Full Article In

AIDS Rev 1999; 1: 51-56

Immune Reconstitution Under Highly Active Antiretroviral Therapy (HAART)

Guislaine Carcelain, Taisheng Li and Brigitte Autran

Laboratoire d'Immunologie Cellulaire, Hôpital Pitié-Salpétrière, Paris, France

Abstract

Highly active antiretroviral therapies (HAART) have been shown to induce a major and durable viral load reduction accompanied by stable CD4 increases that had never been observed previously. Consequently, dramatic declines in the mortality and morbidity of HIV-infected persons have been registered in all industrialized countries. All these observations had raised the question of immune restoration and its mechanisms. Recent studies have concluded that at whatever the stage of the disease HAART is introduced, it allows immune restoration and protection against opportunistic pathogens. The single condition required for this goal is an efficient and durable inhibition of virus replication. HIV does not definitively alter the lymphoid tissues nor the immune defenses, even after years of infection and severe immunedeficiency, except for HIV-specific CD4 T helper cells. The delay in recovery or the lack of reconstitution of a solid immunity against HIV itself might prompt additive therapeutic strategies based upon immune interventions, such as the administration of IL-2 or therapeutic vaccinations to resuscitate immune responses to HIV.

Key words

Immune reconstitution. HAART. Opportunistic infections. Thymus.

Introduction has been registered in all industrialized countries6,7. The course of HIV infection has been dramatic- These rapid successes contrast with the slower im- ally modified since the introduction of highly active mune reconstitution observed after myeloablative 8 antiretroviral therapy (HAART), combining inhibitors chemotherapy in adults and involves both a re- of the HIV-1 reverse transcriptase and protease. circulation of mature peripheral T cells and a 1,4,5 Despite some controversiesNo partabout ofthe extentthis topublicationregeneration of maynaïve T becells from thymic origin . which the immune system can normalize, it is gen- Although these recent advances warrant increased erally admitted nowadays that a numerical and optimism, HAART by reducing the virus burden is reproduced or photocopying 1,10 functional CD4 cell profile more akin to asympto- unable to restore immunity against HIV itself , ex- matic HIV-infected individuals can be restored in cept when introduced at the very early stage after 11 AIDS patients and withoutcan confer hostthe protection prior writtenvirus inoculation permission. Considering that improvements against opportunistic events1-5. The best hallmark in T cell homeostasis, functions and repertoires of such immune restoration is the massive decline contribute to a better understanding of the patho- in the mortality and morbidity related toof AIDS the that publisherphysiology of the HIV infection and to the definition of new end-points for antiretroviral therapies, we will Correspondance to: hereby review the immunological data obtained Brigitte Autran during the past two years with such therapy, and Laboratoire d'Immunologie Cellulaire, CNRS UMR 7627 will discuss the mechanisms, current limitations and Hôpital Pitié-Salpétrière© Permanyer Publications 2010 47-83, bld de l’hôpital, Bâtiment CERVI perspectives of immune restoration. 75013 Paris, France AIDS Rev 1999; 1

Fig. 1. The two-phase increase in CD4 cells among patients who respond to HAART. (1A) HAART initiation during late disease: a first increase, usually rapid and large, represents redistribution of memory CD4 T cells that had been previously sequestered in lymphoid tissues; (1B) a second slow but steady increase reflects regeneration of naïve CD4 T cells.

