| 1. |
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| 2. |
- Esbjörnsson, Joakim, et al.
(författare)
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Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection.
- 2012
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:3, s. 224-232
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood. METHODS: We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution. RESULTS: The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection. CONCLUSIONS: Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency-Swedish Agency for Research Cooperation with Developing Countries and others.).
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| 3. |
- Nowroozalizadeh, Salma
(författare)
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Activation and dysregulation of innate immunity in HIV-1 and HIV-2 infections
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Toll-like receptors (TLRs) are pattern recognition receptors, expressed by antigen presenting cells (APCs) that recognize conserved molecular patterns of diverse microorganisms. TLR triggering activates APCs, leading to expression of innate effector molecules and signals that initiate adaptive immune responses. Studies have revealed that the use of TLR agonists might offer novel approaches for the development of therapeutic and prophylactic measures. Two types of human immunodeficiency virus (HIV) can cause acquired immune deficiency syndrome (AIDS): HIV-1, which is found worldwide and HIV-2, which is mostly detected in West Africa and known to be less transmissible and less pathogenic. During HIV infection, the constant battle between the virus and the immune system because of rapid viral turnover results in chronic immune activation that is thought to exhaust several compartments of the immune system. The interactions between HIV and the innate immune system remain, however, relatively unexplored. Studies in this thesis show that the replication of both HIV-1 and HIV-2 strains can be suppressed in vitro by the TLR9 agonist, CpG oligodeoxynucleotide (ODN). Additionally, conjugation of ODNs with a phosphorothioate backbone to cholera toxin B subunit enhanced the anti-HIV activity. These results indicate that the use of TLR agonists might have implications for the development of new HIV intervention strategies. Furthermore, studies on the impact of HIV on TLR stimuli responsiveness reveal that both advanced HIV-1 and HIV-2 infections were associated with defective IFN-α responses after in vitro TLR9 stimulation. In addition, defective IL-12 expression after TLR7/8 stimulation was observed in HIV-1-infected individuals. Moreover, levels of microbial translocation, measured as concentrations of lipopolysaccharide (LPS) in plasma, were elevated in both HIV-1- and HIV-2-infected individuals with AIDS. The plasma LPS levels correlated with CD4+ T cell count and viral load, in addition to TLR responsiveness. These results suggest that alterations in innate immune responses and microbial translocation are associated with the pathogenesis of both HIV-1 and HIV-2 infections. Studies on the immunological consequences of treatment interruption-(TI) associated viremia in HIV-1-infected individuals, showed that circulating dendritic cells were reduced and that TLR stimuli responsiveness was dysregulated. Moreover, analyses of immune activation markers showed that the frequency of HLA-DR+ T cells and spontaneously released IL-12 increased during TI, whereas microbial translocation remained unaffected. Hence, innate immunity and T cell markers of immune activation are affected during HIV-1 infection even after short-term viremia, but prolonged viremia appears to be required for the detection of microbial translocation. This thesis adds knowledge on the potential use of TLR agonists for the development of novel approaches to prevent HIV infection, but also emphasizes the need for better understanding of the role of TLR responsiveness during the pathogenesis of HIV-1 and HIV-2 infections.
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| 4. |
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| 5. |
- Nowroozalizadeh, Salma, et al.
(författare)
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Microbial Translocation Correlates with the Severity of Both HIV-1 and HIV-2 Infections
- 2010
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 201:8, s. 1150-1154
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Tidskriftsartikel (refereegranskat)abstract
- Microbial translocation has been linked to systemic immune activation during human immunodeficiency virus (HIV) type 1 infection. Here, we show that an elevated level of microbial translocation, measured as plasma lipopolysaccharide (LPS) concentration, correlates with AIDS in both individuals infected with HIV type 1 and individuals infected with HIV type 2. LPS concentration also correlates with CD4(+) T cell count and viral load independently of HIV type. Furthermore, elevated plasma LPS concentration was found to be concomitant with defective innate and mitogen responsiveness. We suggest that microbial translocation may contribute to loss of CD4(+) T cells, increase in viral load, and defective immune stimuli responsiveness during both HIV type 1 and HIV type 2 infections.
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| 6. |
- Nowroozalizadeh, Salma, et al.
