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Landscape review of current HIV ‘kick and kill’ cure research - some kicking, not enough killing Thorlund, Kristian; Horwitz, Marc S; Fife, Brian T; Lester, Richard; Cameron, D. William Aug 29, 2017

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REVIEW Open AccessLandscape review of current HIV ‘kick andkill’ cure research - some kicking, notenough killingKristian Thorlund1*, Marc S. Horwitz2, Brian T. Fife3, Richard Lester4 and D. William Cameron5,6AbstractBackground: Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of anumber of agents to reactivate (‘Kick’) the well-known latent reservoir. This approach is rooted in the assumptionthat once these cells are reactivated the host’s immune system itself will eliminate (‘Kill’) the virus. While manyagents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latentreservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivatedreservoirs. Thus, there is a need for more emphasis on ‘kill’ strategies in HIV cure research, and how these mightwork in combination with current or future kick strategies.Methods: We conducted a landscape review of HIV ‘cure’ clinical trials using ‘kick and kill’ approaches. Weidentified and reviewed current available clinical trial results in human participants as well as ongoing and plannedclinical trials. We dichotomized trials by whether they did not include or include a ‘kill’ agent. We extractedpotential reasons why the ‘kill’ is missing from current ‘kick and kill’ strategies. We subsequently summarized andreviewed current ‘kill’ strategies have entered the phase of clinical trial testing in human participants andhighlighted those with the greatest promise.Results: The identified ‘kick’ trials only showed promise on surrogate measures activating latent T-cells, but did notshow any positive effects on clinical ‘cure’ measures. Of the ‘kill’ agents currently being tested in clinical trials, earlyresults have shown small but meaningful proportions of participants remaining off ART for several months withbroadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was alsorecently observed in a trial combining a conventional ‘kick’ with a vaccine immune booster (‘kill’).Conclusion: While an understanding of the efficacy of each individual component is crucial, no single ‘kick’ or ‘kill’agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple ‘kick andkill’ interventions.IntroductionEven though human Immunodeficiency virus (HIV) wasidentified as the cause of Acquired ImmunodeficiencySyndrome (AIDS) over 30 years ago, we still do not havea general cure [1]. Of the estimated 71 million people in-fected to date, only one documented patient, the BerlinPatient, is believed to have been cured [2]. In this case,the cure was achieved by exploiting the radical measuresrequired to treat the patient’s acute myeloid leukemia.While inspiring to cure enthusiasts, this approach is,however, not applicable to the broader population.Nevertheless, the case of the Berlin patient did propelnew interest in curative HIV research approaches.Most cure research efforts to date have been rooted inthe so called “Kick and Kill” approach – an approachthat is based on the premise the HIV virus partially‘hides out’ in so-called latent reservoirs and that activat-ing these latent reservoirs will result in the destructionof the reactivated cells either by attack by the immunesystem, or by the cytotoxic effects of HIV itself. To date,* Correspondence: thorluk@mcmaster.ca1Department of Health Research Methods, Evidence and Impact, Faculty ofHealth Sciences, McMaster University, Ontario, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Thorlund et al. BMC Infectious Diseases  (2017) 17:595 DOI 10.1186/s12879-017-2683-3however, clinical trials employing kick and killapproaches have yet to deliver promising results.In this article, we review what is currently knownabout viral transmission under antiretroviral therapy(ART) and the mechanisms underlying kick and killapproaches. We conclude that kick and kill has mainlyfocused on the ‘kick’ component and neglected the ‘kill’component. We then review available strategies for the‘kill’ component and summarize a potential approach tocomplete the kick and kill for effective therapy.What is currently known about viral transmission, viralmemory and ART?Today, HIV/AIDS is a manageable, livable disease withmany antiretroviral drugs available that safely and effect-ively suppress plasma viremia and maintain adequateperipheral blood CD4+ T-lymphocyte counts. However,effective treatment does not clear the virus infection,and its suppression requires lifelong treatment. This isbecause the current drugs impair the various stages ofthe viral lifecycle (viral entry to a target cell, reversetranscription, DNA integration, protein cleavage), but donot affect infected cells when these processes are not ac-tive. In general, when the immune system gains controlover an infection, which is signalled by antigenic clear-ance, active inflammation and immunity diminish and amemory of specific immunity comprised of residuallong-lived ‘antigenically committed’ memory T-cell re-mains. This memory can rapidly mount an anamnesticT-cell response upon re-exposure to familiar antigens.For HIV, the immune system never gains suppressivecontrol of the infection or clearance of the virus. Rather,in the attempt to generate HIV-specific immunity, sev-eral of memory T-cells generated to ensure effectivefuture immune responses remain infected because theactive CD4+ T-cell from which they differentiated werealready infected. Thus, a long-lived reservoir of HIV-infected memory T-cells is established. Most