Obstacles to immune reconstitution before compensate for cell losses and be responsible for the era of HAART the rapid increase of CD4 counts observed after re- duction of viral replication with treatment. However The HIV infection generates progressive dis- no evidence could support such hypothesis13,14 orders in the immune system, the hallmark of which and cell proliferation is severely limited during dis- is a major decline in CD4 cell numbers. HIV infec- ease progression by the CD4 T cell energy and lack tion is also accompanied by profound qualitative of IL-2 production15. In addition thymic T cell re- changes in the CD4+ and CD8+ lymphocyte sub- generation of naïve CD4 T cells also decreases as sets and by defects in the functional performances a consequence of thymus involution with age and of peripheral lymphocytes.No By part correcting of thesethis de- publicationinfection by HIV may16. Numerous be phenotypic abnor- fects HAART has helped to better understand the malities were reported such as a preferential loss in role played by HIV in the pathophysiology of im- naïve CD4+ T cells co-expressing the CD45RA and mune disorders. Losses in peripheralreproduced CD4 T cells or photocopyingthe CD62L markers that reflect the altered thymic are thought to result from cumulative virus cell repli- production, an increased expression of activation cation in the CD4 cell subpopulation either by direct cell markers: CD25, HLA-DR, CD38 and Fas that virus pathogenicity and/or,without mostly by the CTL-mediated prior writtenenhance sensitivity permission to apoptosis 17, decreased ex- cytolysis, and from activation-induced cell death of pression of CD28 and CD7, markers associated to "innocent" non-infected cells. Meanwhileof compen- the publisherT cell competence and T-helper differentiation18,19. sation by newly produced T cells progressively di- Function T cell defects were assessed by a pro- minishes during the course of the infection. A major gressive loss in T helper-1 cell reactivity and IL-2 controversy was raised as to whether the turn-over production against recall antigens and opportunistic of peripheral mature CD4+ T cells was massively pathogens15,20, while the CD4 Th-1 response to AIDS REVIEWS enhanced©12. AccordingPermanyer to this hypothesis, anPublications in- HIV might be lost at an early 2010 stage after the pri- 52 creased CD4 cell proliferation should take place to mary infection11. Normalizing these phenotypes and Guislaine Carcelain, et al.: Immune Reconstitution under Highly Active Antiretroviral Therapy (HAART)

Fig. 2. Functional immune reconstitution when HAART is initiated during late disease.The rapid viral load reduction allows an early decrease of T cell activation that correlates with the reappearance of CD4 cell responses to opportunistic antigens contrasting with the lack of restoration of CD4 T cell responses to HIV antigens and a decrease of HIV-specific CTL activity.

