1094 NATURE MEDICINE • VOLUME 6 • NUMBER 10 • OCTOBER 2000

Containing HIV after infectionInvestigation into the ability of anti-retroviral therapy and therapeutic immunization in primary simian

immunodeficiency virus infection of macaques demonstrates the importance of anti-retroviral treatment in earlyinfection. The findings also indicate that it may be possible to boost the virus-specific immune response through

immunization (pages 1140–1146).

MANY HUMAN VIRUSES such as Epstein Barrvirus and cytomegalovirus establish

chronic infections that are contained butnever eradicated by an effective immuneresponse. This is not true for human im-munodeficiency virus (HIV), which infectsthe CD4 T cells that are central to effectiveimmune control. The failure of the im-mune response to contain HIV leads toeventual global immune suppression.

However, a very small percentage ofHIV-infected persons seem to be able tocontrol HIV, with no evidence of diseaseprogression after 20 or more years of un-treated infection1. Data indicating thatthis control is associated with particularlyeffective cellular immune responses (cyto-toxic T lymphocytes (CTLs) and T-helpercells) have raised hopes that the immunesystem might be induced to more effec-tively contain HIV (refs. 2–4). In this issue,Hel et al.5 present data from an animalmodel indicating apparent successful im-mune containment of an AIDS-like virusafter drug therapy and therapeutic immu-nization administered early after initial in-fection. These results are importantadditions to other studies of acute AIDSvirus infections after treatment6,7, and in-dicate that immune control of HIV mayindeed be a realistic goal.

As the immune system is the main tar-get of HIV, treatment strategies based onaugmenting immunity may seem counter-intuitive. In fact it is the advent of highlyactive antiviral therapy (HAART) that nowgives this hypothesis a compelling scien-tific rationale. Although HAART seems in-capable of virus eradication8, it does leadto the generation of new naive cells9. Thisfinding, along with newer data indicatingthat the thymus remains active in adultson HAART (ref. 10), indicate that thesecells might be ‘educated’ to participate inthe host defense against HIV. The possibil-ity of augmenting immunity has also beensupported by the demonstration that thehost immune response, particularly CTLsand T-helper cells, are involved in controlof viremia, and that early HAART leads toan augmentation in T helper-cell re-sponses in people with acute HIV infec-tion2,11,12.

Any attempt to boost HIV-specific im-

munity depends on a source of antigen. Inpatients on HAART, immune responses toviruses other than HIV are restored at leastin part by therapy alone, and have led toimmune recovery inflammatory syn-dromes associated with augmented immu-nity to pathogens such as mycobacteriaand cytomegalovirus. In contrast to thesepathogens, which supply a persistent levelof antigen to the immune system, HAARTtypically leads to such profound HIV sup-pression that even occasional small in-creases in viremia may be insufficient tostimulate cellular immune responses. Thishas prompted two hypotheses: that re-ex-posure to regulated amounts of autologousvirus through structured treatment inter-ruption might boost effective immunity,and that therapeutic immunization mightlead to induction of functional immuneresponses, particularly CTLs and T-helpercells.

The study by Hel et al. directly addressesthese issues in an animal model5. Rhesusmacaques were infected with simian im-munodeficiency virus (SIV), the monkeyequivalent of HIV. After 2 weeks, withvirus rapidly expanding in the blood, theauthors intervened with potent antiviraltherapy and therapeutic immunizationwith a highly attenuated vaccine vectorexpressing SIV gag, pol and env (Fig. 1). Inmacaques receiving vaccine alone, immu-nity to SIV remained weak and disease pro-gressed rapidly. In contrast, the macaquestreated with antiviral therapy and vaccineinduced strong CTL responses to the re-gion of gag that was tested, and also devel-oped T helper-cell responses to gag.

When therapy was discontinued at 27weeks, all of the macaques in whichviremia was controlled during immuniza-tion continued to control viremia5.However, comparison with the macaquesthat received antiviral therapy alonemakes the actual contribution of the im-munization unclear. Despite augmentedSIV-specific cellular immune responses inthose receiving HAART and vaccine com-pared with those with HAART alone, once

therapy was stopped, most (four of seven)of the macaques receiving antiviral ther-apy alone were also able to controlviremia.