of thesecells are not affected by current anti-retroviral therapies,and can hang around in significant numbers in an in-active, or quiescent state for decades with an estimatedhalf-life of about 3½ years on ART [3, 4]. It has been es-timated that systemically, there are somewhere in therange of 106–107 replication competent infected latentCD4+ T-lymphocytes, capable of rapidly re-establishingthe viral population upon withdrawal of ART [5]. Inaddition, recent evidence that a significant proportion ofclonally expanded memory T-cells are replication com-petent [4, 6, 7]. Memory T-cells are therefore consideredto be the most important source of persistent infection.From the perspective of HIV cure research, it is essen-tial to keep in mind that other cell types can becomeinfected by HIV. Particularly, monocytes and macro-phages are thought to be of importance, as they havebeen shown to harbour large quantities of viral particleswithin intracellular endosomes [8–11]. These cells arelong-lived (weeks to years), can infiltrate multiple tissuecompartments including the central nervous system, areresistant to the cytolytic effects of HIV infection, canproduce significant amounts of virus, and are believedbe a key contributor of cell-to-cell transmission, evenduring ART [12–15]. In addition, the direct effects ofART treatment on macrophages is complex and not fullyunderstood [16]. For example, a recent (April 2017) exvivo study on 9 myeloid-only mice infected with M-tropic HIV and treated with 7 weeks of ART showedconventional viral rebound in 3 mice (33%) after inter-ruption of ART [17]. However, this study does notexplain the reason for viral rebound in 33% of the mice.Macrophage can be found in every tissue in the body asspecialized subsets, and are not likely to receive uniformexposure to the drugs systemically. In the aforemen-tioned study, there was a weak trend of a comparablylower number of macrophages in the spleen tissue andhigher number of macrophages in the bone marrowamong the 3 mice with viral rebound. However, largersample sizes are required to validate this observation.Lastly, nucleoside reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs) and protease inhibitors (PIs) are less potent inthese cells during chronic infection as determined by thehalf maximal effective concentration (EC50) and mightbe expected to be less suppressive.Follicular dendritic cells, which are critical cells foundin the B-cell follicles of the lymph nodes and otherlymphoid tissues, are also considered to be an import-ant viral reservoir. This is predominantly because theycan shelter viral particles within endosomal compart-ments or carry multiple particles attached out outermembrane synapses. These particles can then be deliv-ered to large populations of uninfected CD4+ T cellsinside the lymph nodes, thus causing their infectionand viral spread [18, 19]. While ART does reduce theviral titer within this reservoir, evidence suggests thatviral clearance is not complete [20]. The contributionof these reservoirs to plasma viremia during natural in-fection or viral rebound when ART is interrupted is notknown. Thus, we propose a focused evaluation of reser-voirs would be important when studying cureapproaches. At this point, we should acknowledge thatresearch on viral reservoirs, whether latent memory T-cells, macrophages, or dendritic cells, presents severalchallenges due to the limited sensitivity of the assaysand techniques currently available to quantify them.We therefore recommend this article be read in thelight of this general limitation of HIV ‘cure’ research.In the case of the Berlin patient, treatment for acutemyeloid leukemia took place over several months andThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 2 of 12included lymphomyeloid ablative chemo- and radiationtherapies, which are believed to have purged the pa-tient’s T-cells [2]. As a result, two stem cell transplantswere administered from a tissue compatible allogenicdonor (to limit graft-versus-host disease) for immunesystem reconstitution. The donor of the bone marrowwas electively selected to carry a homozygous delta32deletion in CCR5 gene. During the treatment, a grade Ilevel graft-versus-host disease was observed localized tothe skin. Minor adjustments in cyclosporine modifiedand improved the disease and it is unclear if the graft-versus-host episode was a co-factor in the eliminationof virus. While the precise mechanism by which theBerlin patient was cured is not clear, it is generally as-sumed that the above treatment led to the eliminationof the vast majority (if not all) of this latent reservoir,as 10 years (February 2017) has not lapsed since ARTwas interrupted.Kick and kill strategies to dateWhile there are many exciting cure strategies beingpursued, the so called “Kick and Kill” approach hasreceived the most attention. This approach is based onthe premise that activating the latent reservoir willresult in the destruction of the reactivated cells eitherby attack by the immune system, or by the activation-induced cell death associated with viral production inactive CD4+ T-cells. At the same time, expansion ofthe infection is expected to be suppressed by concomi-tant administration of ART. Thus, it was believed thatsimply ‘kicking’ latent cells into activity might beenough to lead to the elimination of the latent reser-voir. This is not a new idea. In fact, the first attempts atactivating the reservoir were carried out over a decadeago and involved treatment with recombinant cyto-kines. For example, Interleukin 2 (IL-2) has been thesubject of a number of studies in humans because of itsability to effect T-cell activation, proliferation and