functions would require both a full thymic function to were observed in the CD8 T cell repertoires as ear- regenerate naïve T cells capable to protect against ly as at primary infection25 and even in long term new pathogens and a correction of memory T cell non progressors. However these perturbations defects that would restore defenses against previ- mostly reflect active mobilization of specific CD8 T ously encountered pathogens. cell clones rather than holes in the repertoire and The HIV also induces major host cell defenses should not either limit the possibility of CD8 T cell mediated by cytotoxic CD8 T lymphocytes, the con- regeneration. tinuous activation of which is maintained by the per- Finally, the lack of significant immunological im- manent HIV replication and leads to progressive ex- provement obtained after monotherapy with nucleo- haustion of the anti-HIV defenses21. The increased side analogues of modest activity26 or the weak ad- expression of CD8 cell activation markers ap- vantage conferred by monotherapy with protease peared as major prognostic markers, in addition to inhibitors27 or by bitherapy even when associated the CD4 cell depletion and the viral load17. Result- to IL-2 infusions22 had reinforced the concept of de- ing from these defects and exhaustion of immune finitive alterations in the immune system that would cells major holes wereNo supposed part to of occur this in the publicationlimit the benefits may of HAART be to an improvement of the CD4 and CD8 subsets, that would progressively re- residual T cell phenotypes, repertoires and functions. strict the diversity of the corresponding T cell reper- toires and, if definitive, werereproduced considered as critical or photocopying obstacles to immune reconstitution in adults22. Fix- The CD4 cell regeneration under HAART: ing these holes would indeed require new T cell illusion or reality? production from the thymuswithout which was the supposed prior to writtenCombined permission drug regimens were shown to induce be irreversibly altered in HIV-infected adults. The a major and durable viral load reduction accompa- observations of HIV-negative bone-marrowof the trans- publishernied by stable CD4 count increases that had never planted adults supported such hypothesis23,24. been observed previously28-30, and raised the ques- However, Gorochov could clearly demonstrate that tion of immune restoration and its mechanisms. massive biases in the CD4 T cell repertoires ap- A first study was conducted in 1996 on patients peared only at the time of AIDS and should not lim- naïve to any antiretroviral drugs who were treated it CD4 ©T cell reconstitutionPermanyer in HIV-positive patients Publicationswith one PI and two nucleoside 2010 analogues in late AIDS REVIEWS when treated earlier2. In contrast, major distortions disease stage (CD4 counts below 250/mm3). We 53 AIDS Rev 1999; 1 demonstrated that the very early increase in CD4 produced by TCR rearrangements during thymic counts was associated with a similar increment in maturation9. However the weak thymic input ob- CD8 counts1. The early increase in CD4 cells was served in this study might not be enough to induce mostly composed of transiently activated memory the magnitude of naïve CD4 cell expansion ob- CD4+ cells that lacked markers of cell proliferation, served after HAART which might reflect in addition thus eliminating the hypothesis of a rapid cell the arrest in consumption and accelerated conver- expansion by proliferation. This was confirmed by sion of naïve cells toward memory cells. various studies performed on lymph nodes and peripheral blood cells5,31. Such findings suggested that the CD4 and CD8 T cells had been previously Functional immune reconstitution under sequestered or recruited in lymphoid tissues at time HAART: successes and limits of active virus replication32,33, due to an altered cy- tokine and chemokine milieu, as shown in animal One of the major questions raised by immune re- models34. The arrest of local virus production35 constitution was whether the major increase of would allow the sequestered T cells to recirculate, memory and naïve CD4 cells following introduction thus increasing peripheral blood cell counts but of potent antiretroviral drug combinations could re- without significant improvement of the total CD4 cell store the lost host defenses in AIDS patients. As numbers. The strong slopes of peripheral blood discussed above, host defenses defects are in- CD4 T cells of 1-5 CD4 cell/mm3/day during the first duced by the depletion in naïve cells that limits the two months5 were usually concurrent to a rapid and host's reactivity against new pathogens and by the major reduction in virus load of approximately 1 or Th1 defects and the abnormal activation of memo- 2 log of magnitude but could also contrast in some ry cells that impair the host's defenses against op- cases with a modest virus reduction of less than 1 portunistic infections. In a first