POTENT COMBINATION ANTI-RETROVIRAL ther-apy provides remarkable restoration of

immunity in HIV patients, with dramaticreductions in morbidity and mortality. Ithas also generated important insightsinto the dynamics and pathogenesis ofHIV. Although in many patients combi-nation therapy suppresses plasma HIVRNA to levels below those that can be de-tected with the most sensitive assays,plasma HIV RNA remains high in a signif-icant minority (20–50 percent) of pa-tients. Pre-existing drug-resistant virus,pharmacologic obstacles, suboptimal useof HIV drugs by physicians, and poor ad-herence to complicated or toxic regimensall contribute to this failure to achievesuppression. One obvious solution is thedevelopment of new drugs that are morepotent against resistant virus and lesstoxic. The paper by Kilby et al.1 in thisissue of Nature Medicine describes early re-sults from the first clinical trial of T-20, apeptide drug that inhibits HIV entry intohost cells. This is the first demonstrationof potent anti-retroviral activity directed

against a target other than reverse tran-scriptase or protease.

T-20 is a synthetic, 36-amino-acid pep-tide corresponding to residues 127–162 inthe ectodomain (extracellular portion) ofthe transmembrane segment (gp41) of theHIV envelope glycoprotein2. The peptide isthought to interfere with the conforma-tional change in gp41 (comparable to the‘spring-loaded’ conformational change inthe hemagglutinin of influenza virus dur-ing virus–host cell fusion) that is triggeredby binding of the HIV envelope glycopro-tein to the host cell CD4 receptor andchemokine co-receptor. T-20 thus preventsfusion of viral and host cell membranes3.The peptide is a specific and potent in-hibitor: a concentration of 2 ng/ml re-duces viral replication by 50 percent.

The investigators report dose–responseactivity in all 16 HIV patients treated withT-20 over the course of the 14-day study.They show a two log reduction in plasma

HIV RNA at the highest dose (100 mg),which is equivalent to the activity of themost potent drugs in the three classesnow in clinical use (nucleoside reversetranscriptase inhibitors, non-nucleosidereverse transcriptase inhibitors and pro-tease inhibitors). The authors confirmthat the relative potency of a particulardrug dose can be documented and as-sessed by frequent monitoring of plasmaHIV RNA turnover4,5.

Documentation of potency is essentialfor any new promising drug, but muchfurther investigation will be needed to as-sess the usefulness of T-20. HIV infectionis chronic and so, too, must be its treat-ment. Tolerance to long-term T-20 ther-apy and its toxicity profile must becharacterized and proven to be satisfac-tory. The durability of T-20 activitydepends on whether chronic administra-tion maintains satisfactory blood levelsand prevents the ‘escape’ of drug-resis-tant viral mutants. One or two mutationsin the target sequence of gp41 are suffi-cient to confer resistance6. Long-term

1232 NATURE MEDICINE • VOLUME 4 • NUMBER 11 • NOVEMBER 1998

NEWS & VIEWS

tion of Ser376 (but not Ser378) in the C-ter-minal portion is important for activationof p53 following IR (ref. 9). Furthermore,this dephosphorylation is not observed incells derived from AT patients, indicatingthat ATM is likely to be involved in de-phosphorylation of Ser376. This dephos-phorylation leads to association of p53with 14-3-3 protein resulting in a con-comitant conformation change in p53that increases its DNA-binding activity.However, it is still unclear whether DNAdamage induced by ultraviolet light alsoresults in dephosphorylation of Ser376.Currently, the only ultraviolet-specific ef-fect on p53 in vivo (not seen with IR orother genotoxic agents) is the phosphory-lation of p53 on Ser389 in mouse, whichcorresponds to Ser392 in human10.

Although much information on the reg-ulation of p53 has accumulated, the mech-anisms by which p53 mediates cell-cyclearrest or apoptosis still remain unclear.There must be some way to specify whichtarget genes of p53 are to be selected. Thedifferent serine phosphorylation sites inthe p53 protein may be the ‘sensors’ thatchoose which target genes become acti-vated. The amount and type of DNA dam-

age and the subsequent activation of dif-ferent p53-modifying proteins may be keyevents in this selection process.