(författare)
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Reply to Redd et al
- 2011
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 203:5, s. 746-746
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- 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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| 8. |
- Nowroozalizadeh, Salma
(författare)
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Studies of innate immune stimulation with CpG in HIV infection
- 2008
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Two types of human immunodeficiency virus (HIV) may cause acquired immune deficiency syndrome (AIDS): HIV-1, the most pathogenic virus of the two and found worldwide, and HIV-2, which is mostly detected in West Africa and known to be less transmissible and which demonstrates slower progression towards immunodeficiency. How CD4+ T cells are lost during these two infections is not yet completely clear; however, a constant battle against the rapid viral turnover, resulting in chronic inflammation, is thought to exhaust several compartments of the immune system. The interaction between HIV and innate immunity remains relatively unexplored, although there are indications that innate immunity can affect HIV disease progression. The Toll-like receptors (TLRs) are pattern recognition receptors, expressed on/in antigen presenting cells (APCs) that recognize conserved molecular patterns of diverse microorganisms. Triggering TLRs induces activation of APC, leading to expression of innate effector molecules and signals that initiate adaptive immune responses. Recent research also revealed that the use of TLR agonists might offer novel approaches to the development of therapeutic and prophylactic measures. In this thesis, the influence of HIV infection on the responsiveness of immune cells to TLR9 agonist (unmethylated cystidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODN)) and TLR7/8 agonist (R-848), was examined. We also investigated whether the innate immune responses mediated by CpG ODN and CpG ODN conjugated to the non-toxic B subunit of cholera toxin (CTB) could suppress HIV replication in vitro. Both advanced HIV-1 and HIV-2 infections were found to result in defective IFN-a responses after TLR9 stimulation with CpG ODN. Moreover, HIV-1-infected individuals displayed defective TLR7/8 responsiveness, as measured by IL-12 secretion after R-848 stimulation. This indicates that, during the immunocompetent phase of the infection, these innate responses may contribute to the control of HIV infection, and the loss of TLR responsiveness during advanced disease phases may contribute to the pathogenesis of HIV and the severity of opportunistic infections. We also demonstrated that CpG ODN could suppress the replication of both HIV-1 and HIV-2 strains. Furthermore, conjugation of ODNs with PS backbone to CTB enhanced the anti-HIV activity. These results may have implications for the development of novel intervention strategies to prevent HIV infection.
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| 9. |
- Nowroozalizadeh, Salma, et al.
(författare)
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Studies on toll-like receptor stimuli responsiveness in HIV-1 and HIV-2 infections
- 2009
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Ingår i: Cytokine. - : Elsevier BV. - 1096-0023 .- 1043-4666. ; 46:3, s. 325-331
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Tidskriftsartikel (refereegranskat)abstract
- Background: HIV-1 and HIV-2 are two related viruses with distinct clinical outcomes, where HIV-1 is more pathogenic and transmissible than HIV-2. The pathogenesis of both infections is influenced by the dysregulation and deterioration of the adaptive immune system. However, their effects on the responsiveness of innate immunity are less well known. Here, we report on toll-like receptor (TLR) stimuli responsiveness in HIV-1 or HIV-2 infections. Methods: Whole blood from 235 individuals living in Guinea-Bissau who were uninfected, infected with HIV-1, infected with HIV-2, and/or infected with HTLV-1, was stimulated with TLR7/8 and TLR9 agonists, R-848 and unmethylated CpG DNA. After TLR7/8 and TLR9 stimuli, the expression levels of IL-12 and IFN-alpha were related to gender, age, infection status, CD4(+) T cell counts. and plasma viral load. Results: Defective TLR9 responsiveness was observed in the advanced disease stage, along with CD4(+) T cell loss in both HIV-1 and HIV-2 infections. Moreover, TLR7/8 responsiveness was reduced in HIV-1 infected individuals compared with uninfected controls. Conclusions: Innate immunity responsiveness can be monitored by whole blood stimulation. Both advanced HIVA and HIV-2 infections may cause innate immunity dysregulation. (C) 2009 Elsevier Ltd. All rights reserved.
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| 10. |
- Nowroozalizadeh, Salma, et al.
(författare)
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Suppression of HIV replication in vitro by CpG and CpG conjugated to the non toxic B subunit of cholera toxin.