study, we demons- log36,37. Since the peripheral blood lymphocytes trated the rapid "de-activation" of the immune sys- represents only 2% of the total lymphocyte com- tem that paralleled the viral load reduction1. This partment, a minimal virus reduction mobilizes was assessed by the disappearance of CD25, enough CD4 cells to substantially increase the peri- HLA-DR and CD38 activation markers on memory pheral numbers at time of severe CD4 cell deple- CD4 T cells and on CD8 T cells. A reduction in the tion. This phenomenon might not be visible when expression of Fas was also observed41 together HAART is given at earlier stages. with the progressive re-expression of several markers The CD4 cell kinetics was reduced approximate- that had been lost during the chronic activation ly ten fold afterward with a continuous gain of 0.1 processes and which are associated with immune CD4 cell/mm3/day during the year following HAART competence or T helper cell function such as CD28 initiation. A plateau is not reached until CD4 counts and CD71. These phenotypic improvements sug- are normalized, provided the virus replication re- gested that the functional defects pre-existing in the mains efficiently controlled (Renaud, in prepara- memory CD4 T cells allowed to recirculate might tion). At that time, the increase in naïve CD4 T cell also be corrected. numbers1,4,5 contrasts with the slower increment in Indeed, such a restoration of CD4 T cell functions both memory CD4 cells and CD8 T cells, suggest- was observed after 3 months of HAART in two se- ing that some true T cell regeneration could take ries of AIDS patients who had previously lost their place after stable virus reduction. Considering the defenses against CMV and mycobacterium tuber- current dogma of a thymic involution in HIV-infected culosis: the memory CD4 cell reactivities against adults and the poor definition of naïve T cells, the these two opportunistic pathogens were restored origin of such cells was strongly debated. Indeed, and persisted over time when HAART was suc- some memory T cells can revert their CD45 isoform cessful at controlling the virus load and at increas- from RO to RA38, although such phenomenon oc- ing CD4 memory cells1,3. The regeneration of new curs mostly in the CD8 compartment. To overcome naïve T cells was not required, suggesting that the such difficulty, we assessed the naïve cell status memory defenses against those pathogens had not on the co-expression of the CD45RA and CD62L- been completely lost prior to treatment. Whether selectin1, the latter allowingNo naïve part cell ofpenetration this publicationin such a functional may reconstitution be was protective was lymph nodes39 and further checked that the rapidly contradicted by some recurrences of CMV CD45RA+62L+CD4+ cells had functional charac- retinitis in the 3 months following introduction of teristics of naïve T cells thatreproduced had not encountered or photocopyingHAART in AIDS patients 42,43. In fact such episodes antigens. Our results were confirmed by various occurred during the first 3 months that followed in- studies4,5 and strengthened the hypothesis of a pre- troduction of HAART, i.e. once the memory CD4 T served capacity to regeneratewithout naïve the cells priorin these writtencells had beenpermission “ authorized ” to recirculate but be- settings that might differ from the massive thymic fore their overactivation had been reduced and alterations induced by chemotherapy ofand theirradia- publishertheir functionality had been restored. After this 3 tion in haematological malignancies8. Indeed the month period, a solid protection was conferred thymic mass preservation in HIV-infected adults against opportunistic pathogens as shown by the was recently confirmed40. Even more recently direct subsequent reduction in CMV viremia and CMV retini- evidence for a thymic participation in the T cell re- tis44 and in the infectious morbidity and mortality 6,7. AIDS REVIEWS generation© following Permanyer HAART was provided by Publications the These successes have however2010 some limits 54 detection in CD45RA+ CD4+ T cells of DNA circles since no apparent restoration of a CD4 cell reactivity Guislaine Carcelain, et al.: Immune Reconstitution under Highly Active Antiretroviral Therapy (HAART) against HIV itself was observed in parallel to the re- nomenon occurred in the CD8 compartment, constitution described above1,10. The CD4 helper though more slowly2. Thus HAART allows correction cells specific for HIV were restored only when of the TCR repertoire via both a thymic regeneration HAART was initiated at time of primary infection11 of the naïve cell diversity and a decreasing activa- and appear to be deleted in chronic disease. A tion and consumption of memory T cells, concur- widely accepted hypothesis for such a lack of rently to virus control. The enormous plasticity of the restoration is the lack of in vivo restimulation in the central and peripheral immune system