This year began with mixed news for the researcheffort to develop an effective HIV vaccine. Areport published in January revealed decliningCD41 T-cell counts in people 15 years after theywere accidentally transfused with bloodcontaining nef-deleted HIV-1, an early warningsign that human recipients of attenuated HIVcould develop AIDS (Ref. 1). Ruth Ruprecht(Dana-Farber Cancer Institute, Harvard, MA,USA) confirmed this possibility by vaccinating16 infant and adult monkeys with an attenuatedform of simian immunodeficiency virus (SIV).The results, which appear in the February issue ofNature Medicine, show that two of the monkeysdeveloped signs of AIDS (Ref. 2), and Ruprechtconcludes that ‘it is not safe to conduct humantests of AIDS vaccines made from live weakenedviruses.’

January also saw the publication by KavitaLole (National Institute of Virology, Pune, India)and colleagues (from India and the USA) of thefull-length sequences of five subtype-C HIV-1isolates and one subtype-A/C hybrid fromrecently infected Indian patients3 (Fig. 1).Previously, of the 46 completely sequenced HIVgenomes, only two were subtype C and neither ofthese originated in India, where subtype-C virusespredominate. Analysis of the sequences show thatthe cytotoxic T-cell epitopes of the C-type virusesare substantially different from the subtype-Blaboratory strains that have been used as the basisfor AIDSVAX, the only AIDS vaccine currentlyin Phase III trials.

But is this not more bad news? ‘No,’ saysLole’s colleague and co-author Robert Bollinger(Division of Infectious Diseases, Johns HopkinsUniversity School of Medicine, Baltimore, MD,USA), ‘I don’t expect our data to set vaccinetrials back at all. The more knowledge we have ofthe virus and how it behaves, the more effectivelywe can interpret trial results.’ However, heaccepts that the prototype subtype-B vaccinesmight not provide effective immunity, not onlybecause they are type B and therefore likely to beineffective against type C or other subtypes, butalso because they have been developed usingviruses that have been passaged repeatedly in thelaboratory. ‘It might be necessary to makevaccines from freshly isolated HIV strains sincethese are much more similar to the viruses thatthe body will encounter in real life’, he says.

Bollinger stresses that ‘the history of HIV-vaccine development is littered with false hopesand disappointments but research efforts mustforge ahead on all fronts. We can’t afford to behesitant, even in the face of continued problems.’As the global HIV pandemic continues to spiralout of control, the need for an effective vaccinebecomes ever more pressing. The number ofpeople infected worldwide has jumped by 10% inthe last year to 33.4 million. And, as time goes on,the gap between the figures for more developedcountries and those in the developing worldcontinues to diverge rapidly. By the year 2000,over 90% of all people infected by HIV will be indeveloping countries.

The greatest rate of increase in HIV infectionis in India and sub-Saharan Africa where there islittle access to HIV testing, public educationprogrammes or to the growing armoury of anti-viral drug treatments that HIV-positive Westernersbenefit from. Although cost is a factor – theannual cost of providing drugs for a patient withHIV infection in the UK, for example, is currently£7000 whereas most African countries spend only£5 per head per year on all healthcare – it is notthe only one. Enrica Paze (Dr AmbrosoliMemorial Hospital, Kalongo, Uganda), who has

first-hand experience of the effects of the AIDScrisis in Africa, is unimpressed by the suggestionthat free drugs donated by the pharmaceuticalgiants in the West would help the AIDS problemin the developing world. ‘The complicatedschedule of administration of HIV treatment leadsto adherence problems even in the West. InUganda we achieve a TB [tuberculosis] therapycompletion rate of ~25% and this treatmentconsists of getting the patient to take one or twotablets a day for 6 months. If such a simpleregimen of drug treatment is so hard to achieve,how could we expect to administer the complextreatment recommended for AIDS?’ she asks.

