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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) and IL-7 are the most intriguing molecules in immune-based HIV infection treatment. An in vitro IL-2/IL-7 cross-talk due to IL-2-driven IL-7 receptor-alpha-chain (IL-7R alpha) down-modulation, potentially blocking IL-7 signalling has been described. We investigated the in vivo IL-2 effect on IL-7/IL-7R system, measuring free IL-7, and IL-7R alpha CD4 and CD8 in 12 HIV-positive patients enrolled in a randomized IL-2 trial. Compared to HAART alone, IL-2 induced a parallel expansion in total and naive CD4, TRECs and IL-7 plasma levels, with no IL-7R alpha CD4 and IL-7R alpha CD8 changes (P>0.05), suggesting that in vivo IL-2 boosts IL-7 production without down-modulating IL-7R alpha, preserving IL-7-mediated T-lymphocyte homeostatic regulation. Our data confirm the pivotal role of IL-2 and IL-7 in the regulation of T-lymphocyte homeostasis in HIV infection.
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PMID:IL-7/IL-7 receptor system regulation following IL-2 immunotherapy in HIV-infected patients. 1525 8

Correlates of immune reconstitution after highly active antiretroviral therapy (HAART) are not completely understood, in particular as far as viro-immunological discordant responses are concerned. HIV-positive patients on stable HAART for > or = 1 year were recruited. Viro-immunological responses were categorized according to positive or negative area under the curve (AUC) variations for HIV plasma viral load (pVL) and CD4+ T-cell counts measured at least every 4 months. The following parameters were evaluated: lymphocyte spontaneous apoptosis (LSA), intracellular Bcl-2 expression in both CD4-CD45RA+ and CD4-CD45R0+, IL-7 and IL-15 plasma concentrations, and lymphocyte TRECs levels. Sixty-one patients were enrolled. A significant inverse correlation was found between CD4+ T-cell count and pVL AUC (r = 0.45; p = 0.0003). Patients with pVL response had higher levels of Bcl-2 in CD4-CD45R0+ (mean 65,409 MESF vs. 54,018 MESF; p = 0.089) and higher IL-15 (mean 1.34 pg/mL vs. 1.05 pg/mL; p = 0.069, respectively). Higher LSA and lower TRECs levels were found in viro-immunological non-responder patients with respect to those who had viro-immunological response (mean 24.84% vs. 14.89%; p = 0.01, and mean 17,796 copies/10(6) cells vs. 29,251 copies/10(6) cells; p = 0.68, respectively). Virological suppression may allow Bcl-2 and IL-15 hyperexpression during incomplete immune-reconstitution phase, while more complete immune reconstitution appeared to be marked by both high TRECs and low LSA levels, possibly indicating both central and peripheral CD4+ T-cell repopulations at this stage.
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PMID:Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART). 1527 5

IL-2 is currently used in HIV-infected patients to treat CD4+ T lymphopenia. In order to document a mechanism accounting for its capacity to restore immune function, we studied the effects of IL-2 administration in mice. IL-2 treatment of C57BL/6 mice for 4 days leads to a transient accumulation of CD4+ T lymphocytes. Whereas memory and activated CD4+ T lymphocytes accumulate after IL-2 treatment in both lymphoid and nonlymphoid organs, naive CD4+ T cells only accumulate in the former. IL-2 transiently increases CD4+ T lymphocyte numbers in lymphopenic IL-7(-/-) mice. Studies in T-cell-reconstituted Rag(-/-) gamma c(-/-) mice and in thymectomized mice demonstrated that IL-2 acts directly on peripheral CD4+ T lymphocytes. In vivo labeling of thymocytes showed that IL-2 also stimulates the release of CD4+ thymocytes from the thymus. Therefore, IL-2 treatment acts centrally and peripherally to increase the size of the naive CD4+ T lymphocyte compartment. This dual activity of IL-2 treatment may influence the quality of restoration of this compartment, especially regarding the ability to reconstitute a normal T lymphocyte repertoire.
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PMID:Effects of exogenous IL-2 administration on the homeostasis of CD4+ T lymphocytes. 1535 9

IL-2 is used in conjunction with highly active antiretroviral therapy to increase the CD4 cell count in HIV-positive patients. The mechanisms involved remain ill-defined. Here we show that during the first cycle of IL-2 therapy, IL-7 and Flt-3L plasma levels are increased, whereas levels of stem cell factor are unchanged. This supports the hypothesis that aside from stimulating CD4 T cells IL-2 may also indirectly affect lymphocyte production through the stimulation of lymphopoietic cytokines.
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PMID:IL-7 and Flt-3L plasma levels are increased during highly active antiretroviral therapy-associated IL-2 therapy. 1557 33

Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4+ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4+ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5+ cells but also showed evidence of CPE on CCR5- cells. Furthermore, infection of FTOC by R5 HIV-1 induced IL-10 and transforming growth factor beta (TGF-beta) expression. Both IL-10 and TGF-beta in turn induced CCR5 expression in FTOC. Induction of CCR5 expression via cytokine induction by R5 HIV-1 infection of CCR5+ thymocytes likely permitted further viral replication in newly CCR5+ thymocytes. CCR5 expression, therefore, is a key determinant of pathogenesis of R5 HIV-1 in FTOC.
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PMID:R5 human immunodeficiency virus type 1 infection of fetal thymic organ culture induces cytokine and CCR5 expression. 1559 39