therefore absence of antigen stimulation due to an efficient prevents the constitution of definitive holes in the T virus control with treatment. We checked that those cell repertoire and allows in time an immune cells were not even sequestered in the tissues (Li, restoration. in preparation). The regeneration in new naïve CD4 cells did not help at restoring such activity even af- Conclusion ter 2 or 3 years of treatment45. However we recent- ly showed that the HIV-specific T-helper cells were In conclusion HAART, at whatever the stage of not definitively deleted and could be restored in vitro the disease it is initiated, allows immune restoration after appropriate antigen-presentation and Th-1 cell and protection against opportunistic pathogens. The activation45. This question of T-helper cell activity single condition required for immune reconstitution against HIV appears of utmost importance consid- is an efficient and durable inhibition of virus replica- ering the central role played by those cells in the tion. These positive effects can be obtained at late generation and maintenance of the effect of im- stages of the disease even when the patients have mune defenses mediated by CTLs and antibodies, been heavily pre-treated. They also demonstrate both arms being profoundly reduced after thera- that HIV does not definitively alter the lymphoid tis- peutic reduction of the viral burden46,47. One of the sues nor the immune defenses, even after years of best hallmarks of this unrestored immunity against infection and severe immune suppression, except HIV is the constant rebound in virus replication for HIV-specific CD4 T helper cells. Thus initiating which is observed when HAART is stopped, what- HAART in late or in early disease will differ by: 1) the ever the stage of the disease at which HAART was time required to normalize the immune functions initiated. Altogether these findings underline the ne- and cell counts; and 2) the lack of amplification of cessity of designing new strategic interventions HIV-specific T cells in late disease. In both cases aiming at restoring such essential immune reactivi- the main obstacle for a durable immune reconstitu- ties against HIV. tion is the necessity for long term drug maintenance which exposes to serious side effects. The delay in recovery or the lack of reconstitution of a solid im- munity against HIV itself might prompt additive ther- Reconstitution of the T cell repertoire: the apeutic strategies based upon immune interven- controversies tions. Several immune therapies are currently be- An enormous diversity of foreign antigens, ap- ing evaluated such as periodic IL-2 infusions in or- proximately 1013 to 1015, are recognized by T cells der to accelerate and amplify immune reconstitu- through their T cell receptor to antigen (TCR).This is tion or therapeutic vaccinations to resuscitate im- ensured during intra-thymic maturation by the di- mune responses to HIV. At a time where virus versity of recombination in the gene fragments en- eradication does not appear plausible with the cur- coding for TCR, each TCR providing the specificity rent drug regimens, the ultimate goal of HAART for a given antigen. Each antigen encounter trans- might be to help at transforming treated patients in forms the corresponding naïve T cells in specific long term non progressors. memory T cells that proliferate. The TCR diversity is thus maximal in the thymic-born naïve T cells and is Acknowledgments reduced in the memory cell compartment which represents a selection from the naïve compartment. The studies reported in this review could not The overall diversity of the T cell repertoire de- have been performed without the valued collabora- creases with age and chronicNo partexposure of to antigens.this publicationtion of Roland mayTubiana, be Hocine Mohand and Pr. Such a process is accelerated during HIV infection, Christine Katlama from the Service des Maladies In- particularly in the CD8 subset because HIV-specif- fectieuses, at Hôpital Pitié-Salpétrière; with Do- ic CD8 CTL clones are permanentlyreproduced activated orto photocopyingminique Mathez and Jacques Leibowitch, Labora- limit virus dissemination2,25 while the thymus input toire d’Immuno-Virologie, Hôpital Raymond Poin- decreases with intra-thymic infection9,40. A first caré, Garches; and with Guy Gorochov, Catherine study of the T cell repertoirewithout conducted the within prior the 3- writtenBlanc, Marc permission Renaud, Fernanda Grassi, Isabelle 6 months following antiretroviral therapy failed to Porcher at the Laboratoire d'Immunologie Cellu- demonstrate corrections of the TCR repertoireof the ab- publisherlaire, CNRS UMR 7627, directed by Pr. Patrice De- normalities22. Our group however showed that the bré at Hôpital Pitié-Salpétrière, Paris, France. CD4 T cell repertoire normalized after HAART but only after the 6th month of an efficient treatment2. References This process occurred once the memory CD4 cells