Paze emphasizes the short-term need for healtheducation programmes to decrease HIVprevalence but accepts that a widely availableHIV vaccine effective against all subtypes of HIVwill be the only workable solution in the longterm. ‘Although the properties of HIV are makingit very difficult to develop a vaccine, the blanketvaccination of all uninfected children before theyreach sexual maturity would seriously dent theepidemic within a couple of generations.’

But are we any nearer to that goal than wewere in 1984 when HIV was first characterized asthe infective agent responsible for AIDS? While

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Ups and downs on the road to an HIV vaccine

Figure 1. The three known HIV subtype-A and subtype-C hybrid genomes indicating the regions of eachthat are related to the two parental subtypes. The genomes were isolated from infected individuals from (a) Zambia, (b) Rwanda and (c) India. Reproduced with permission from Ref. 3.

ZAM184

gag envvifpol

revtat vpu

rev neftat

vpr

92RW009.6

95IN21301

Subtype BSubtype A

a

b

c

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some experts are pessimistic, Jack Nunberg’s group(University of Montana, Missoula, MT, USA) havecountered some of the gloom with their report of anambitious, but very successful, experiment to elicitanti-HIV antibodies that can kill fresh primaryisolates from all the major subtypes4. ‘It has beenknown for a long time that infected people producea low level of antibodies that can neutralize freshisolates of HIV. No HIV vaccine candidate has everbeen able to induce neutralizing antibodies, evenagainst homologous primary isolates and we beganby asking why,’ explains Nunberg.

In 1996–1997, the discovery of the role of co-receptors in the fusion of HIV to the host cellled Nunberg to speculate that the molecularchoreography that occurs during HIV cellpenetration could be exposing epitopes that areusually hidden. He reasoned that if the process ofpenetration could be ‘frozen’ in time, then itmight be possible to identify the intermediates inthe ‘docking’ process.

Nunberg et al. engineered two types of cell;one that expressed the two HIV proteins, gp120and gp 41, the other that expressed the CD4receptor and the CCCR5 co-receptor.‘We mixedthe cells,’ says Nunberg, ‘and five hours later sawthat the cells had begun to interact and had startedto form multinucleate syncytia. We then treatedthe mixture with a weak solution of formaldehydeto cross-link the intermediates that wehypothesized were present.’

The preparation was used to immunize micetransgenic for human CD4 and CCR5 receptors.This ensured that any antibody response wouldnot be complicated by response to these humancell proteins. When the antibodies that had beenelicited in the mice were tested for theirneutralizing capacity against primary HIVisolates, the results surprised everybody in thegroup. ‘We achieved neutralization of 23 out of24 primary isolates from around the world,irrespective of phylogenetic clade. [One of thesubtype-C viruses neutralized was one of thosesequenced in Lole’s study.] This is absolutelyunprecedented’, says Nunberg

Stuart Ray (Johns Hopkins University Schoolof Medicine), another co-author of Lole’s study,finds Nunberg’s results very exciting. ‘The theorybehind these experiments is consistent withexisting paradigms. The HIV-envelope protein is asort of bullfighter’s cape. Most of it is there purelyfor show, it can mutate endlessly but the life cycleof the virus remains unaffected. Only a small partof the molecule, the part involved in fusion withthe host cell, might be conserved. If Nunberg hassucceeded in finding this part of the molecule, thatwould be fantastic, but this research is in its earlystages.’ Bollinger agrees that the results makesense biologically but also urges caution. ‘It isimportant to note that this work was carried out ina mouse model. We need to see what happens inprimates and then humans’, he says.

Nunberg himself stresses that he is only at thestart of a promising lead towards an HIV vaccinecandidate. ‘It could be that all HIV viruses have acommon functional apparatus that mediates thefusion event and that we have some of theepitopes involved within our grasp but we need togo back and do lots of experiments to confirmand refine our findings. If everything goes well,we then only have a research tool. We might needto spend many years using that tool to engineer arecombinant vaccine and take the long road fromconcept to clinically approved product.’

