$ $eve$s #i# not re"oun# to their pretreatment $eve$* in#i%atin that the set point of the vira$ $oa# ,as permanent$y re#u%e#& The e/a%t me%hanism throu h ,hi%h mono! The provision of immunotherapy throu h anti!"o#y infusion has a venera"$e an# va$ua"$e re%or# in the treatment of infe%tious #isease& In '()'* the first No"e$ Pri+e in Physio$o y or Me#i%ine ,as a,ar#e# to Emi$ von Behrin for -serum therapy* espe%ia$$y its app$i%ation a ainst #iph!theria*. an# more re%ent$y* poste/posure prophy!$a/is a ainst ra"ies has %om"ine# anti"o#y treatment ,ith a%tive immuni+ation& A$thou h immunotherapy for %hroni%* persistent infe%tions is more pro"$emati%* ne, stu#ies "y Barou%h et a$&' an# Shin ai et a$&0 on the treatment of rhesus ma%a1ues in#i%ate that mono%$ona$ anti!"o#ies sho, mu%h promise in %$earin infe%tion ,ith a hy"ri# form of the simian immuno#efi!%ien%y virus 2SI34 that "ears the enve$ope anti ens of the human immuno#efi%ien%y virus type ' 2HI3!'4 an# SI3* referre# to as SHI3& 5urin the past fe, years* severa$ nove$ mono%$ona$ anti"o#ies that have "een #erive# from %e$$s from HI3!infe%te# persons %om"ine e/traor#inari$y hi h poten%y ,ith "rea#th in neu!tra$i+in #iverse strains of HI3!'& The impetus for this ,or6 has %ome from va%%ine resear%h that is "ase# on the premise that a "etter

%$ona$ anti"o#ies ,or6 remains to "e e$u%i#ate#& Their effe%tiveness as potent neutra$i+ers of in!fe%tious HI3 parti%$es has "een esta"$ishe#* "ut it is a$so thou ht that they may re#u%e the num!"er of virus!pro#u%in %e$$s& Su%h #estru%tion of the fa%tories of virus pro#u%tion 2Fi & '4 may "e me#iate# throu h anti"o#y! #epen#ent %e$$u$ar %ytoto/i%ity or throu h %e$$ $ysis "y %omp$ement& The num"er of %e$$s infe%te# ,ith vira$ 5NA