1. Autran B, Carcelain G, Li T, et al. Positive effects of combined AIDS REVIEWS had normalized© Permanyer their activation status and after Publications the anti-retroviral therapy on CD4+ T cell2010 homeostasis and function 55 increase in naïve T cells numbers. The same phe- in advanced HIV disease. Science 1997; 277: 112-6. AIDS Rev 1999; 1 2. Gorochov G, Neumann A, Kereveur A, et al. 1998. Perturbation 26. Rinaldo C, Huang X, Piazza P, et al. Augmentation of cellular im- of CD4 and CD8 T cell repertoires during progression to AIDS mune function during the early phase of zidovudine treatment of and influence of antiviral therapy. Nature Med 1998; 4: 215-21. AIDS patients. J Infect Dis 1991; 164: 638-45. 3. Li T, Tubiana R, Katlama C, et al. Long lasting recovery in CD4+ 27. Kelleher A, Carr A, Zaunders J, et al. Alterations in the immune T cell function mirrors viral load reduction after highly active response of human immunodeficiency virus (HIV)-infected sub- anti-retroviral therapy in patients with advanced HIV disease. jects treated with an HIV-specific protease inhibitor, Ritonavir. J Lancet 1998; 351: 1682-6. Infect Dis 1996; 173: 321-9. 4. Lederman M, Connick E, Landay A, et al. Immunologic responses as- 28. Collier A, Coombs R, Schoenfeld D, et al. Treatment of human socaited with 12 weeks of combination antiretroviral therapy consisting of immunodeficiency virus infection with saquinavir zidovudine and Zidovudine, Lamivudine and Ritonavir: Results of AIDS clinical trials zalcitabine. N Engl J Med 1996; 334: 1011-7. group protocol 315. J Infect Dis 1998; 178: 70-9. 29. Katzenstein D, Hammer S, Hugues M, et al. The relation of vi- 5. Pakker N, Notermans D, De Boer R, et al. Biphasic kinetics of rologic and immunologic markers to clinical outcomes after nu- peripheral blood T cells after triple combination therapy in HIV-1 cleoside therapy in HIV-infected adults with 200 to 500 CD4 infection: A composite of redistribution and proliferation. Nature cells per cubic millimeter. N Engl J Med 1996; 335: 1091-8. Medicine 1998; 4: 208-14. 30. Hammer S, Squires K, Hughes M, et al. A controlled trial of two 6. Hogg R, O’Shaughnessy M, Gataric N, et al. Decline in deaths nucleoside analogues plus indinavir in persons with human im- from AIDS due to new antiretrovirals. Lancet 1997; 349: 1294. munodeficiency virus infection and CD4 cell counts of 200 per 7. Palella F, Delaney K, Moorman A, et al. Holmberg and the HIV cubic millimeter or less. N Engl J Med 1997; 337: 725-39. outpatient study investigators. Declining Morbidity and mortality 31. Racz K, Stellbrink H, van Lunzen J, et al. The unenlarged lymph among patients with advanced human immunodeficiency virus nodes of HIV-1-infected, asymptomatic patients with high CD4 T infection. N Engl J Med 1998; 338: 853-60. cell counts are sites for virus replication and CD4 T cell prolifer- 8. Mackall C, Granger L, Sheard M, et al. T-cell regeneration after ation. The impact of highly active antiretroviral therapy. J Exp bone marrow transplantation: Differential CD45 isoform expres- Med 1998; 187: 949-59. sion on thymic-derived versus thymic-independent progeny. 32. Rosok B, Bostad L, Voltersvik P, et al. Reduced CD4 cell counts Blood 1993; 82: 2585-894. in blood do not reflect CD4 cell depletion in tonsilar tissue in 9. Douek D, McFarlard R, Keiser P, et al. Changes in thymic func- asymptomatic HIV-1 infection. AIDS 1996; 10: 35-8. tion with age and during the treatment of HIV infection. Nature 33. Cheynier R, Henrichwark S, Hadida F, et al. HIV and T cell ex- 1998; 396: 690-5. pansion in splenic white pulps is accompanied by infiltration of 10. Plana M, García F, Gallart T, et al. Lack of T-cell proliferative re- HIV-specific cytotoxic T lymphocytes. Cell 1994; 78: 373-87. sponse to HIV-1 antigens after 1 year of highly active antiretrovi- 34. Sprent J, Tough D. Lymphocyte life-spen and memory. Science ral treatment in early HIV-1 disease. Lancet 1998; 352: 1194-5. 1994; 265: 1395-400. 11. Rosenberg E, Billingsley J, Caliendo A, et al. Vigorous HIV-1 35. Cavert W, Notermans D, Staskus K, et al. Kinetics of response specific CD4+ T cell responses associated with control of in lymphoid tissues to antiretroviral therapy of HIV-1 infection. viremie. Science 1997; 278: 1447. Science 1997; 176: 960-4. 