- 2008
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Ingår i: Current HIV research. - : Bentham Science Publishers Ltd.. - 1873-4251 .- 1570-162X. ; 6:3, s. 230-8
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Administration of oligodeoxynucleotides (ODNs) containing CpG motifs generates a rapid and potent response of CC-chemokines, known as ligands of the HIV-1 co-receptor CCR5, in the murine female genital tract. The present study explored the potential HIV inhibitory activities of different human CpG prototypes either alone or conjugated to the non-toxic subunit of cholera toxin (CTB). Results showed that in vitro replication of both HIV-1 and HIV-2 can be suppressed by different human CpG prototypes. Importantly, the conjugation of CpG ODN to CTB (CTB-CpG) enhanced the antiviral activity of CpG against primary HIV-1 isolates of both R5 and X4 phenotypes in peripheral blood mononuclear cells (PBMC) as well as U87.CD4 co-receptor indicator cells. CTB-CpGs triggered higher amounts of MIP-1alpha, and MIP-1beta in PBMC than the corresponding CpG ODNs, which may explain the superior antiviral effect of CTB-CpG against R5 virus in PBMC. Incubation of PBMC with CpG ODN and CTB-CpG did not alter surface expression of HIV-1 receptors indicating that the observed anti-HIV-1 effect is not mediated through down regulation of HIV-1 receptors on target cells. Further, the enhanced antiviral effect of CTB-CpG was dependent on the presence of phosphorothioate backbone in the ODN, whereas the presence of CpG motif in ODNs was dispensable. These results have implications for the development of novel intervention strategies to prevent HIV infection.
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| 11. |
- Özkaya Sahin, Gülsen, et al.
(författare)
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Effect of Complement on HIV-2 Plasma Antiviral Activity Is Intratype Specific and Potent
- 2013
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Ingår i: Journal of Virology. - 1098-5514. ; 87:1, s. 273-281
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Tidskriftsartikel (refereegranskat)abstract
- Human immunodeficiency virus type-2 (HIV-2) infected individuals develop immunodeficiency with a considerable delay and transmit the virus at a lower rate as compared to HIV-1 infected. Conceivably, comparative studies on immune responsiveness of the HIV-1 and HIV-2 infected hosts may help to explain differences in pathogenesis and transmission between the two types of infection. Previous studies have shown that the neutralizing antibody response is more potent and broader in HIV-2 than HIV-1 infection. In the present study we have further examined the function of the humoral immune response and studied the potentiating effect of complement (C') on antiviral activity of plasma from singly HIV-1 or HIV-2 infected, as well as HIV-1/HIV-2 dually infected individuals. Neutralization and antibody-dependent complement-mediated inactivation of HIV-1 and HIV-2 isolates were tested in a plaque reduction assay using U87.CD4-CCR5 cells. Results showed that addition of C' increased intra-type antiviral activity of both HIV-1 and HIV-2 plasma, although the C' effect was more pronounced with HIV-2 than HIV-1 plasma. Using the area-under-curve (AUC)-based readout, multivariate statistical analysis confirmed that type of HIV infection was independently associated with the magnitude of the C' effect. Analysis carried out with purified IgG indicated that the C' effect was largely exerted through the classical C' pathway involving IgG in both HIV-1 and HIV-2 infections. In summary, these findings suggest that antibody binding to HIV-2 structures facilitates efficient use of C', and may thereby be one factor contributing to a strong antiviral activity present in HIV-2 infection.
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| 12. |
- Özkaya Sahin, Gülsen, et al.
(författare)
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Potent Intratype Neutralizing Activity Distinguishes Human Immunodeficiency Virus Type 2 (HIV-2) from HIV-1
- 2012
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Ingår i: Journal of Virology. - 1098-5514. ; 86:2, s. 961-971
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Tidskriftsartikel (refereegranskat)abstract
- HIV-2 has a lower pathogenicity and transmission rate than HIV-1. Neutralizing antibodies could be contributing to these observations. Here we explored side by side potency and breadth of intratype and intertype neutralizing activity (NAc) in plasma of 20 HIV-1, 20 HIV-2 and 11 dually HIV-1/2 (HIV-D) seropositive individuals from Guinea-Bissau, West Africa. Panels of primary isolates, five HIV-1 and five HIV-2, were tested in a plaque reduction assay using U87.CD4-CCR5 cells as targets. Intratype NAc in HIV-2 plasma was found to be considerably more potent, and also broader, than intratype NAc in HIV-1 plasma. This indicates that HIV-2 infected individuals display potent type-specific neutralizing antibodies, whereas such a strong type-specific antibodies are absent in HIV-1 infection. Furthermore, potency of intratype NAc was positively associated with viral load of HIV-1, but not HIV-2, suggesting that NAc in HIV-1 infection is more antigen stimulation-dependent than in HIV-2 infection where plasma viral loads typically are at least tenfold lower than in HIV-1 infection. Intertype NAc of both HIV-1 and HIV-2 infected was instead of low potency. HIV-D subjects had NAc to HIV-2 with similar high potency as singly HIV-2 infected individuals, whereas neutralization of HIV-1 remained poor, indicating that the difference in NAc between HIV-1 and HIV-2 infections depends on the virus itself. We suggest that immunogenicity and/or antigenicity, meaning the neutralization phenotype, of HIV-2 is distinct from HIV-1, and that HIV-2 may display structures that favour triggering of potent neutralizing antibody responses.
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