ATM is certainly one of the most im-portant p53-modifying proteins.However, various clinical manifestationsof AT—such as predominant neuronaldegeneration in the cerebellum, or hy-pogonadism—cannot be explained byloss of p53 phosphorylation through dys-functional ATM. Other proteins that aretargets of ATM kinase activity or otherdomains of ATM may have importantroles in these pathological conditions.The results of the Canman and Baninstudies show the direct link between ATMand p53, and shed light on the molecularmechanism that underlies hypersensitiv-ity to IR in AT patients and their greatersusceptibility to cancer. But we need torealize that what we have found is but asmall sample of the various physiologicalfunctions of ATM. Let’s not forget thatsometimes it is hard to see the wood forthe trees.

1. Savitsky, K. et al. A single ataxia telangiectasia genewith a product similar to PI-3 kinase. Science 268,1749–1753 (1995).

2. Banin, S. et al. Enhanced phosphorylation of p53 by

ATM in response to DNA damage. Science 281,1674–1677 (1998).

3. Canman, C.E. et al. Activation of the ATM kinase byionizing radiation and phosphorylation of p53.Science 281, 1677–1679 (1998).

4. Savitsky, K. et al. The complete sequence of the cod-ing region of the ATM gene reveals similarity to cellcycle regulators in different species. Hum. Mol. Genet.4, 2025–2032 (1995).

5. Kastan, M.B. et al. A mammalian cell cycle checkpointpathway utilizing p53 and GADD45 is defective inataxia telangiectasia. Cell 71, 587–597 (1992).

6. Shieh, S.-Y., Ikeda, M., Taya, Y. & Prives, C. DNAdamage-induced phosphorylation of p53 alleviatesinhibition by MDM2. Cell 91, 325–334 (1997).

7. Woo, R.A., McLure, K.G., Lees-Miller, S.P., RancourtD.E. & Lee. P.W.K. DNA-dependent protein kinaseacts upstream of p53 in response to DNA damage.Nature 394, 700–705 (1998).

8. Ko, L.J. et al. p53 is phosphorylated by CDK7-cyclin Hin a p36MAT1-dependent manner. Mol. Cell. Biol. 17,7220–7229 (1997).

9. Waterman, M.J., Stavridi, E.S., Waterman J.L.F. &Halazonetis T.D. ATM-dependent activation of p53involves dephosphorylation and association with 14-3-3 proteins. Nature Genet. 19, 175–178 (1998).

10. Lu, H., Taya, Y., Ikeda, M. & Levine A.J. Ultraviolet ra-diation, but not γ-irradiation or etoposide-inducedDNA damage, results in the phosphorylation of themurine p53 protein at serine 389. Proc. Natl. Acad.Sci. USA 95, 6399–6402 (1998).

Laboratory of Molecular MedicineHuman Genome CenterInstitute of Medical ScienceThe University of TokyoTokyo, Japan

Nailing down another HIV target The T-20 peptide targets the HIV envelope glycoprotein, inducing dose-dependent reductions in plasma HIV RNA

that are equivalent to those induced by existing drugs (pages 1302–1307).

DOUGLAS D. RICHMAN

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NATURE MEDICINE • VOLUME 4 • NUMBER 11 • NOVEMBER 1998 1233

studies of combination therapy using T-20 and other anti-retroviral drugs willthus be essential.

The issue of chronic administration isnot trivial. A 36-amino-acid moleculecannot be absorbed after oral administra-tion. This precludes the consideration ofthis drug for initial use in asymptomaticHIV patients. Chronic parenteral admin-istration will only be considered for pa-tients who, because of drug resistance,have exhausted more convenient op-tions. In addition, the distribution of alarge hydrophobic molecule into criticalcompartments of HIV replication, such asthe genital tract and central nervous sys-tem, remains a concern.

The observations reported by Kilbyand colleagues provide a proof-of-con-cept and certainly any new drug thatshows promise against HIV is very wel-come. But this study raises several ques-tions. First, if a complicated peptide

shows this level of potency, could asmaller molecule with more desirablepharmacologic characteristics (oralbioavailability and central nervous sys-tem penetration) be designed with simi-lar activity? Second, are there otheressential interactions of HIV proteinswith the host cell that can be interruptedwith small molecule ligands? Viral re-verse transcriptase, protease and inte-grase have been the obvious targets forHIV drug discovery so far. However, asthis study suggests, many other essentialnon-enzymatic targets (including pro-tease dimerization, matrix zinc fingers7,and tat-TAR RNA complexes8) are provid-ing new opportunities to enable us tocontend with this challenging virus.

