Functional T Cell Reconstitution and Human Immunodeficiency Virus–1–Specific Cell‐Mediated Immunity during Highly Active Antiretroviral Therapy

Pontesilli, O.; Kerkhof-Garde, Susana R.; Notermans, Daan W.; Foudraine, Norbert A.; Roos, M. T. L.; Klein, Michél R.; Danner, Sven A.; Lange, Joep M. A.; Miedema, Frank

doi:10.1086/314837

Cited by 112 publications

(84 citation statements)

References 41 publications

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“…The pelleted RNA was resuspended in diethyl-pyrocarbonate-treated water and the poly (A) 1 portion of total RNA, was converted into cDNA using 2´5 mm oligo(dT) (Perkin Elmer, Norwalk, CT, USA) and 2´5 units MULV reverse transcriptase (Perkin Elmer). The sequences of 24 TCRBV subfamilies specific primers (BV 1, 2, 3, 4, 5´1, 5´3, 6´1, 6´2, 7,8,9,11,12,13,14,15,16,17,18,20,21,22,23,24) and of a TCR constant b-chain (BC) primer used in this study were previously described by Maslanka et al [20]. Amplications of target cDNA were performed as reported by Gorochov et al [5].…”

Section: Study Populationmentioning

confidence: 99%

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T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

Giovannetti

Pierdominici

Mazzetta

et al. 2001

Clinical and Experimental Immunology

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SUMMARYThe immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated. 20 HIV-1-infected patients with mean CD4 1 T cell count of 298/m l, plasma viral load of 4´7 log 10 copies/ml and naive for protease inhibitors (PI) were studied during12 months of HAART. An increased number of both CD4 1 and CD8 1 naive T cells and a normalization of the frequency of CCR5-and CXCR4-expressing CD4 1 T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IL-4-and (IFN)-g-, producing T cells and a decreased percentage of CD8 1 IFN-g 1 cells. A correlation between the frequency of IFN-g-producing T cells and that of memory, CCR5 1 and CD95 1 T cells was demonstrated in both CD4 1 and CD8 1 subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4 1 but not the CD8 1 T cell subset. However, the level of perturbation of the third complementaritydetermining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN-g response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease.

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Section: Study Populationmentioning

confidence: 99%

“…HIV-1 specific CTL precursors (CTLp) were expanded in vitro as described by [21]. Frequencies of CTLp specific for HIV Gag and Pol were determined using standard methods of limiting dilution analysis as previously described [15].…”

Section: Hiv-1 Specific Ctl Responsesmentioning

confidence: 99%

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

Giovannetti

Pierdominici

Mazzetta

et al. 2001

Clinical and Experimental Immunology

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“…However, restoration of immune responses by inhibition of apoptosis appears to be confined to the setting of recall responses indicating important differences in the requirements for induction of responses to recall and naive antigens after thymic-independent T-cell reconstitution. This phenomenon may partially explain the restoration of recall responses and protection from opportunistic infections, which has been observed during immune reconstitution of HIV-infected patients [53][54][55][56] and cannot be clearly attributed to restoration of T-cell repertoire via thymic-dependent pathways. 57 The widely accepted model for T-cell death holds that there are 2 primary pathways that ultimately end in apoptosis.…”