in $ymph no#es an# mu%osa a$so #iminishe#* a%!%or#in to ana$ysis of "iopsy spe%imens7 one anti"o#y in parti%u$ar ,as effe%tive in re#u%in vira$ $oa# an# the num"er of infe%te# %e$$s&' A #ifferent therapeuti% immuni+ation strate y ,as re%ent$y reporte# "y Hansen et a$&*8 ,ho infe%te# Figure 1. A CD4+ T Lymphocyte Infected with HIV. The host cell (green) is infected by and rod!ces "#$ articles (red). Recent st!dies indicate that otent monoclonal antibodies not only ne!tral%ize released &ir!s b!t may hel to destroy infected cells. The scanning electron microgra h )as obtained by Dr. Da&id "oc*ley from an infected c!lt!re ro&ided by Dr. Weiss.
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CLINICAL IMPLICATIONS O BASIC RESEARCH ma%a1ues ,ith a mo#ifie# simian %ytome a$o!virus e/pressin SI3 anti ens an# then o"serve# %$earan%e of SI3 after stimu$atin spe%ifi% mem!ory T %e$$s& Thus* anti"o#ies an# %e$$! me#iate# immunity may have syner isti% therapeuti% po!tentia$& =iven the effe%tiveness of ora$ antiretrovira$ treatment* ,hat a#vanta e mi ht "e proffere# "y ino%u$ation ,ith mono%$ona$ anti"o#ies> The ans,er may "e a $on !term effe%t an# an a$ter!native treatment for those in ,hom antiretrovi! ra$ treatment has fai$e#& Moreover* a %om"ination of %onventiona$ #ru s an# immunotherapy may "e "etter than either a$one& One of the pro"$ems ,ith anti"o#y therapy is the nee# for repeate# in:e%tions of the mono%$ona$ anti"o#y in or#er to maintain $eve$s suffi%ient to %ontro$ the virus& An a$ternative is to #e$iver the enes en%o#in the heavy an# $i ht %hains of the mono%$ona$ anti"o#y so that the patient %an enerate it inter!na$$y& Ba$a+s et a$&; have stu#ie# this approa%h& ?sin a mouse mo#e$ %ontainin human $ym!phoi# tissue* they o"serve# that the eneti% #e!$ivery of a neutra$i+in mono%$ona$ anti"o#y throu h a vira$ ve%tor "$o%6e# HI3!' infe%tion& Moreover* a sin $e intramus%u$ar in:e%tion in!#u%e# $ife$on e/pression of the mono%$ona$ anti!"o#y at hi h p$asma $eve$s* su estin that this approa%h %ou$# "e %onsi#ere# for immunother!apy as ,e$$ as immunoprophy$a/is& Potent neutra$i+ation of anti!HI3 mono%$ona$ anti"o#ies %an a$so prevent ne, infe%tion ,hen $o%a$$y a#ministere# "efore a mu%osa$ SHI3 %ha$$en e& It is often assume# that mu%osa$ im!munity re1uires se%retory I A responses* a$thou h ,e 6no, that prote%tion a ainst %ervi%a$ %an%er throu h human papi$$omavirus va%%ines is main!$y a%hieve# throu h I =& @at6ins et a$&A re%ent$y reporte# that the use of passive mono%$ona$ anti!"o#y prote%tion ,ith #imeri% I A' 2,hi%h %aptures virus parti%$es an# prevents their trans!%ytosis a%ross mu%osa$ %e$$s4 ,as more effe%tive than #ire%t neutra$i+ation of SHI3* ,hereas the nontrans%ytoti% #imeri% I A0 isotype of the same mono%$ona$ anti"o#y offere# poor prote%tion& This o"servation shou$# "e "orne in min# if mono%$ona$ anti"o#ies are to "e #eve$ope# as va ina$ mi%ro"i%i#es for the prevention of HI3!' transmission& Mono%$ona$ anti"o#ies a$rea#y have a ,e$$!esta"$ishe# ro$e in immunotherapy for %an%er an# autoimmune #isease& There is no reason to hesitate to e/p$ore their %$ini%a$ potentia$ for use in the %ontro$ of %hroni% infe%tion ,ith virus!es su%h as HI3!'* espe%ia$$y iven the re%ent #ata on the effe%ts of treatment ,ith hi h$y potent* "roa#$y neutra$i+in mono%$ona$ anti"o#ies& 5is%$osure forms provi#e# "y the author are avai$a"$e ,ith the fu$$ te/t of this arti%$e at NE9M&or & 7rom the Di&ision of #nfection and #mm!nity, 5ni&ersity 8ollege ,ondon, ,ondon. '& Barou%h 5H* @hitney 9B* Mo$#t B* et a$& Therapeuti% effi%a%y of potent neutra$i+in HI3!'!spe%ifi% mono%$ona$ anti"o#ies in SHI3!infe%te# rhesus mon6eys& Nature 0)'87A)8B00;!C& 0& Shin ai M* Nishimura D* E$ein F* et a$& Anti"o#y!me#iate# immunotherapy of ma%a1ues %hroni%a$$y infe%te# ,ith SHI3 suppresses viraemia& Nature 0)'87A)8B0FF!C)& 8& Hansen S=* Piata6 M 9r* 3entura AB* et a$& Immune %$ear!an%e of hi h$y patho eni% SI3 infe%tion& Nature 0)'87A)0B'))!;& ;& Ba$a+s AB* Chen 9* Hon CM* Rao 5S* Dan L* Ba$timore 5& Anti"o#y! "ase# prote%tion a ainst HI3 infe%tion "y ve%tore# immunoprophy$a/is& Nature 0)'07;C'BC'!;& A& @at6ins 95* Sho$u6h AM* Mu6htar MM* et a$& Anti!HI3 I A isotypesB #ifferentia$ virion %apture an# inhi"ition of trans%yto!sis are $in6e# to prevention of mu%osa$ RA SHI3 transmission& AI5S 0)'870FBF'8!F0)& D I! 1".1"#$%&'()ci*r1+14#,, Copyright 2014 Massachusetts Medical Society.

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