1. Kilby, J.M. et al. Potent suppression of HIV-1 repli-cation in humans by T-20, a peptide inhibitor ofgp41-mediated virus entry. Nature Med. 4,1302–1307 (1998).

2. Wild, C., Oas, T., McDanal, C., Bolognesi, D. &

Matthews, T. A synthetic peptide inhibitor of HIVreplication: Correlation between solution structureand viral inhibition. Proc. Natl. Acad. Sci. USA 89,10537–10541 (1992).

3. Chan, D.C., Fass, D., Berger, J.M. & Kim. P.S. Corestructure of gp41 from the HIV envelope glycopro-tein. Cell 89, 263–273 (1997).

4. Wei, X. et al. Viral dynamics in human immunode-ficiency virus type 1 infection. Nature 37, 117–122(1995).

5. Ho, D.D. et al. Rapid turnover of plasma virionsand CD4 lymphocytes in HIV-1 infection. Nature373, 123–126 (1995).

6. Rimsky, L.T., Shugars, D.C. & Matthews, T.Determinants of HIV-1 resistance to gp41-derivedinhibitory peptides. J. Virol. 72, 986–992 (1998).

7. Rice, W.G. et al. Inhibitors of HIV nucleocapsid pro-tein zinc fingers as candidates for the treatment ofAIDS. Science 270, 1194–1197 (1995).

8. Mei, H.-Y. et al. Inhibitors of protein-RNAcomplexation that target the RNA: Specific recog-nition of human immunodeficiency virus type 1TAR RNA by small organic molecules. Biochemistry(in the press).

Departments of Pathology and MedicineUniversity of California San Diego andSan Diego VA Medical CenterSan Diego, California 92093-0679, USA

NEWS & VIEWS

OUR UNDERSTANDING OF AIDS pathogene-sis has been influenced profoundly

by mathematical analyses of viral dynam-ics within infected individuals1–5. Thesestudies show that even during periods ofclinical quiescence an active process of de-struction and replacement of HIV-in-fected cells continues;thus, they have changedthe way we think aboutboth treatment and thenatural history of HIV.Emboldened by the suc-cess of this quantitativeapproach to virology,scientists have begun toapply similar methodsto other chronic viralinfections. In a land-mark paper in Science,Neumann et al.6 use amathematical model toquantify the dynamicsof infection with the he-patitis C virus (HCV),and to estimate the anti-viral efficacy of treat-ment.

Since its identifica-tion in the late 1980s,HCV has emerged as aleading cause of

chronic liver injury around the world.Primary HCV infections are typically ac-quired from sexual or parenteral expo-sure. Although some infections are

cleared spontaneously, most evolve topersistence, with the result that about1–2 percent of the general population ischronically infected. Many such patientsexperience asymptomatic carriage of thevirus, but a substantial fraction with per-sistent HCV infection display evidence of

liver injury, and 10–20percent of such casesprogress to cirrhosisover a 20-year inter-val7. HCV cannot begrown in culture andwill not infect conve-nient laboratory ani-mals, so little is knownof the molecular mech-anisms of viral replica-tion, and even less isknown about the dy-namics of viral popula-tions within infectedhosts. Hence, the de-velopment of effectivetreatment strategieshas been severely con-strained. The mostwidely used treatmentfor HCV is α-interferon(IFN)—a therapeuticbase hit, but certainlynot a home run. Only

Mathematicians turn their attention to hepatitis C Mathematical models can increase our understanding of the pathogenesis and treatment of viral infections

including that caused by the hepatitis C virus.

SALLY BLOWER & DON GANEM

Dynamics of hepatitis C virus infection

Rate of productionof target cells, S

Reduction in theinfection rate due

to IFN

Reduced virionproduction due

to IFN

Rate of infectionof target cells

(I_η) βVT

Rate of productionof virions(I_ε) pI

Uninfectedtarget cells

T

Productivelyinfected

target cellsI

Cell deathdT

Viral loadV

Clearanceof virions

cV

Cell deathδI

A flow-diagram of a mathematical model, developed by Neumann et al.6, that reflectsthe dynamics of hepatitis C virus infection within the host in the presence or absence ofinterferon (IFN) treatment.

Bob

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