The persistence of HIV-1 in virally suppressed infected individuals on highly active antiretroviral therapy (HAART) remains a major therapeutic problem. The use of cytokines has been envisioned as an additional therapeutic strategy to stimulate latent proviruses in these individuals. Immune activation therapy using IL-2 has shown some promise. In the present study, we found that IL-7 was significantly more effective at enhancing HIV-1 proviral reactivation than either IL-2 alone or IL-2 combined with phytohemagglutinin (PHA) in CD8-depleted PBMCs. IL-7 also showed a positive trend for inducing proviral reactivation from resting CD4(+) T lymphocytes from HIV-1-infected patients on suppressive HAART. Moreover, the phylogenetic analyses of viral envelope gp120 genes from induced viruses indicated that distinct proviral quasispecies had been activated by IL-7, as compared with those activated by the PHA/IL-2 treatment. These studies thus demonstrate that different activators of proviral latency may perturb and potentially deplete only selected, specific portions of the proviral archive in virally suppressed individuals. The known immunomodulatory effects of IL-7 could be combined with its ability to stimulate HIV-1 replication from resting CD4(+) T lymphocytes, in addition to other moieties, to potentially deplete HIV-1 reservoirs and lead to the rational design of immune-antiretroviral approaches.
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PMID:IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. 1563 Apr 52

Although the primary determinant of cell tropism is the interaction of viral envelope or capsid proteins with cellular receptors, other viral elements can strongly modulate viral replication. While the HIV-1 promoter is polymorphic for a variety of transcription factor binding sites, the impact of these polymorphisms on viral replication in vivo is not known. To address this issue, we engineered isogenic SIVmac239 chimeras harboring the core promoter/enhancer from HIV-1 clades B, C, and E. Here it is shown that the clade C and E core promoters/enhancers bear a noncanonical activator protein-1 (AP-1) binding site, absent from the corresponding clade B region. Relative ex vivo replication of chimeras was strongly dependent on the tissue culture system used. Notably, in thymic histocultures, replication of the clade C chimera was favored by IL-7 enrichment, which suggests that the clade C polymorphism in the AP-1 and NF-kappaB binding sites is involved. Simultaneous infection of rhesus macaques with the 3 chimeras revealed a strong predominance of the clade C chimera during primary infection. Thereafter, the B chimera dominated in all tissues. These data show that the clade C promoter is particularly adapted to sustain viral replication in primary viremia and that clade-specific promoter polymorphisms constitute a major determinant for viral replication.
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PMID:HIV-1 clade promoters strongly influence spatial and temporal dynamics of viral replication in vivo. 1569 84

Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1(LAI)) primes CD8(+) T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8(+) T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8(+) T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4(+) and CD8(+) T-cell death induced by HIV-1(LAI). Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1(LAI) and IL-7 is one of the mechanisms involved in progression to AIDS.
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PMID:Interleukin 7 increases human immunodeficiency virus type 1 LAI-mediated Fas-induced T-cell death. 1570 41

Highly active antiretroviral therapy (HAART) induces a substantial control of HIV viral replication, but it allows for only a partial immune reconstitution, thus prompting the rationale for the adjuvant use of immunomodulants. Based on its in vitro action as a major T cell growth factor, interleukin (IL)-2 has now been extensively investigated for its potential to correct the HIV-driven immune deficiencies, possibly translating into immunological control over HIV infection. Specific immunological end points have thus far been addressed within extensive Phase I/II trials, disclosing a broad insight into several aspects of the IL-2-mediated immune reconstitution allowing for interesting clinical speculation. Indeed, preliminary results indicate that adjuvant IL-2 induces a significant CD4 cell rescue in patients with no immune recovery following long-term HAART, thus standing as a valid and safe therapeutic option for these patients. Furthermore, in these patients, the IL-2-mediated immune reconstitution is characterized by a rise in both peripheral turnover and de novo T cell synthesis, with reversion of the skewed HIV-driven immunophenotypic pattern, a substantial increase in IL-7 production and in several markers of immune function. Combined, these findings indicate IL-2 has a beneficial effect in correcting the severe disruption in T cell homeostasis induced by HIV, through the interaction with T cells and cytokine microenvironment. However, whether or not these immunological effects translate into an actual immunological competency and therefore clinical benefit, still awaits demonstration from ongoing large, controlled clinical studies.
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PMID:Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap? 1573 Dec 1

Cytokine-based therapies have been examined for purging viral reservoirs and immunomodulation in HIV infection. However, single cytokines did not result in either HIV eradication or an efficient HIV-specific immune response. We hypothesize that cytokines with distinct biologic effects need to be combined for immunotherapy of HIV infection. In this study, we investigated the anti-HIV activity and immune-enhancing effects of the combination of IFN-alpha and IL-7. In human lymphocyte aggregate cultures infected ex vivo with the X4 HIV strain NL4-3, IFN-alpha/IL-7 potently inhibited HIV replication and preserved CD4(+) T cells, probably by up-regulating Bcl-2. IFN-alpha/IL-7 also strongly inhibited R5 HIV replication. Furthermore, in allogeneic MLRs, IFN-alpha/IL-7 increased T cell proliferation and IFN-gamma production. IFN-alpha alone also had strong anti-HIV activity, but neither preserved CD4(+) T cells nor increased T cell responses in MLRs. IL-7 alone maintained T cells and enhanced T cell activation in MLRs, but only moderately inhibited or increased HIV replication. Thus, coadministration of IFN-alpha/IL-7 combines the potent anti-HIV activity of IFN-alpha with the beneficial effects of IL-7 on T cell survival and function. We speculate that IFN-alpha will block viral replication, activate APCs, and up-regulate MHC molecules, thus allowing IL-7 to display its effects for generating an efficient immune response. In this scenario, the known reactivation of latent HIV by IL-7 may be advantageous.
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PMID:Uncoupled anti-HIV and immune-enhancing effects when combining IFN-alpha and IL-7. 1614 18


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