sur-vival; however, the observed clinical effect at tolerabledoses did not warrant further pursuit of these relativelytoxic therapies [21, 22]. Since the first studies on cyto-kines, several sophisticated T-cell reservoir activationstrategies leveraging our increasing knowledge of themechanisms that preserve latency have been attempted.Two such approaches include: 1) treatments targetingthe release of chemically sequestered cellular transcrip-tion factors essential to the initiation or propagation ofviral transcription (e.g. NF-αB, NFAT, P-TEF, AP-1) and2) epigenetic modulation of the HIV promotor site tofavour HIV transcription. Below, the evidence on indi-vidual agents that fall within these two strategy categor-ies are outlined. Further Table 1 presents and overviewof ‘kick’ strategies that have been tested in clinical trialsin humans to date.Agents for targeting cellular transcription factorsWith respect to ‘kick’ agents targeting cellular transcrip-tion factor, studies have included Protein Kinase C ago-nists (e.g. prostratin, bryostatins), which activate thecanonical NF-αB pathway ultimately resulting in initi-ation of viral transcription [15, 23, 24]. However, theseagents are generally toxic and clinical studies involvinghuman participants have shown very little effect at toler-able doses [25]. Hexamethylene bisacetamide (HMBA)and Disulfram have been identified as affecting latencyreversal by stimulating the release of positive transcrip-tion elongation factor b (P-TEFb) (from Hexim-1 and7SK snRNA) via the Akt pathway [26–29]. P-TEFb catal-yses phosphorylation of a number of transcriptional reg-ulators at the HIV promotor site which supporttranscriptional initiation and elongation. Experimentswith these pharmaceuticals in vitro showed promise, buttwo clinical trials of Disulfram in humans have yieldedonly a modest activation of the latent reservoir with in-determinate evidence of a reduction in the T-cell latentreservoir [30, 31]. To our knowledge, no future trials ondisulfram are planned [32]. Interleukin (IL)-7 is requiredto stimulate homeostatic proliferation of resting memoryT-cells, and it has therefore been hypothesized that IL-7could potentially act as a latency reversing agent forresting infected CD4+ T-cells. To date, results inhumans have been conflicting. One randomized placebocontrolled dose-response trial adding recombinanthuman IL-7 to current ART in 32 patients with with lowCD4+ T-cell counts (101–400 cells/mcg) showed anincrease in thymic output, improved T-cell receptorrepertoire, and increased cell cycling and bcl-2 expres-sion [33]. By contrast, another randomized clinical trialcombining IL-7 with raltegravir and maraviroc in 29patients with CD4+ T-cell counts >350cells/mcg did notshow any change in HIV DNA in peripheral bloodmononuclear cells [34]. This negative finding is notsurprising since other studies have shown that IL-7 con-tributes to viral persistence, leading to proliferation ofinfected cells and is not sufficient in reversing latency inquiescent T cells [35, 36]. Currently, one future IL-7clinical trial is planned in which IL-7 will be combinedwith LIPO 5 DC, an experimental dendritic cell basedtherapeutic vaccine. Another class of agents, toll-likereceptor (TLR) agonists, have been shown induce HIVexpression and HIV specific immunity in patients receiv-ing ART [32]. The latency reversing properties associ-ated with the TLRs comprise activation via the NF-κB,NFAT, or AP-1 pathways [37, 38]. In addition, stimula-tion of TLR-7 have been shown effective as an adjuvantto therapeutic vaccination in SIV-infected rhesus mon-keys [39]. Currently, one single arm (phase I) clinicaltrial has investigated TLR-agonists, namely the novelMGN1703 TLR-9 agonist in 15 virologically suppressedThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 3 of 12HIV infected individuals [40]. In this trial, CD8+ T-cellsand natural killer (NK) cells significantly increased duringtreatment, thus suggesting enhanced immune response tothe virus. In 6 of the 16 participants viral RNA copies alsoincreased from <20 to >1500 copies/mL, potentially sug-gesting re-activation of the latent reservoir. Two moreTable 1 Overview of ‘kick’ studies in humans completed to dateStudy DrugStudiedPatientEligibilityNo. Pts StudyDesignTx Doseand DurationLengthof StudyKeyfindingsAgents targeting cellular transcription factorsLehrmann 2005 ValproicAcid (HDACi)Viral RNA < 50cp/mLfor at least 2 years4 Proof-of-concept 500-750 mgbid for 3 months18 weeks 68%–83% reduction inresting infected CD4T-cells in 3 of 4 patientsSagot-Lerolle et al.2008ValproicAcid (HDACi)Viral RNA < 50cp/mLfor at least 2 year24 Retrospectivematchedcohort study(pilot)Not reported(retrospective)2 years No difference in viral DNAquantified in PBMCsArchin2010ValproicAcid (HDACi)Viral RNA < 50cp/mL forat least 6 months; healthyCD4 T-cells >300/μL12 Single armphase 1 trial1000 mg qd(Depakote ER)16 weeks No sustained depletion ofresting CD4+ T-cellinfection observedRouty et al.2012ValproicAcid (HDACi)Viral RNA < 50cp/mL forat least 1 year; healthyCD4 T-cells >200/μL56 Multicenterrandomizedcross-overtrialUp to 500 mg bid(as per tolerance)16 weeks (×2)No reduction in CD4T-cells withreplication-competent HIVElliot et al.2014Vorinostat(HDACi)Not reported BaselineCD4 T-cell countrange from 371 to 113620 Proof-of-conceptsingle arm400 mg bidfor 14 days12 weeks Cell-associated unsplicedRNA Increased by 7.4fold at 14 daysArchinet al. 2013Vorinostat(HDACi)Viral RNA < 50cp/mL forat least 6 months; healthyCD4 T-cells >300/μL11 Proof-of-conceptsingle arm200 mg initially400 mg after 2–3and 4–5 weeks5 weeks RNA expr. in restingCD4+ T-cells increased4.8 fold (1.5–10)Rasmussenet al. 