12. Ho D, Neumann A, Perelson A, et al. Rapid turnover of plasma 36. Kaufmann D, Pantaleo G, Sudra P, et al. CD4-cell count in HIV- virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 1-infected individuals remaining viraemic with highly active anti- 373: 123-6. retroviral therapy (HAART). Lancet 1998; 333: 723. 13. Wolthers K, Bea G, Wisman A, et al. T cell telomere length in 37. Piketty C, Castiel P, Belec L, et al. Discrepant responses to triple HIV-1 infection: no evidence for increased CD4+ T cell turnover. combination antiretroviral therapy in advanced HIV disease. Science 1996; 274: 1543-7. AIDS 1998; 12: 745-50. 14. Tissot O, Viard J, Rabian C, et al. No evidence for proliferation 38. Bell E, Sparshott SM. Interconversion of CD45R of CD4 T cells in the blood CD4+ T cell pool during HIV-1 infection and triple in vivo. Nature 1990; 348: 163-6. combination therapy. AIDS 1998; 12: 879-84. 39. Picker L, Treer J, Ferguson D, et al. Control of lymphocyte recir- 15. Clerici M, Stocks N, Zajac R, et al. Detection of three distinct culation in man. Differential regulation of the peripheral lymph patterns of T helper cell dysfunction in asymptomatic, HIV- node homing receptor L-selection on T cells during the virgin to seropositive patients: Independence of CD4+ cell numbers and memory cell transition. J Immunol 1993; 150: 1105-21. clinical staging. J Clin Invest 1989; 84: 1892-9. 40. McCune J, Loftus R, Schmidt D, et al. High prevalence of thymic 16. Hellerstein M, McCune J. T cell turnover in HIV-1 disease. Im- tissue in adults with human immunodeficiency virus-1 infection. munity 1997; 7: 583-9. J Clin Invest 1998; 101: 2301-8. 17. Giorgi J, Fahey J, Smith D, et al. Early effects of HIV on CD4 41. Badley A, Dockrell D, Algeciras A, et al. In vivo analysis of lymphocytes in vivo. J Immunol 1987; 138: 3725-30. Fas/Fas-L interactions in HIV-infected patients. J Clin Invest 18. Autran B, Legac E, Blanc C, et al. TH0/TH2 function of 1998; 102: 79-87. CD4+CD7- T lymphocyte subset in normal and HIV-seropositive 42. Jacobson M, Zegans M, Pavan P, et al. Cytomegalovirus retini- individuals. J Immunol 1885; 154. 3: 1408-17. tis after initiation of highly active antiretroviral therapy. Lancet 19. Borthwick NJ, Bofill M, Combert W, et al. Lymphocyte activation 1997; 349: 1443-5. in HIV-1 infection II. Functional defects of CD28 T cells. AIDS 43. Gilquin J, Piketty C, Thomas U, et al. Acute cytomegalovirus in- 1994; 8: 431-41. fection in AIDS patients with CD4 counts above 100x106 cells/l 20. Lane H, Masur H, GelmannNo E, et al .part Correlation of between this immuno- publicationfollowing combination may antiretroviral be therapy including protease logic function and clinical subpopulations of patients with the ac- inhibitors. AIDS 1997; 11: 1659-60. quired immune deficiency syndrome. Am J Med 1985; 78: 417-22. 44. Li T, Tubiana R, Fillet A, et al. Negativation of cytomegalovirus 21. Autran B, Hadida F, Haas G. Evolutionreproduced and plasticity of CTL orre- photocopyingblood culture with restoration of CD4+ T cell reactivity to CMV sponses against HIV. Curr Opin Immunol 1996; 8: 546-53. after HAART in an HIV-1 infected patient. J AIDS Hum Retrovi- 22. Connors M, Kovacs J, Krevat S, et al. HIV infection induces rol 1999. In press. changes in CD4+ T cellwithout phenotype and thedepletion prior within the written45. Carcelain permission G, Tubiana R, Li T, et al. Long-term recovery in CD4+ CD4+ T cell repertoire that are not immediately restored by an- T cell function with highly efficient antiretroviral therapy. 6th Con- tiviral or immune based therapies. Nature Med 1997; 3: 533-40. ference on Retrovirus and Oppotunistic Infections. Chicago, 23. Mackall C, Hakin F, Gress R.T-cell regeneration:of all repertoiresthe publisherUSA 1999. are not created equal. Immunol Today 1997; 18: 245-51. 46. Ogg G, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific 24. Gorochov G, Debré P, Leblond V, et al. Oligoclonal expansion of cytotoxic T lymphocytes and plasma load of viral RNA. Science CD8+CD57+ T cells with restricted T-cell receptor b chains vari- 1998; 279: 2103-6. ability after bone-marrow transplantation. Blood 1994; 83: 587-95. 47. Dalod M, Harzic M, Pellegrin I, et al. Evolution of cytotoxic T lym- 25. Pantaleo G, Demarest J, Soudeyns H, et al. Major expansion of phocytes responses to HIV-1 in patients with symptomatic pri- AIDS REVIEWS CD8+© T cells withPermanyer a predominant Vb usage during the primaryPublicationsmary infection on antiretroviral triple2010 therapy. J Infect Dis 1998; 56 immune response to HIV. Nature 1994; 370: 463-7. 178: 161-9.