New drug makes host cell machinery unavailable to HIV

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In March, Hollis–Eden Pharmaceuticals(HEP; San Diego, CA, USA) announced thatthey have a new drug candidate with potentanti-HIV activity. The development team,headed by James Frinke (HEP Vice Presidentof Research and Development) and DavidAnderson (Washington Regional Primate

Research Center) attended the 12thInternational Conference for AntiviralResearch in Jerusalem, Israel, to report on ayear-long efficacy trial in macaques.

HE2000 was originally synthesized in the1960s. Its potent anti-viral activity wasdiscovered early on, but then it was lost for

several years before being screened for anti-HIV potential. ‘HE2000 works well againstHIV in vitro and is now showing promisingresults in animal studies’, explains Frinke.‘Although the mechanism by which thecompound acts is not well understood, weknow that HE2000 binds to the glucose-6-phosphate dehydrogenase (G6PDH) enzymein mammalian cells (Fig. 1). It is likely thatthe compound inhibits the metabolicpathways that are ‘hijacked’ by HIV duringits intracellular replication cycle’, he adds.The team is continuing research to pinpointthe molecular action of HE2000 but the lackof detailed mechanistic knowledge is not seenas a reason to delay the Phase I/II clinicaltrials, which were approved by the US Foodand Drug Administration (FDA) in March.

This approval was obtained largely on thestrength of primate studies conducted by DavidAnderson and colleagues at the WashingtonRegional Primate Research Center (Universityof Washington, Seattle, WA, USA). Anderson’steam developed a recombinant SIV/HIV strain,called SHIV-229, to create a rapidlypathogenic animal model for testing HE2000and other drug and vaccine candidates. Thisvirulent retrovirus infects pigtailed macaquesand produces an AIDS-like illness that leads toCD41 cell depletion and symptoms of severeimmunodeficiency by 24 weeks post-inoculation. ‘In our latest study, we took sixmacaques whose condition was already indecline and treated three of them with multiple5 mg kg21 doses of HE2000. The other threeremained untreated as controls. We thenmonitored all animals weekly for bloodchemistry, viral titres of SHIV RNA,T-lymphocyte subset levels and general clinicalcondition’, says Anderson.

Although the numbers of animals usedwere small, the results were impressive. Thethree untreated monkeys lived for an averageof 193 days. They experienced the weight lossand steadily declining health that typifiesAIDS. In contrast, the three macaques in thetreated group have shown reduced viral load,increased CD41 cell counts and they havestarted to regain weight at the normal rate fortheir age. Currently, the average survival timefor this group is 384 days. (Two animals arestill alive; the death of the third was owing toan anaesthesia complication and wasunconnected with the SHIV infection.) Theresearch team are using the macaques toexperiment with different dose regimensbefore moving to human studies, and the twoanimals that survived are now on their fourthregimen of HE2000 therapy.

‘Phase I/II human trials started during April,and we have enrolled 48 patients who willreceive four different doses of HE2000 for 90days. We will monitor them constantly,assessing the efficacy of the drug and lookingfor possible side effects’, says Frinke. So far,

New drug makes host cellmachinery unavailable to HIV

Figure 1. HE2000 targets the energy cycle of HIV-infected cells. In an uninfected cell, glucose-6-phos-phate dehydrogenase (G6PDH) controls the rate of the pentose phosphate pathway, an energy-producingcycle. G6PDH activity is regulated by hormones. (a) In an HIV-infected cell, natural hormones levels arereduced, increasing G6PDH activity and stimulating the pentose pathway to increase the output of energyand nucleic acid precursors that are required for viral replication. (b) HE2000 acts as a non-competitive inhibitor of G6PDH. This results in regulation of the pentose pathway, which depletes the available energyand nucleic acid precursors needed for viral replication.

Normal cellularfunctions

Normal cellularfunctions

IncreasedG6PDHactivityHormone

depleted

Pentosepathway

stimulated

Normalpentose pathway

rate restored

Viral energyand nucleic acid

precursors

Viral energy and nucleicacid precursors depleted

Virusreplicates

Viralreplication

suppressed

Virus infects cella

Virus infects cell

HE2000inhibits G6PDH

b

The UK Wellcome Trust and the US NationalHuman Genome Research Institute (NHGRI)have announced that they will release extrafunding to the tune of US $158 million toproduce a ‘working draft’ of the humangenome by February 2000 – more than a yearand a half ahead of schedule – in acollaboration between the Wellcome-Trust-funded Sanger Centre (Hinxton, UK) and threeNHGRI-funded centres: the WhiteheadInstitute (Cambridge, MA, USA), WashingtonUniversity School of Medicine (St Louis, MO,

USA) and Baylor College of Medicine(Houston, TX, USA).