2014Panobinostat(HDACi)Viral RNA < 50cp/mL forat least 2 years; healthyCD4 T-cells >500/μL15 Phase 1/2 20 mg three times/week for 8 weeks32 weeks Cell-associated RNAIncreased duringtreatment by 3.5 foldSoegaard2015Romidepsin Viral RNA < 50cp/mL forat least 2 years; healthyCD4 T-cells >500/μL6 Proof-of-conceptphase IIOne 4 h 50 mginfusion per weekfor 3 weeks70 daysafter lastinfusionPlasma RNA increased todetectable levels in 5/6 patientsKatlama2016IL-7 agonistRaltegravirMaravirocViral RNA < 200cp/mL last3 years, <50cp/mL last6 months, CD4 T-cells >350/μL29 Randomizedtrial8 weeks ofRAL + MARintensification,then 3 x weekly30mcg/kg of IL-728 weeks Data safety monitoringboard stoppedtrial at 28 weeks due toconcerns of >1500 CD4+T-cell countsLevy Y2012IL-7recombinantViral RNA < 50cp/mL forat least 6 months; healthyCD4 T-cells: 100–400/μL32 Randomizedtrialweekly 10, 20, or30mcg/kg for3 weeks52 weeks IL-7 well tolerated up to20mcg/kg. Brisk increasein CD4 count.Sereti2009IL-7recombinantViral RNA < 50cp/mL (grp 1)Viral RNA < 50,000cp/mL (grp 2)for at least 12 months; healthyCD4 T-cells > 100/μL25 Randomizeddouble blindSingle dose of 3, 10,30, 60 or 100μg/kg8 weeks 30μg/kg max tolerabledose. Significant increasein transient HIV-RNA in6 patients. Increase incentral memoryphenotype T-cellsVibholm2017TLR-9 agonist(MGN1703)Viral RNA < 50cp/mL forat least 12 months; healthyCD4 T-cells >350/μL15 Phase 1/2aSingle arm60 mg MGN1703subcutaneouslytwice weekly for4 weeks4 weeks(80 daysfollow-up)Pronounced activation ofplasmacytoiddendritic cells. Significantincrease in proportions ofactivated cytotoxic NKcells and CD8+ T cellsEpigenetic modulation agentsElliott et al.2015Disulfram Viral RNA < 50cp/mL forat least 3 years; healthyCD4 T-cells >350/μL30 Non-randomizedprospectivedose-escalationThree days of500 mg, 1000 mg,or 2000 mg30 days Approximately 2-foldincrease in cell-associatedRNASpivaket al. 2014Disulfram Viral RNA < 50cp/mL for min1 year; healthy CD4 T-cells>500/mcg for min 24 weeks16 Pilot singlearm500 mg/dayfor 14 days84 days Well-tolerated, but latentreservoir did not changein sizeGutiérrezet al. 2016Bryostatin-1 Viral RNA < 50cp/mL forat least 2 years; healthyCD4 T-cells >350/μL12 Double-blindrandomizedphase I trialPlacebo 10mcg/mm220mcg/mm2672 days No detectable differencein cell-associatedunspliced RNAThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 4 of 12clinical trials are being planned to investigate the latencyreversing effects of TLR agonists [32].Epigenetic modulation agentsIn the case of epigenetic modulation, the histone deace-tylase (HDAC) inhibitors are the most studied pharma-ceutical agents to reactivate the latent reservoir. Thesestudies have received comprehensive review by others[41, 42]. Briefly, in the latent state, HDAC enzymesaccumulate around the HIV promotor site favouringdeacetylation of the associated nucleosomes and hencerestricting HIV replication. Researchers have demon-strated a number of different HDAC inhibitors (e.g. val-proic acid, vorinostat, panobinostat, Romidepsin,suberoyl bis-hydroxamic acid) stimulate transcription,thus activating the latent cells both in vitro and in vivo.In clinical trials, however, treatment with these agentsresulted in no significant reduction of the latent viralreservoir of memory T-cells although there was evidencethat infected cells were being activated (see Table 1).Despite disappointing results in these early clinical trials,a total of nine trials examining these agents, either aloneor in combination with immune boosters, are plannedor ongoing [32].Another class of compounds that have been examinedas latency reversing agents include Histone methyl trans-ferase inhibitors (chaetocin and BIX-01294) [43, 44].These agents affect histone methylation and/or demethyl-ation stimulating or repressing transcription in a mannerakin to the deactylase inhibitors. Also, the DNA cytosinedemethylation agent 5-aza-2-deoxycytidine (Aza-CdR)can reverse latency by demethylating CpG islands Regionsof DNA usually found near gene promotor sites with highdensity of cytosine-phosphate-guanine (CpG) clusters inthe HIV transcription initiation site [45]. All these agentshave been shown to reverse latency in vitro and/or ex vivo,but have not been tested in vivo as far as we are aware[43–45].The missing ‘kill’ in ‘kick and kill’While there are a number of factors that might explainthe failure of the latency reversal agents to meaningfullyimpact the T-cell reservoir in initial studies, it is import-ant to recognize that the entire kick and kill paradigm isbased on the premise that latently infected cells willeither expire due to virus induced lysis/apoptosis or bedestroyed by cytotoxic T-cell (CTL) response soon afteractivation. Recent evidence, however, suggests that thismay not be the case [35, 46, 47]. For example, in onestudy of latency reversal in CD4+ T-cells obtained fromHIV-infected donors, Shan and colleagues found thatreactivation of latent infected cells by the HDAC inhibi-tor vorinostat did not affect the reservoir [47]. Further-more, the addition of CD8+ T cells from patients onsuppressive ART did not induce cell death. Anotherstudy suggested that the HDAC inhibitors in generalmay suppress the CTL response. In particular, it wasobserved that vorinostat, panobinostat and romidepsinimpaired the ability of HIV-specific CTL to eliminateinfected CD4+ T-cells ex vivo [46]. Other data suggestthat the vigorous CTL response observed during acuteinfection may be lost during chronic infection, and thus,that CTL response might be impaired independent ofadministration of HDAC inhibitors [48]. Collectively,these observations suggest that ‘Kicking’ alone is likelyinsufficient