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NATURE MEDICINE VOLUME 10 | NUMBER 3 | MARCH 2004 229

HIV escape: there and back againJohn D Altman & Mark B Feinberg

HIV mutates to avoid the pressure of the immune system. This process is balanced by the need of the virus to replicateefficiently. Two studies examine this dynamic as the virus infects new hosts (pages 275–281 and 282–289).

HIV is a moving target. The virus replicatesrapidly and has a high mutation rate creat-ing highly diverse ‘quasispecies’. These qua-sispecies are fertile substrates fordarwinian selective pressures favoring thebest-adapted, most ‘fit’ genetic variants.Efforts to develop effective treatments andvaccines must overcome the complex evo-lutionary dynamics in HIV-infected indi-viduals and within affected populations.

As HIV spreads from individual to indi-vidual, genetically diverse viruses confrontthe most highly polymorphic gene familyin humans—that encoding the humanleukocyte antigen (HLA) class I and II pro-teins. These proteins determine which spe-cific peptide sequences (epitopes) arepresented to and recognized by host CD8+

and CD4+ T cells, respectively. In the con-frontation between genetically diverse HIVvariants and genetically diverse humanhosts, viral variants can be selected thatharbor mutations in specific viral epitopesthat escape recognition by host immuneeffector cells. This process, in which repli-cating HIV quasispecies adapt in responseto selective pressures exerted by host virus-specific immune responses, has been beststudied in the case of HIV-specific cyto-toxic T lymphocytes (CTLs), which recog-nize and kill virus-infected cells.

In this issue, two reports examine theforces governing selection of CTL escapevariants within individuals, and the abilityof these variants to persist upon second- Given the difficulties in eliciting anti-

body responses that effectively neutralizeHIV, efforts to develop an effective vaccinehave focused on the induction of cellularimmune responses (especially CD8+ Tcells) to HIV antigens3. Although vaccine-elicited CTL responses are unlikely to pre-vent infection outright, they will hopefullycontrol HIV replication, slow the progres-sion to AIDS and decrease secondary trans-mission.

ary transmission1,2. These reports provideinformative examples of how relative viralfitness costs associated with different CTLescape mutations can influence whichvariants emerge in infected individuals,and which are transmitted to and persistwithin new hosts. The results frame fun-damental questions that need to beresolved as the AIDS pandemic expandsand as vaccine development efforts striveto stop it.

Figure 1 Balancing selection pressure against fitness cost. (a) Targeting of multiple epitopes by cytotoxic Tlymphocytes (CTLs). In some cases, CTL responses may positively select for mutant viruses containingsequences within these epitopes that are no longer recognized by the CTL9. Each selected mutation will carrya potential replicative fitness cost. (b) A primary host capable of making CTL responses to epitopes A, B andC. The fitness landscape changes and mutants are positively selected, even at the cost of reduced viral fitness(though some mutations, as in epitope C, may be incompatible with replication). (c) The selected mutants arereturned to a nonselecting environment, such as a host that does not share HLA alleles with the donor.Reversion will depend on where the mutation lies along the fitness continuum. (d) Transmission of selectedmutants to a host that shares HLA alleles with the donor. Not only do the neutral mutations remain fixed(such as epitope A), but the mutations associated with a significant replicative fitness cost (such as epitopeB) also fail to revert. This strongly suggests that ‘selecting secondary hosts’ mount an effective CTL responsespecific for the wild-type epitope B, although such responses have thus far eluded detection.

a CTL pressure and fitness cost

inearirus map

eplicationtness cost

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John D. Altman is in the Department of

Microbiology and Immunology, and Mark B.

Feinberg is in the Department of Medicine and the

Department of Microbiology and Immunology,

Emory University School of Medicine; both authors

are also at the Emory Vaccine Center,

Atlanta, Georgia 30329, USA.

e-mail: mbf@sph.emory.edu

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230 VOLUME 10 | NUMBER 3 | MARCH 2004 NATURE MEDICINE

This hope has been tempered by recentstudies that have suggested that, with timeand successive transmission events, CTLescape mutations may become fixed in cir-culating HIV quasispecies in response toselective pressure from CTL responsesrestricted by the most prevalent HLA alle-les4,5. If these inferences are correct, HIVpopulations may evolve to become increas-ingly ‘invisible’ to the CTL responsesrestricted by the HLA alleles that predomi-nate in a given human population—mak-ing HIV vaccine immunogen selection aneven more complicated process than cur-rently appreciated6. For such population-level outcomes to occur, however, CTLescape variants would need to persist andbe favored as the virus is transmitted fromone person to another.

Escape from the epitope-specific CTLresponses generated by an infected personis not universal. Indeed, many epitope-encoding sequences persist in replicatingvirus populations, even in the face ofstrong specific CD8+ T-cell responses7. Thereasons why some epitopes targeted byCTLs give rise to escape mutations, whileothers do not, are not completely under-stood. In some cases, structural constraintson key viral functions make certain poten-tial escape mutations incompatible withvirus replication. However, for these andother, less constrained, epitopes, CTLs maypersist but be functionally impaired. Theconsequences of CTL escape and dysfunc-tion help explain why there is no clear asso-ciation between the level of HIVantigen–specific CD8+ T cells and controlof viremia8.

Mutations at epitopes targeted by differ-ent CTL responses can arise with widelyvarying kinetics9. Rapidly emerging vari-ants are likely to face a low ‘genetic barrier’(requiring only one or a few nucleotidechanges) and carry a low fitness cost. Incontrast, mutations arising later are likelyto carry a higher fitness cost and mustovercome higher genetic barriers, requiringadditional compensatory mutations, toenable appreciable viral replication (Fig. 1a).