These studies allow for many salientconclusions to be drawn, and generatequestions for future studies. They conclu-sively show that cellular immunity can beboosted by therapeutic immunization inthe early stages of an AIDS virus infection,and that this is only successful if viremia iscontained when vaccine is administered.They also show that lowering viral loadduring early SIV infection alters the viralset-point, and adding to previous stud-ies6,7. To what extent the immune re-sponses present are responsible forenhanced immune control is yet to be de-termined, and it will be essential to exam-ine the function of neutralizing antibodiesas well.

Additional questions include whetherthe CTL response can be broadened ratherthan simply boosted, and whether thelong-term clinical benefits of vaccine plusHAART are likely to be better than HAARTalone. Although the viral set-pointachieved is lower after stopping therapy,how long this will be maintained can onlybe determined with additional follow-up.Whether more than one treatment inter-ruption will further augment virus-specificimmune responses and better controlviremia has not been tested.

What are the immediate clinical conse-quences of this study for HIV infection?The findings of Hel et al.5 add importantcontrolled data to anecdotal cases inwhich subjects have controlled viremiaafter medicines are discontinued13,14. Butall of these cases involved animals or hu-mans that were treated in the earlieststages of acute infection. The larger ques-tion facing the clinical community andpersons afflicted with HIV is whetherstructured treatment interruption or thera-peutic vaccination will be beneficial inchronic infection. There is a clear scientificrationale to support the potential for ther-apeutic vaccination, although structuredtreatment interruption may be a muchmore difficult approach.

Dealing with chronic infection repre-sents a greater challenge, in part because

BRUCE D. WALKER & ERIC S. ROSENBERG

NEWS & VIEWS © 2000 Nature America Inc. • http://medicine.nature.com

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NATURE MEDICINE • VOLUME 6 • NUMBER 10 • OCTOBER 2000 1095

NEWS & VIEWS

virus variability is greater. Thisleaves the immune system to dealwith a large number of viral vari-ants, rather than the homogeneouspopulation seen in acute infection.In addition, the lack of virus-spe-cific T-helper cells in patients withtreated chronic infection raisesconcerns as to whether effectiveimmune augmentation can beachieved, as it is apparent that T-helper cells are essential in orchestrating effective immune re-sponses15. Clinical studies will nodoubt answer these questions, butuntil they are completed in highlycontrolled clinical research set-tings, HIV-infected persons are ad-vised to remain on theirmedications.

1. Harrer, T. et al. Cytotoxic T lymphocytes inasymptomatic long-term nonprogressingHIV-1 infection. Breadth and specificity ofthe response and relation to in vivo viralquasispecies in a person with prolonged in-fection and low viral load. J. Immunol. 156,2616–2623 (1996).

2. Rosenberg, E.S. et al. Vigorous HIV-1-spe-cific CD4+ T cell responses associated withcontrol of viremia. Science 278,1447–1450 (1997).

3. Ogg, G.S. et al. Quantitation of HIV-1-spe-cific cytotoxic T lymphocytes and plasmaload of viral RNA. Science 279, 2103–2106(1998).

4. Kalams, S.A. et al. Association betweenvirus-specific cytotoxic T-lymphocyte andhelper responses in human immunodefi-ciency virus type 1 infection. J. Virol. 73,6715–6720 (1999).

5. Hel et al. Viremia control following anti-retroviral treatment and therapeutic immu-nization duringn primary SIV251 infection ofmacaques. Nat. Med. 6, 1140–1146 (2000).

6. Watson, A. et al. Early postinfection antiviraltreatment reduces viral load and preventsCD4+ cell decline in HIV type 2-infectedmacaques. AIDS Res. Hum. Retrovir. 13,1375–1381 (1997).

7. Lifson, J.D. et al. Containment of simian im-munodeficiency virus infection: cellular im-mune responses and protection fromrechallenge following transient postinocu-lation antiretroviral treatment. J. Virol. 74,2584–2593 (2000).