to eliminate the latent T-cell reservoir.Another limitation of current kick and kill clinicalstudies is the almost ubiquitous focus on T-cell reser-voirs. By now, it has been well-document that severalother secondary reservoirs may be a key contributor tothe persistence of the HIV virus. To this end, we havealready discussed the likely significant role that mono-cytes and macrophages play in the persistence of theHIV virus. As these cells are known to be relativelyresistant to the cytopathic effect of the HIV infection,stimulating them may only serve to increase the produc-tion of virions and/or associated viral proteins. Anotherlatent reservoir that is believed to sustain viral transmis-sion during ART are the dendritic cells. Dendritic cellscan shelter viral particles within endosomal compart-ments or carry multiple particles attached out outermembrane synapses. Dendritic cells can live for severalyears, during which they can slowly gather increasingamounts of viral particles [49]. To our knowledge, inter-action of latency reversing agents and dendritic cells hasnot been explored. However, since dendritic cells gener-ally do not integrate or replicate viral RNA, latencyreversing agents are not expected to affect dendriticcells. Although controversy still exists on the importanceof dendritic cells as a component of the latent reservoir,with our current understanding, one could argue a feas-ible and efficient kill strategy targeting dendritic cellsmight be essential in attaining a cure.Kill strategiesWith recent results suggesting the simple reversal of la-tency (kick) strategy to be insufficient for purging the la-tent reservoir, it is time to look more closely atapproaches that focus on killing reactivated cells. Suchagents might have the potential to act directly on latentcells removing the need for the latency reversing drug.Here, we look at some approaches that focus on ‘the Kill.’Broadly neutralizing monoclonal antibodiesApplication of broadly neutralizing monoclonal anti-bodies (mAb) for prevention, post exposure prophylaxisand the treatment of HIV have has been increasinglypursued since the advent of single cell based cloningThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 5 of 12methods has made isolation of mAb against the virusmainstream [50–53]. These proteins target the virus en-velope proteins composed of multiple HIV gp120 surfaceproteins coupled to gp41 transmembrane proteins. Fortreatment purposes, there are numerous mAb beingstudied; some exhibiting significant breadth and potencyagainst hundreds of HIV variants [54, 55]. Fig. 1 illus-trate the general mechanism of action associated withbroadly neutralizing monoclonal antibodies for the treat-ment of HIV. To date, two of these have advanced toclinical trials in human participants. In the first case, ad-ministration of a single dose (30 mg/kg) of 3BNC117(which targets the CD4+ binding site of the viral spike)to viremic subjects (N = 17, 2 on ART) resulted in a0.8–2.5 log10 decrease in viremia which persisted for28 days [56]. Similarly, six of eight subjects treated withthe CD4+ blocking monoclonal VRC01 (40 mg/kg, IV)experienced a 1.1 to 1.8 log10 reduction in plasmaviremia. In this latter case, the two non-responderswere shown to be infected with resistant variants priorto treatment. This observation highlights the importancethat resistance avoidance will be critical if these therapiesare to be successful. In both trials, resistant viral variantsemerged in at least some patients after clearance of theantibodies. Further, studies in animal models indicatechanges in just one to three target protein residues isenough to allow for viral escape [54]. Thus, as it is withART, combinations of mAbs targeting different epitopeswill likely be required for clinical application and earlystudies both in vitro and in animal models suggest thatthis could be a viable approach [57, 58].Until recently, the primary focus of studies around thetherapeutic use of mAb for HIV has been on active in-fection and the ability of mAbs to block viral infiltrationinto cells. However, these agents also have potential toorchestrate the destruction of the latent reservoir viaantibody-dependent cell-mediated cytotoxicity (ADCC)[59]. ADCC is mediated by the antibody Fc chain whichcan recruit natural killer (NK) cells, macrophages,polymorphonuclear phagocytes or complement. RecentFig. 1 Representation of ability broadly neutralizing antibody to (a) bind to multiple variants of gp120; (b) induce killing of the HIV infected cellby attraction of natural killer cells (left), macrophages (middle) and complement (right)Thorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 6 of 12studies suggest that some of the broadly neutralizingmAb appear to direct ADCC in latent HIV-infected T-cells [60]. This has been demonstrated in vitro with mul-tiple broadly neutralizing mAbs (including 3BNC117and VRC01) where research demonstrated varying de-grees of ADCC in laboratory strains (CD4+ lymphoidcells (MT4) infected with the prototypic R5-tropicNLAD8 or X4-tropic NL4.3) and primary HIV isolates.Of the mAbs tested in laboratory strains, 5 strongly in-duced ADCC (NIH45–46, 3BNC117, 10–1074, PGT121,10E8), two less so (PG16, VRC01) with the balance beinginactive. With respect to primary HIV isolates obtainedfrom infected patients, the effect was somewhat attenu-ated requiring a combination of 5 mAbs (NIH45–46,3BNC117, 10–1074, PG16 and 10E8, each at 1.5 mg ml)to induce cell death in some but not all strains. The re-duced activity was associated with a reduced number ofavailable binding sites in the infected cells. Interestingly,the same combination of five mAbs induced cell deathex vivo in