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confidence: 98%

Interleukin-7 restores immunity in athymic T-cell–depleted hosts

Fry

Christensen

Komschlies

et al. 2001

Blood

149

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Thymic-deficient hosts rely primarily on antigen-driven expansion to restore the peripheral T-cell compartment following T-cell depletion (TCD). The degree to which this thymic-independent pathway can restore immune competence remains poorly understood but has important implications for a number of clinical conditions including stem cell transplantation and human immunodeficiency virus (HIV) infection. A model of HY-mediated skin graft rejection by athymic, TCD mice was used to show that restoration of naive and recall responses via peripheral expansion requires transfer of only 25 ؋ 10 6 lymph node (LN) cells representing approximately 10% of the T-cell repertoire. Consitutive expression of bcl-2 in the expanding inocula restored recall responses to HY at a substantially lower LN cell dose (1 ؋ 10 6 ), which is normally insufficient to induce HY-mediated graft rejection in athymic hosts. Interestingly, bcl-2 had no effect on primary responses. Interleukin-7 (IL-7) potently enhanced thymic-independent peripheral expansion and led to HY graft rejection using an LN cell dose of 1 ؋ 10 6 in both primary and recall models. The restoration of immune competence by IL-7 appeared to be mediated through a combination of programmed cell death inhibition, improved costimulation, and modulation of antigenpresenting cell (APC) function. These results show that immune competence for even stringent antigens such as HY can be restored in the absence of thymic function and identify IL-7 as a potent modulator of thymic-independent T-cell regeneration. ( IntroductionAcute depletion of the T-cell compartment occurs in a number of clinical situations including stem cell transplantation, human immunodeficiency virus (HIV) infection, and after intensive cytotoxic therapy for cancer. Restoration of immune competence following T-cell depletion (TCD) requires the regeneration of a functionally intact, diverse T-cell pool that is capable of responding to foreign antigens and, potentially, altered self-antigens expressed by tumors. Previous studies have shown that there are 2 main pathways capable of substantial peripheral T-cell regeneration: thymic-dependent regeneration from bone marrow progenitors and thymic-independent peripheral expansion of mature T-cell populations. 1 The relative contribution of these 2 pathways is dynamic and dependent on the degree of thymic function. Current concepts hold that the capacity of the host to restore immune competence depends primarily on the extent to which thymic pathways contribute to T-cell regeneration. However, due to disease, therapy-related toxicity, and age-related changes, thymic function is frequently limiting, resulting in a relative reliance on thymic-independent peripheral expansion in many clinical situations associated with TCD. [2][3][4][5][6][7][8] The degree to which the peripheral expansion of mature T-cell populations can restore host immune competence following TCD remains poorly understood and is the focus of this report.Peripheral expansion is predicted to give rise to limit...

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“…Our data are based on a large number of subjects longitudinally followed up, and show that HAART might biologically suppress the infectious virus in plasma. Thus, the second decline in virus isolation rate might constitute supportive evidence for the effectiveness of HAART, which has been well established (2,8,10,12).…”

mentioning

confidence: 85%

Decline in the HIV‐1 Isolation Rate in Japan: A 12‐Year Observation

Nakasone

Takamatsu

Watanabe

et al. 2000

Microbiology and Immunology

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Since 1988, we have isolated HIV-1 from 614 HIV-1-infected persons (total sample =2,785) in Japan. During the past 12 years, we have found a decline in the HIV-1 isolation rate in Japan, with two identifiable turning points, 1991-1992 and 1996-1997. The two turning points correspond to shifts in anti-HIV-1 therapy. These findings suggest that HIV-1 in Japan is currently biologically well controlled, probably due to anti-HIV-1 therapy. On the other hand, this decline is inconsistent with the recent increase of genetic drugresistant HIV-1 in Japan. Further studies are needed to clarify mechanisms that might explain the discrepancy.Key words: HIV-1, Virus isolation, JapanSince 1988, we have isolated HIV-1 from a number of HIV-1-infected persons (n = 614, sample= 2,785) in Japan (4, 11). Most subjects are hemophiliacs (n= 307, sample = 1,962) who had repeatedly received intravenously administered infected blood products. The number of subjects infected by sexual transmission (n =-128, sample =532) is increasing steadily year by year, though subjects infected by vertical transmission (n= 14, sample = 14) are highly uncommon in this population. The study subjects include those with unknown transmission route (n = 165, sample = 277), although most of these infections are suspected to have been the result of sexual transmission. Profiles of the subjects are summarized in Table 1. The AIDS Surveillance Committee in Japan reported 4,838 HIV-1-infected individuals in Japan for the year 1999. Among the 4,838, 1,434 (30%) were hemophiliacs, 2,486 (51%) were infected by sexual transmission, 22 (0.5%) by vertical transmission, 22 (0.5%) were intravenous drug users, and 874 (18%) had an unknown transmission route. Compared with the group of all Japanese HIV-1 patients, our subjects are characterized by a predominance of hemophiliacs and vertical transmission.Isolation of the virus from both plasma (or serum) and peripheral blood mononuclear cells (PBMC) of the subjects was carried out based on a phytohemagglutinin (PHA)-stimulated PBMC cocultivation system, as recommended by Hollinger et al (3). In brief, plasma or PBMC were cocultivated with PHA-stimulated PBMC from an HIV-1-seronegative individual in RPMI-1640 containing 15% fetal calf serum, 50 U/ml of penicillin, 50After 7 days of culturing, the medium was changed and additional PHA-stimulated PBMC was fed. Cocultivation was maintained for more than 2 weeks. Isolated

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Functional T Cell Reconstitution and Human Immunodeficiency Virus–1–Specific Cell‐Mediated Immunity during Highly Active Antiretroviral Therapy

Cited by 112 publications

References 41 publications

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity

Interleukin-7 restores immunity in athymic T-cell–depleted hosts

Decline in the HIV‐1 Isolation Rate in Japan: A 12‐Year Observation

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