8. Finzi, D. et al. Latent infection of CD4+ Tcells provides a mechanism for lifelong per-sistence of HIV-1, even in patients on effec-tive combination therapy. Nature Med. 5,512–517 (1999).

9. Autran, B. et al. Positive effects of com-bined antiretroviral therapy on CD4+ T cellhomeostasis and function in advanced HIVdisease. Science 277, 112–116 (1997).

10. Douek, D.C. et al. Changes in thymic func-tion with age and during the treatment ofHIV infection. Nature 396, 690–695(1998).

11. Schmitz, J.E. et al. Control of viremia insimian immunodeficiency virus infection byCD8+ lymphocytes. Science 283, 857-860(1999).

12. Jin, X. et al. Dramatic rise in plasma viremiaafter CD8(+) T cell depletion in simian im-munodeficiency virus-infected macaques. J.Exp. Med. 189, 991–998 (1999).

13. Lisziewicz, J. et al. Control of HIV despitethe discontinuation of antiretroviral ther-apy. N. Engl. J. Med. 340, 1683–1684(1999).

14. Ortiz, G.M. et al. HIV-1-specific immune re-sponses in subjects who temporarily con-tain virus replication after discontinuationof highly active antiretroviral therapy. J.Clin. Invest. 104, R13–18 (1999).

15. Zajac, A.J. et al. Viral immune evasion dueto persistence of activated T cells withouteffector function. J. Exp. Med. 188,2205–2213 (1998).

Harvard Medical SchoolPartners AIDS Research Center149 13th Street CNY 5212Charlestown, MA 02129Email: bwalker@helix.mgh.harvard.edu

Fig. 1. Strategy for SIV therapeutic immunization. Macaques (n =24) infected with pathogenic SIV were allowed to establish acuteinfection, then treated with anti-retroviral therapy (ART) plus‘mock’ vaccine (left), ART plus a highly attenuated SIV-gag-pol-env-based vaccine (center), or SIV vaccine alone. After discontinu-ation of ART, virus rebounded in most macaques. However, six ofeight vaccinated macaques showed suppressed viral replicationand contained viral replication thereafter. Unexpectedly, four ofseven ‘mock-vaccinated’ macaques were also able to controlviremia after ART was discontinued. This indicates that ART is veryeffective in controlling viremia when administered during early in-fection, and that virus-specific immune responses can be ex-panded by therapeutic immunization. (*) 1 death due todrug-associated toxicity.

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Skin stem cells – a hairy issue.The hair follicle is a major repository for epidermal stem cells. Learning more about the processes that regulate the

differentiation of these cells will improve the prospects for skin replacement and treatments for skin cancers.

MANY PEOPLE ONLY think about hair folli-cle activity when they need a haircut

or shave. However, recent research indi-cates that hair follicle epithelial cells alsoplay a key role in skin stem cell biology. Ina recent issue of Cell, Taylor et al. reportedthe use of an elegant double-labeling tech-nique to trace the distribution and prolif-erative activity of hair follicle epithelialcells over long periods in newborn andwounded adult mice1. The authorsdemonstrated that progeny of epithelialcells, located in the upper follicle bulge,not only incorporate into hair-forming el-ements low down in the follicle, but alsomove up and out from the follicle outer

root sheath (ORS) into the epidermis ofadjoining skin.

This is new experimental evidence thatthe follicular stem cell population has adual function in making hair and con-tributing to skin epidermis. It is impor-tant because identifying skin stem cellsand learning about the processes that reg-ulate these stem cells will improve theprospects for skin replacement, skin-based tissue engineering and treatmentsfor skin cancers. These findings may also

aid skin-based gene therapies, as recentstudies in hair follicle transfection havedemonstrated that progenitor cells are se-lectively targeted by a lipid-based deliverysystem2.

Follicle epithelium has long been recog-nized as a source of epidermis in healingwounds. Indeed, clinically, this phenome-non underpins autologous split-thicknessgrafting, a process in which the epidermisand some underlying dermis is removedfrom a healthy skin site and grafted to a de-fective region. At the donor site, the re-placement epidermis comes fromremnants of hair follicles and gland epithe-lium in the dermis. The findings of Taylor

COLIN JAHODA &AMANDA REYNOLDS

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