reactivated (by phytohemagglutinin PHA)latent CD4+ isolates obtained from 5 out of 6 ARTsuppressed HIV infected subjects.Direct in vivo studies of mAb induced ADCC arelimited to animal models [60, 61]. In a study of HIV in-fected (HIV-1YU2) humanized mice, researchers found thatanimals treated with mAb mixture (3BNC117, 10–1074,and PG16) were slower to rebound upon withdrawal oftreatment relative to ART treated mice (74–107 days vs28–84 days) [60]. This finding was interpreted as an indi-cation of a reduced latent reservoir mediated via Fc medi-ated ADCC [54]. This was supported using the samecombination of mAb, but with the Fc effector function re-moved. Here, nine of 15 of the mice on the knock outregimen rebounded within 44 days after cessation of ther-apy relative to 1 of 21 mice receiving the unmutated mAb(p = 0.0004). Further, rebound viremia was 50-fold higherin the mice on the knock out mAb (p = 0001).In humans, evidence of ADCC is indirect. Resultsfrom the RV144 trial vaccine trial showed a 31% reduc-tion in HIV acquisition (P = 0.04), however, the anti-bodies induced by the vaccine did not suppress primaryHIV isolates and it was therefore theorized that the ob-served effect might be associated with ADCC [62]. Mod-elling studies of passively administered 3BNC117 alsosuggest that the observed results cannot be attributed toclearance of free virus alone and that Fc mediatedADCC likely a contributing factor [61]. Taken togetherall these results suggest that addition of mAbs to thekick and kill strategies deserve investigation.Integrin receptor targeted antibody therapyIn a recent report, an antibody therapy targeting CD4+T-cell proteins appeared to confer impressive viral con-trol in primates recently infected with Simianimmunodeficiency virus (SIV) [63]. In this study, ART-treated SIV-infected rhesus macaques received eight in-fusions of a primatized monoclonal antibody against theα4β7 integrin both during ART, and for a period afterdiscontinuing ART. After cessation of ART, all eight testanimals achieved viral control (low to undetectablelevels) after a period of modest viral rebound (note: 2 of8 never exhibited rebound). Virologic control was sus-tained for over 45 weeks after discontinuing ART. Thisis in contrast to the seven macaques in the control arm(which received nonspecific rhesus immunoglobulin Ginstead of α4β7 mAb) where all the animals reboundedto high viral loads (6 logs) within 2 weeks of stoppingART. Furthermore, CD4+ T-cell counts recovered to‘healthy’ levels in the α4β7 mAb treated animals soonafter the first administration of the antibody andremained stable for over 25 weeks off all therapy. Therewas no recovery in the controls.The mechanism for the observed effect of the anti-α4β7 integrin in this study is not entirely clear. Theα4β7 integrin is a CD4 cell surface protein that is instru-mental in the trafficking of these cells to the gastrointes-tinal tissue. During acute infection, a great deal ofdamage occurs in the gastrointestinal tissue including aprecipitous drop in CD4+ T-cells, damage to the intes-tinal epithelium and the rapid establishment of the viralreservoir. It was believed that limiting access of CD4+T-cells to the gut with the anti-α4β7 might mitigate thisdamage. Whether that explains the results can not bedetermined from this study as CD4+ counts in the smallintestine began to recover during the period of adminis-tration of the anti-α4β7. Another potential mechanismmay be the property that anti-α4β7 monoclonal anti-bodies allow for the production of anti-v2 antibodies,which have been shown to mediate antibody-dependentcellular phagocytosis (ADCP), and thus contribute to thesuppression of the proliferation of infected cells [64].Collectively, the observations of this study may be im-portant to cure research although it is not clear if theywould extend to later stages of disease.BiTEs and DARTsBispecific T-cell Engagers (BiTEs) and Dual-Affinity Re-targeting Molecules (DARTS) are variations of bispecificantibodies, which are engineered with the binding re-gions of two different antibodies such that they bind twodifferent antigens. Both BITEs and DARTs belong to aclass of these compounds which exclude the antibody Fcregion. Progress in the use of these agents for the treat-ment of cancer has recently spurred research in their ap-plication to the treatment of HIV-1.BiTEs are comprised of two antibody single chain vari-able fragments linked together by a short flexible peptide[65]. One fragment is targeted towards CD3 protein ofThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 7 of 12the T-cell receptor complex which signals T-cell effectorfunctions. In a recent study of a BiTE incorporating thelight chain of the broadly neutralizing antibody VRC07,researchers found that the resulting VRC07-CD3 BiTEinduced CTL elimination of latently infected cells iso-lated from peripheral blood mononuclear cells (PBMCs)of infected donors ex vivo [66]. Fig. 2 illustrates, in brief,the assembly process and the general mechanism ofaction associated with BiTEs for the treatment of HIV.In subtle contrast to BiTEs, DARTs are constructedfrom the variable heavy domain of one antibody linkedto the light variable domain of another [55]. DART pro-teins have shown to mediate CTL clearance of latentlyinfected CD4+ T-cells both in vitro and ex vivo [67, 68].Thus, proof-of-concept of these agents as potential killagents seems to have been met. It will be interesting ifthese results can be recapitulated in vivo.Chimeric antigen receptors (CARs)Another class of kill agents with renewed excitement areHIV specific T-cells engineered with chimeric antigen re-ceptors (CARs) [69]. CAR receptors are