| 1. |
- Buggert, Marcus, et al.
(författare)
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T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection.
- 2014
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.
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| 2. |
- Hejdeman, Bo
(författare)
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Studies on medical and immunological intervention in HIV-1 infection
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The very first HIV-1 infected patients who received antiretroviral combination therapy (HAART) were severely ill and had very low CD4+ T cell counts. We describe a group of severely ill HIV- I infected patients monitored for the first two years of their HAART. The patients were subdivided retrospectively into viral responders and viral low responders. Memory and naive T cells increased in both groups and membrane bound activation markers decreased. There were no clinical differences in number of deaths or HIV related events during two years follow up in the two groups. However after seven years there were clinical differences. Virological clearance was achieved in half of the patients in the original viral low responder group. Differences in adherence to HAART may explain the diverse outcome in the two groups. This study argues for continued treatment with HAART in spite of viral failure and subsequent development of primary and secondary resistance mutations. If treatment with HAART is interrupted the CD4+ T cell count again decreases and viral load increases to the same level as before treatment. A group of HIV- I infected patients with a history of long time HAART, well suppressed plasma viral loads and recovered CD4+ T cell counts, were followed during long-term treatment interruption (LTI). We found that CD4+ T cell decrease during treatment interruption was an inverse reflection of CD4+ T cell increase during treatment. A close correlation between pre-HAART nadir CD4+ T cell counts (lowest ever), levels of CD4+ memory cells at the start of LTI and the duration of LTI, indicates that CD4+ T cell memory levels may not be fully recovered even after a long period of effective HAART, irrespective of absolute CD4+ T cells count reached during treatment. HAART does not improve the specific immune response against HIV. Therapeutic vaccination would be a valuable addition to antiviral chemotherapy as immune stimulation potentially helps to reduce the need for antiretroviral drugs by strengthen or inducing new immunological responses. We monitored the long-term immune responses of HIV-infected patients immunized with HIV envelope rgpl60 before HAART was introduced. HIV specific T-helper cell responses induced by immunization were maintained at high levels up to 7 years after the last injection. The addition of HAART in these patients did not alter this HIV-specific response but gave a profound reduction in viral load and increased total CD4+ T cell counts. Immunization with rgp160 was combined with HAART in another group of patients. As controls, patients treated with HAART only, were followed in addition to two groups receiving tetanus as a non HIV specific vaccine (one group with and one without HIV infection). In keeping with previous rgpl60 immunization studies, we were able to demonstrate a positive effect of rgp 160 on CD4+ T cell count, measurable six to twelve months after the last immunization. The HIV-specific T cell response was maintained at very high levels up to two years in HAART treated patients, but not to the same extent in non-HAART treated patients, despite comparable or even higher CD4+ T cell levels during follow up. CD4 specific responses to recall antigens (tetanus toxoid and tuberculin) were boosted by the rgp 160 immunization. HIV specific immunization during HAART might thus induce responses potentially beneficial during a future planned treatment interruption. In order to control HIV, effective CD4 and CTL responses are needed in addition to sufficient levels of neutralizing antibodies. Plasmid DNA vaccines can stimulate CTL by intracellular protein production, presented via the HLA class I pathway. They may also stimulate B cells to generate antibodies. We describe a study where DNA constructs encoding the rev, tat and nef regulatory HIV- I genes were given to asymptomatic HIV-1 infected patients on stable HAART and with undetectable viral load. The results were compared with a prior non-randomized study where the same genes were given separately in a ten fold lower total dose to patients with similar CD4+ T cell levels but not on HAART. New HIV-specific proliferative responses were found in all immunized patients who lacked this response before immunization. The specific cytolytic capacity decreased in the placebo group but not in the immunized groups. We did not find that HAART per se was important for the immediate response to the chosen DNA plasmids, in patients with comparable CD4+ and CD8+ T cell levels, even though the total DNA dose was ten folds higher. Since both nef and tat have immune suppressive activities, these properties may have been more prominent in a combination of the genes in a higher dose. We have clinical evidence that long-term antiviral treatment causes viral suppression and clinical benefits in both viral responders and low-responders. An important variable for prediction of successful interruption of treatment appeared to be retained CD4+ memory cells, directly correlated with nadir CD4+ T cell count. HIV immunization together with antiviral treatment enhanced the magnitude and duration of new HIVspecific immune responses. Immunization with HIV antigens alone has improved short-term survival and almost always induces new HIV-specific T cell responses. This shows that new memory cells can be induce by vaccination in the chronic phase of infection, which should permit extended treatment interruption.
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| 3. |
- Johansson, Susanne E, et al.