This latest funding boost reaffirms theimportance that the publicly funded HumanGenome Project places on maintaininggenomic data in the public domain. MichaelMorgan, Chief Executive of the WellcomeTrust Genome Campus, describes publicaccess as ‘crucial for the real medical benefits[of human genomic data] to be realizedefficiently.’ Data release will comply with theBermuda Agreement, which calls for all

publicly funded, large-scale DNA sequencingprojects to release sequence assemblies of >1 kb within 24 hours of assembly. This is instark contrast to the US National Institute ofAllergy and Infectious Diseases (NIAID), whorecently announced that they will be delayingrelease of microbial sequence data for up to amonth (Box 1).

The publicly funded project will use astrategy that minimizes the total amount ofsequencing necessary: each chromosome willbe mapped first so that a set of minimallyoverlapping BAC (bacterial artificialchromosome) clones – the ‘minimal tilingpath’ – can be chosen for sequencing. EachBAC will then be fragmented and subclonedinto sequencing vectors; individual subcloneswill be chosen at random and the ends of each

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Securing public access to genomicinformation: the race is on

On 25 January 1999 Anthony Fauci, director ofthe US National Institute of Allergy andInfectious Diseases (NIAID; Bethesda, MD,USA) announced a new data release policy formicrobial genome sequences: researchersfunded by NIAID grants will be able to publiclyrelease sequence data as late as one month aftercompleting the sequence.

The policy guidelines (available athttp://www.nih.gov/grants/guide/index.html)state that sequence must be released into thepublic domain, in segments of at least 1 kb ofcontiguous base pairs, within one month of athree-times coverage of a prokaryotic genomeor eukaryotic chromosome. These guidelinesdisregard the Bermuda Agreement, but John LaMontagne, deputy director of NIAID, defendsthe new policy, explaining that it is consistentwith the major objective of the Agreement,‘which is to ensure the release of sequence datato the scientific community in the most expedi-tious manner possible.’ Most prokaryotic

genomes contain only ~3 Mb, whereas eukary-otic genomes are 10–100 times larger. Unless aprokaryotic genome is particularly intractable(for example, if it is very GC- or AT-rich), its se-quence can now be obtained relatively quicklyand easily. The new policy is designed to protectthe intellectual property rights of the groups thatapply to NIAID for funding to sequence patho-genic genomes, explains La Montagne. ‘Onemonth seems a reasonable compromise whichwill give the investigator enough time to addressthe issue of intellectual property while not un-duly delaying the release of the genomic infor-mation.’

Not surprisingly, the policy has not been uni-versally welcomed, especially by researchers atBeowulf Genomics, the Wellcome Trust-fundedmicrobial-genome-sequencing initiative. Mostof Beowulf’s sequencing is carried out at theSanger Centre, which has played a central rolereleasing sequences into the public domain assoon as possible. Julian Parkhill of the Sanger

Centre says, ‘The organisms we are working onare very pathogenic, and many cause tropicaldiseases. We have to get the data into the widerscientific community, as this is the best way forvital work on drug and vaccine design to bestarted in as wide a range of laboratories as pos-sible.’ Dan Lawson, also of the Sanger Centre,thinks that, despite appearances, the new NIAIDpolicy represents a tightening of the rules. ‘Thisis a very clear statement of policy. It’s not just arecommendation; it will be binding on anygroup awarded an NIAID grant. There will beno need for long, protracted discussions on re-lease policy before each individual grant isawarded.’ Other US government bodies, such as the Department of Energy (which supportsthe sequencing of prokaryotes, includingMicrococcus radiodurans), are also adoptingsimilar sequence release policies.

Clare SansomFreelance science writer

Box 1. Sequence releases: intellectual property rightstake precedence at NIAID

animal and toxicology studies have shown thatHE2000 is well tolerated. It gives no adverseeffects, even at doses well in excess of thoserequired for therapy. Nevertheless, warnsFrinke, ‘we will need to be vigilant to thepossibility of drug reaction since we cannotask the study participants to stop taking theircurrently prescribed medication whilst theyare in the trial.’

When the first stage of the trial is complete,results from the interim analysis will be usedto initiate further dosing regimens. Ultimately,

the team at HEP also intends to investigate thepotential of HE2000 against other viralinfections. ‘The compound has a broadspectrum of activity against many differenttypes of virus, including cytomegalovirus andthe polio virus’, says Anderson. Interestingly,HE2000 also has an anti-malarial effect andAnderson speculates that the inhibition ofG6DPH might compromise the red blood cellsthat contain intracellular parasites, causingthem to lyse prematurely and so diminishingthe parasitic load. But Anderson stresses that

this is purely theoretical. It does raise thepossibility, however, that if both HIV andmalaria could be tackled by targeting host cellenzymes, the infectious agents would be lesslikely to develop resistance to the treatment.‘Developing a drug therapy that is activeagainst all strains of HIV and that cannot berendered ineffective by viral evolution is ourmost important goal’, concludes Frinke.

Kathryn SeniorFreelance science writer