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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 to of 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 18,19 "innocent" non-infected cells. Meanwhile of compen- the publisherT cell competence and T-helper differentiation . sation by newly produced T cells progressively di- Function T cell defects were assessed by a pro- REVIEWS 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 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 thymus without 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-marrow of 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. REVIEWS 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 when treated earlier2. In contrast, major distortions disease stage (CD4 counts below 250/mm3). We 53 AIDS