comprised of atarget specific surface protein coupled to an intracellularsignalling domain to activate the cytotoxic response. Thefirst CAR was based on a soluble CD4+ receptor(intended to bind to infected cells expressing HIVgp120) coupled to an intracellular CD3 ζ signalling pro-tein. In vitro, these designer cells were as effective atkilling infected cells and CTL clones isolated from in-fected patients [70]. Unfortunately, when tested on HIVinfected subjects, they had no effect on clinical out-comes (although they were well tolerated and persistedfor years). Because of this, CAR research was aban-doned. However, recent progress in treatment of cancerwith CARs coupled with the discovery of broadly neu-tralizing antibodies (which serve as CAR receptormodels) has renewed interest in their application to HIVrenewed [71]. In vitro, these antibody-modelled CARsshow promise, but it remains to be seen if they will beeffective in vivo. Fig. 3 illustrates the assembly of a CARengineered T cell and the general mechanism of actionassociated with CARs for the treatment of HIV.Second mitochondria-derived activator of CaspasesSecond Mitochondria-derived Activator of Caspases(SMAC) mimetics are small molecule drugs that showpotential to induce cell death in reactivated latent cells.Caspases are proteolytic enzymes involved in apoptosisand IAPs (Inhibitors of Apoptosis Protein) are regulatoryproteins that inhibit caspase activity by either bindingdirectly to the enzyme (e.g. XIAP) or by blocking signalsthat lead to their activation (e.g. IAP2, IAP3). SMAC isan endogenous protein that suppresses the activity ofthe IAPs thus promoting cell death. Several small mol-ecule drugs fashioned after the key binding domain ofSMAC have been developed to combat apoptosis resist-ant cancer cells with some already entering clinical trials[72]. While studies are still in the early stages, re-searchers are currently exploring these agents to elimin-ate the HIV latent reservoir. In a recent report, in vitrotreatment of HIV infected central memory T-cells with 3SMAC mimetics (birinapant, GDC-0152 and emblin)targeting XIAP activity successfully induced a significantdose-dependent increase in apoptosis [73].Another study of SMAC mimetics demonstrated la-tency reversing abilities by looking at SMAC inhibitorsof IAP1 and IAP2, two proteins that are known to in-hibit NF-κB inducing Kinase (NIK) by ubiquitination. InFig. 2 Assembly of BiTEs from two different variable regions of monoclonal antibodies and their mechanism of action. The BiTE first attaches to aCD8+ T cell before assisting the CD8+ T cell in binding to an HIV infected CD4+ T cell. Upon binding the CD4+ T cell the CD8+ T cell will releasegranzymes and induce death of the HIV infected CD4+ T cellThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 8 of 12the absence of IAP1 and IAP2, NIK will accumulate, ini-tiating a series of reactions that result in the activationof NF-κB which can translocate to the nucleus and initi-ate HIV transcription. Researchers tested four SMACmimetics (SBI-0637142, LCL161, GDC-0152, TL32711)specifically targeting IAP1 and/or IAP2 and all exhibitedlatency reversing capacity in a Jurkat latency model [74].SBI-0637142 and LCL161 were also tested ex vivo inCD4+ T-cells collected from HIV patients on suppres-sive ART, and while neither seemed to initiate activationof these cells on their own, there was a potent synergis-tic effect when they were used in combination with theHDAC inhibitor panobinostat. Taken together, these re-sults suggest an exciting potential for SMAC mimeticsin kick and kill strategies.Immune checkpoint antibodiesThe role of programmed cell death receptor 1 (PD-1)and PD1 ligand (PD-L1) expression in HIV patients havebeen investigated in several studies [75]. Elevated ex-pression of PD1 has been demonstrated in both HIVspecific CD8+ T cells and CD4+ T-cells. In particular,the interaction of PD-1 and PD-L1 are suspected to be amajor contributor to the persistence of infected CD4+T-cells [76]. High PD1 expression has been shown corre-lated with the exhaustion of CD8+ T-cells [77]. Anti-bodies for PD-L1 ligand have been developed for severallate stage cancers and these have shown effective in in-ducing natural apoptosis and increasing overall survival.Case studies of cancer patients with HIV receiving PD-L1 antibodies have also reported promising results suchas substantial lowering of viral loads [78]. Given thepromise of these early results, clinical trials have beeninitiated. In one completed 8-person phase trial (6 pa-tients receiving one infusion of nivolimumab 0.3 mg/kg,2 patients receiving normal saline as placebo), two of thenivolimumab treated patients showed evidence of rever-sal of CD8+ T-cell exhaustion 4 weeks after the infusion[79]. Two larger trials are currently ongoing [32].Therapeutic vaccinationWhile most vaccine research has focussed on preven-tion, numerous clinical studies of therapeutic vaccines inHIV infected subjects have been conducted [80, 81].Some of these have shown modest drops in viral load(0.5 to 1 log drop) using various approaches to boost theimmune system, and thus, can arguably be considered‘kick’ strategies. For example, in the single arm REDUCstudy, subjects received multiple doses of Vacc-4× (asynthetic gag peptide) with recombinant humanizedgranulocyte macrophage colony-stimulating factor(rhu-GM-CSF) followed by administration of theHDAC inhibitor romidepsin [82]. The rationale for thisstudy was based on previous data that suggested theVacc-4×/rhu-GM-CSF vaccine induced killing of in-fected cells. While the results of the treatment showeda significant (p = 0.01) 40% reduction in the proviralDNA, it did not have any effect in time to reboundafter treatment interruption. Researchers concluded thetreatment required fine tuning. Another vaccine trial,the BCN01 trial, suggested that a combination of theChAd.HIVconsv and the MVA.HIVconsv prime boostvaccines are efficacious in redirecting CD8+ T-cell re-sponse towards regions where HIV-1 is highly con-served [83]. Further, a recent extension study ofBCN01, the BCN02 proof-of-concept study, in whichanother boost with MVA.HIVconsv was followed bythree weekly 5 mg/m2 doses of romdepsin and a secondMVA.HIVconsv boost, demonstrated highly promisingresults as an therapeutic strategy that encompassesboth a kick and a kill component [84]. Of the 15 pa-tients enrolled in this proof-of-concept study, the mostFig. 