Mutations with a relatively low fitnesscost are expected to revert slowly or not atall upon transfer to a second host, even ifthe new host does not share the samerestricting HLA allele as the original host(Fig. 1b–d). In this way, escape mutationscan propagate throughout a popula-tion4,5,10, as has also been observed forinfluenza A (ref. 11). The fate, upon trans-mission, of escape mutations with high fit-

ness costs is more complicated, and rever-sion may not occur if the new host sharesthe relevant HLA class I allele (and CTLresponse to the parental epitope) with thevirus donor.

Leslie et al.1 focused on a specific CTLepitope in the HIV-1 Gag protein1. Thisepitope is restricted by two related HLAalleles, HLA-B57 and HLA-B*5801, both ofwhich are associated with delayed progres-sion of HIV disease12. The authors foundthat the majority of B57-positive orB*5801-positive HIV-infected individualsselect for CTL escape variants in this Gagepitope. Notably, the authors also observedthat the gag mutation that enabled CTLescape reverted to wild type after transmis-sion to individuals with HLA class I allelesother than B57 and B*5801. In contrast, asecond mutation within the same epitopedid not revert after transmission to HLA-unrelated hosts.

These data indicate that relative fitnesscosts can influence the selection for andreversion of CTL escape variants in HIV-infected individuals. They also show thatthe ability of CTL escape variants to dis-seminate within human populations iscomplex, involving the magnitude of selec-tion pressure exerted by specific CTLs, thefitness costs associated with CTL escapemutations, and the relative probability thatthe emergent escape variants will be trans-mitted to individuals who share the rele-vant restricting HLA class I alleles.

Friedrich et al.2 explored CTL escapemutant fitness and persistence after trans-mission of SIV in experimentally infectedrhesus macaques2. The authors focused onthree well-characterized epitopes (one eachin Gag, Tat and Nef) that are restricted bydefined macaque MHC class I alleles. Thekinetics of selection for CTL escape vari-ants in these epitopes had been definedpreviously, with mutations arising in theTat epitope early in infection, in the Nefepitope somewhat later, and in the Gag epi-tope less readily and only after prolongedinfection.

Friedrich et al. found that an SIV variantengineered to include all three CTL escapemutations replicated less well than thewild-type virus in tissue culture. However,despite the significant fitness impairmentobserved ex vivo, the engineered virusremained stable after infecting macaquesexpressing restricting MHC class I alleles.In contrast, the Gag and Nef epitopesreverted to wild-type sequences withinweeks after infection of MHC class I–mis-matched macaques, whereas the Tat epi-

tope did not revert. These data indicatethat the Tat escape variants carry little, ifany, fitness cost, whereas the specific Gagand Nef mutations do carry such a burden.In the absence of a relevant immuneresponse, the revertants outcompete thesluggish escape variants.

Not surprisingly, both studies documentsimilar phenomena, as evolutionary theorypredicts that some CTL epitopes will revertand others will not, depending on relativefitness and the magnitude of selective pres-sure. The data are also in line with thedynamics of HIV evolution in response toantiretroviral drug treatment. We nowappreciate how considerations of drugpotency, genetic barriers and fitness costsinfluence the emergence of drug-resistantHIV variants. With these insights, theeffectiveness of antiretroviral therapy hasimproved substantially13. HIV replicationcan now be durably controlled usingrational combinations of drugs that indi-vidually do not appear very promising, butcollectively can modulate the outgrowth ofviral variants with reduced susceptibility toantiviral drugs.

Just as we have learned to juggle combi-nations of antiretroviral drugs, we mustsimilarly learn to define the most effectivearray of immunogens in a vaccine. Theultimate goal is to produce HIV vaccinesthat elicit immune responses that containvirus replication as effectively as contem-porary antiretroviral therapies. These newstudies of CTL escape help illuminate theopportunities and challenges that lieahead, as AIDS vaccine efforts strive toovercome the extraordinary diversity ofHIV and its complex interactions with thehuman immune system.

1. Leslie, A.J. et al. Nat. Med. 10, 282–289 (2004). 2. Friedrich, T.C. et al. Nat. Med. 10, 275–281

(2004). 3. McMichael, A.J. & Hanke, T. Nat. Med. 9,

874–880 (2003).4. Moore, C.B. et al. Science 296, 1439–1443

(2002).5. Yusim, K. et al. J. Virol. 76, 8757–8768 (2002).6. Gaschen, B. et al. Science 296, 2354–2360

(2002).7. Draenert, R. et al. J. Virol. 78, 630–641 (2004).8. Betts, M.R. et al. J. Virol. 75, 11983–11991

(2001).9. Klenerman, P., Wu, Y. & Phillips, R. Curr. Opin.

Microbiol. 5, 408–413 (2002).10. Trachtenberg, E. et al. Nat. Med. 9, 928–935

(2003).11. Gog, J.R., Rimmelzwaan, G.F., Osterhaus, A.D. &

Grenfell, B.T. Proc. Natl. Acad. Sci. USA 100,11143–11147 (2003).

12. Carrington, M. & O’Brien, S.J. Annu. Rev. Med.54, 535–551 (2003).

13. Feinberg, M.B. in The Human ImmunodeficiencyVirus: Biology, Immunology, and Therapy (ed.Emini, E.A.) 384–440 (Princeton UniversityPress, Princeton, 2002).

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