1 Greenough, T.C., Sullivan, J.L. and Desrosiers,R.C. (1999) Declining CD4 T-cell counts in aperson infected with nef-deleted HIV-1, NewEngl. J. Med. 340, 236–237

2 Baba, T.W. et al. (1999) Live attenuated,multiply deleted simian immunodeficiencyvirus causes AIDS in infant and adultmacaques, Nat. Med. 5, 194–203

3 Lole, K. et al. (1999) Full-length human immunodeficiency virus type 1 genomesfrom subtype C-infected seroconverters inIndia, with evidence of intersubtyperecombination, J. Virol. 73, 152–160

4 LaCasse, R. et al. (1999) Fusion-competentvaccines: broad neutralization of primaryisolates of HIV, Science 283, 357–362

Kathryn SeniorFreelance science writer

Rapid updateFDA rejects new ’flu drugThe US Food and Drug Administration (FDA) hasvoted against recommending Relenza (zanamivir),Glaxo Wellcome’s neuraminidase inhibitor for thetreatment of influenza A and B, for approval in theUSA. Although they were impressed by Relenza’ssafety profile, the Antiviral Drugs AdvisoryCommittee were not convinced of its efficacy inone of the three clinical trials presented. Relenzahas already been approved in Sweden, andapproval in Australia has been recommended.Glaxo Wellcome is now working with the FDA tosecure Relenza’s approval in the USA as soon aspossible.

Chlamydia mimics muscle protein to dodge theimmune systemIn a report published in the 5 March issue ofScience, K. Bachmeier and colleagues (Universityof Toronto, Canada) show that an antigen on thesurface of the intracellular pathogen Chlamydia,which has long been suspected by some of being acausative agent in heart disease, resembles themuscle protein myosin. Chlamydia probably use

this ‘molecular mimicry’ of a human protein toevade the host immune system, but if this tacticfails, the host runs the risk of developing anautoimmune reaction to muscle tissue.

New molecular virology centre opens in LondonThe Wohl Virion Centre, which aims to improvehuman health by bringing together internationallyrenowned clinical and non-clinical molecularvirologists, officially opened on 17 February. Thecentre will be headed by Robin Weiss, and willinitially concentrate its research efforts on HIV andAIDS (Paul Clapham), AIDS-associated cancers(Chris Boshoff), novel viruses (Robin Weiss) andviral vectors for gene therapy (Yasu Takeuchi). TheCentre is based at the Windeyer Institute forMedical Research (http://www.ucl.ac.uk/windeyer-institute/).

Leptin antagonists for immunosuppression? Professor Robert Lechler and colleagues atImperial College (London, UK), who discoveredthat leptin can cause a hypersensitivity response toimmunizations, have reached a licence agreementwith Millennium BioTherapeutics (Cambridge,MA, USA) to develop leptin antagonists asimmunosuppressants. Under the agreement,

Millennium will provide reagents for evaluation by Professor Lechler’s group. It is hoped thatthe agreement will result in novel immunosuppressants with potential intransplantation and the treatment of autoimmunedisease.

Potential use for Herceptin in prostate cancerA study by Charles Sawyers and colleagues(University of California, Los Angeles, CA, USA),published in the March issue of Nature Medicine,reveals that androgen-independent prostate tumourscan be generated in mice by stimulating the HER-2/neu signalling pathway. Prostate cancer iscurrently treated by chemical or surgical castration,which removes the antigens necessary for tumourgrowth, but unfortunately, prostate tumours have anasty habit of becoming androgen insensitive.Sawyers’ findings suggest that agents that block theHER-2/neu pathway (such as Herceptin – an anti-HER-2 antibody that was recently approved for thetreatment of HER-2-positive breast cancer) mightprevent prostate cancer cells from converting to theandrogen-insensitive phenotype.

Catherine BrooksbankMolecular Medicine Today