3 Assembly of a CAR engineered CD8+ T-cell its mechanism of action. The CAR engineered CD8+ T cell binds to an HIV infected CD4+ T cell.Upon binding the CD4+ T cell the CAR engineered CD8+ T cell will release granzymes and induce death of the HIV infected CD4+ T cellThorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 9 of 12recently presented data (CROI, February 2017) revealedthat four patients have remained off ART for 7, 12, 14,and 22, weeks respectively. Longer term follow-up re-sults cast further light on the efficacy of this thera-peutic combination.ConclusionsFor patients, clinicians and healthcare funders alike, de-veloping a sterilizing HIV cure which completely clearsthe virus would be the ultimate goal. However, a ‘func-tional cure’ that would allow the body to control thevirus in the absence of other treatments (i.e. ART) for aconsiderable duration of time is generally consideredmore realistic. A functional cure would provide muchneeded relief to patients on rigorous daily antiretroviralregimens. Further, it would likely have a greater impactthan conventional ART in settings where adherence orfrequent access to medication presents a challenge. ‘Kickand kill’ cure approaches have taken the lead in cure re-search, but to date results have been disappointing. Thismay stem from the fact that previous approaches havenot taken full advantage of available kill approaches, andthus missed out on the opportunity to kill a sufficientquantity of re-activated cells or even the resting cellsthemselves. Here we have reviewed five kill approachesthat show potential to reduce or eliminate the latent res-ervoir. These might be used alone, in combination witheach other and/or in combination with latency reversingagents. Given the complexity of HIV infection and themultiplicity of compartments (cellular and tissue) in-volved, it seems highly unlikely that there will be a single‘magic cure bullet’. Instead, the cure is almost certainlygoing to require a multipronged approach involving newdrug combinations. While an understanding of the effi-cacy and safety of each potential component is crucial,we believe it is paramount that future research includesan additional focus on finding the best combination oftherapies to clear infected cells.AbbreviationsADCC: Antibody-dependent cell-mediated cytotoxicity; AIDS: AcquiredImmunodeficiency Syndrome; ART: Antiretroviral therapy; BITE: Bispecific T-cell Engagers; CAR: Chimeric antigen receptors; CTL: Cytotoxic T-cell;DARTS: Dual-Affinity Re-targeting Molecules; EC50: Half maximal effectiveconcentration; HDAC: Histone deacetylase; HIV: Human immunodeficiencyvirus; II: Integrase inhibitors; IL: Interleukin; mAb: Monoclonal Antibody;NNRTI: Non-nucleoside reverse transcriptase inhibitors; NRTI: Nucleosidereverse transcriptase inhibitors; PD1: Programmed cell death receptor 1; PD-L1: PD1 ligand; PI: Protease inhibitors; P-TEFb: Positive transcriptionelongation factor b; SIV: Simian immunodeficiency virus; SMAC: SecondMitochondria-derived Activator of Caspases; TLR: Toll-like receptorAcknowledgementsDWC recieves a salary award from the Department of Medicine, University ofOttawa at The Ottawa Hospital.FundingNo funding was received for this study.Availability of data and materialsNot applicableAuthors’ contributionsKT and MSH conceived the conceptual framework for this study. MSH wrotethe first manuscript outline. KT wrote the first manuscript draft and led allrevisions of the manuscript. BTF, RL, and DWC all contributed significantly tothe content and writing of this manuscript. All authors have read the lastversion of the manuscript and have consented to submit for publication. Allauthors read and approved the final manuscript.Ethics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsAll authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Health Research Methods, Evidence and Impact, Faculty ofHealth Sciences, McMaster University, Ontario, Canada. 2Faculty ofMicrobiology and Immunology, University of British Columbia, Vancouver,Canada. 3Department of Medicine, Center for Immunology, University ofMinnesota, Minneapolis, Minnesota 55455, USA. 4Department of Medicine,University of British Columbia, Vancouver, Canada. 5Faculty of Medicine,University of Ottawa, Ottawa, Ontario, Canada. 6Division of Infectious Diseases,Department of Medicine, University of Ottawa at The Ottawa Hospital /Research Institute, 501 Smyth Road, Ottawa K1H 6V2, Ontario, Canada.Received: 16 April 2017 Accepted: 15 August 2017References1. 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Viral control induced by HIVconsv vaccines and romidepsin in earlytreated individuals. Seattle, WA: Conference on Retroviruses andOpportunistic Infections (CROI). 2017. Abstract 119LB Session O-11.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Thorlund et al. BMC Infectious Diseases  (2017) 17:595 Page 12 of 12

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