(författare)
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NK cell activation by KIR-binding antibody 1-7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients
- 2010
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Ingår i: CLINICAL IMMUNOLOGY. - : Elsevier BV. - 1521-6616 .- 1521-7035. ; 134:2, s. 158-168
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells may be protective in HIV infection and are inhibited by killer cell immunoglobulin-like receptors (KIRs) interacting with MHC class I molecules, including HLA-C. Retention of HLA-C despite downregulation of other MHC class I molecules on HIV infected cells might protect infected cells from NK cell recognition in vitro. To assess the role of inhibitory HLA-C ligands in the capacity of NK cells to recognize autologous infected T cells, we measured NK cell degranulation in vitro in viremic patients, controllers with low viremia, and healthy donors. No difference in NK cell response to uninfected compared to HIV-1(IIIB) infected targets was observed. Activation of NK cells was regulated by KIRs, because NK cell degranulation was increased by 1-7F9, a human antibody that binds KIR2DL1/L2/L3 and KIR2DS1/S2, and this effect was most pronounced in KIR haplotype B individuals.
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| 4. |
- Johansson, Susanne E, et al.
(författare)
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NK Cell Function and Antibodies Mediating ADCC in HIV-1-Infected Viremic and Controller Patients
- 2011
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Ingår i: Viral immunology. - : Mary Ann Liebert. - 0882-8245 .- 1557-8976. ; 24:5, s. 359-368
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the Fc gamma RIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were divided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-gamma expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.
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| 5. |
- Kindberg, Elin, 1981-, et al.
(författare)
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A nonsense mutation (428G→A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection
- 2006
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Ingår i: AIDS. - : Ovid Technologies (Wolters Kluwer Health). - 0269-9370 .- 1473-5571. ; 20:5, s. 685-689
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The human FUT2 gene encodes the α(1,2)fucosyltransferase that determines secretor status. Homozygous for the nonsense mutation are called non-secretors and are unable to express histo-blood group antigens in secretions and on mucosal surfaces. In this study we have investigated the importance of the FUT2 fucosyltransferase activity on the progress of HIV-1 infection. METHODS: Swedish blood donors (n = 276), 15 long-term non-progressors (LTNP) and 19 progressors were genotyped with respect to the nonsense mutation 428G→A in the FUT2 gene. In addition 265/276 blood donors and 19 progressors with rapid or expected progression rate were Δ32 CCR5 genotyped. RESULTS: Of 276 blood donors 218 (79%) were found to be secretor positive (se+), either homozygous (se+/+) wild type (30%) or heterozygous (se+/-) (49%) and 58 (21%) were homozygous non-secretors (se-/-). Five LTNP (33%) were found to be secretor-positive (se+/+, se+/-) and 10 (67%) se-/-. Of the 19 individuals with normal HIV-1 progression 15 (79 %) were found to be secretor positive and four (21%) were non-secretors. No frequency differences were found in the Δ32 CCR5 allele among the groups studied. CONCLUSION: Strong association (P < 0.001) was observed between the nonsense mutation 428G→A in the FUT2 gene and a slow disease progression of HIV-1 infection. © 2006 Lippincott Williams & Wilkins.
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| 6. |
- Nowroozalizadeh, Salma, et al.
(författare)
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Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness.
- 2013
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Ingår i: Human Vaccines & Immunotherapeutics. - : Informa UK Limited. - 2164-5515 .- 2164-554X. ; 9:10, s. 2103-2110
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Tidskriftsartikel (refereegranskat)abstract
- Viremia during human immunodeficiency virus type-1 (HIV-1) infection results in progressive impairment of several components of the immune system. Here a unique model of repeated treatment interruptions (TIs) was used with the aim to reveal the effect of controlled short-term viremia on innate stimuli responsiveness and circulating dendritic cells (DCs). Sequential peripheral blood samples from HIV-1-infected patients on combination antiretroviral therapy, subjected to repeated TI cycles as part of a therapeutic DNA vaccination study, were analyzed. In vitro responsiveness of peripheral blood mononuclear cells to toll-like receptor (TLR) stimuli was analyzed by cytokine secretion, and frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were monitored by flow cytometry. These parameters were found not to be significantly different between the vaccinated and placebo groups. Instead, independent of vaccination altered in vitro TLR responsiveness was observed in parallel with TI cycles. TLR7/8-triggered secretion of IL-12 and IFN-α, as well as TLR9-triggered secretion of IL-12, was hyperactivated. In contrast, expression of IFN-α after TLR9 stimulation decreased during the initial cycle of TI. Reduced frequencies of pDCs and mDCs, compared with baseline, were noted before and during the second TI, respectively. Furthermore, spontaneous ex vivo release of IL-12 from PBMC was noted during cycles of TI. In conclusion, these results suggest that consequences of short-term TI include dysregulated TLR responses and fluctuations in the frequencies of circulating DCs. Knowledge of these immunological factors may influence the continuation of stringent treatment schedules during HIV infections.
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