| 1. |
- Nowroozalizadeh, Salma, et al.
(author)
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Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness.
- 2013
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In: Human Vaccines & Immunotherapeutics. - : Informa UK Limited. - 2164-5515 .- 2164-554X. ; 9:10, s. 2103-2110
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Journal article (peer-reviewed)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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| 2. |
- Arimide, Dawit Assefa, et al.
(author)
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High Level of HIV Drug Resistance and Virologic Nonsuppression among Female Sex Workers in Ethiopia : A Nationwide Cross-Sectional Study
- 2022
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In: Journal of Acquired Immune Deficiency Syndromes. - 1525-4135. ; 89:5, s. 566-574
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Journal article (peer-reviewed)abstract
- Objective:To determine viral load (VL) nonsuppression (VLN) rates, HIV drug resistance (HIVDR) prevalence, and associated factors among female sex workers (FSWs) in Ethiopia.Methods:A cross-sectional biobehavioral survey was conducted among FSWs in 11 cities in Ethiopia in 2014. Whole blood was collected, and HIVDR genotyping was performed. Logistic regression analysis was performed to identify factors associated with VLN and HIVDR.Results:Among 4900 participants, 1172 (23.9%) were HIV-positive and 1154 (98.5%) had a VL result. Participants were categorized into antiretroviral therapy (ART) (n = 239) and ART-naive (n = 915) groups based on self-report. From the 521 specimens (ART, 59; ART-naive, 462) with VL ≥1000 copies/mL, genotyping was successful for 420 (80.6%) and 92 (21.9%) had drug resistance mutations (DRMs). Pretreatment drug resistance (PDR) was detected in 16.5% (63/381) of the ART-naive participants. Nucleoside reverse transcriptase inhibitor (NRTI), non-NRTIs (NNRTIs), and dual-class DRMs were detected in 40 (10.5%), 55 (14.4%), and 35 (9.2%) of the participants, respectively. Among 239 participants on ART, 59 (24.7%) had VLN. Genotyping was successfully performed for 39 (66.1%). DRMs were detected in 29 (74.4%). All 29 had NNRTI, 23 (79.3%) had NRTI or dual-class DRMs. VLN was associated with age 35 years or older, CD4+T-cell count <350 cells/mm3, and being forced into selling sex. PDR and acquired drug resistance were associated with CD4+T-cell count <350 cells/mm3(P < 0.001).Conclusions:The high VLN and HIVDR rates among FSWs underscore the need for targeted interventions to improve ART access and virologic monitoring to maximize the benefit of ART and limit the spread of HIV and HIVDR.
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| 3. |
- Medstrand, Patrik
(author)
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Human Endogenous Retroviruses: Studies on Transcriptional Activity and Genetic Variability.
- 1996
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Doctoral thesis (other academic/artistic)abstract
- Endogenous retroviruses (ERVs) are believed to be remains of germ-line infections that have become fixed in the population. They are involved in pathophysiological conditions, in mechanisms leading to infection protection, and directly in the physiology of the organism by participating in the regulation of cellular gene expression. It has been estimated that human ERVs (HERVs) make up about 0.6% of the total human DNA content. This study was undertaken to gain insight into the structure and activity of HERV elements. Initially, we used a PCR-based screening method to identify new HERV sequences by utilizing primers corresponding to conserved regions of infectious and endogenous retroviral gag, pol and env sequences. In one study we identified a set of novel pol sequences, related to the mouse mammary tumour virus (MMTV), which were assigned to six distinct groups (HML-1 to HML-6). We subsequently characterized full-length elements of two HML groups, named HERV- K(HML6) and HERV-K(HML1). In another study, mouse leukemia virus (MLV)-related env sequences encoding putative immunosuppressive sequences were identified. We investigated the ability of these sequences to be expressed at the RNA-level. The results revealed a differential transcription pattern in human tissues. In addition, the level of transcripts differed between individuals. These studies show that HERV sequences are regulated in a complex fashion. We also screened human DNA for functional HML reverse transcriptase (RT)-encoding sequences. We found that clones belonging to the HERV-K family produced fusion proteins after induction in E.coli. Enzyme assays indicated that some proteins displayed RT activity, but further investigations are needed to establish this relationship. In conclusion, we have identified novel HERV sequences, some of which were shown to be full-length retroviral structures. The present investigation also established that HERVs are expressed at different levels in many tissues and cells, which may be of significance. The data presented here will improve the classification of HERV-K related elements and allow detailed studies of a subset of HERV elements.
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| 4. |
- Sallam, Malik, et al.
(author)
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Genetic characterization of human immunodeficiency virus type 1 transmission in the Middle East and North Africa
- 2017
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In: Heliyon. - : Elsevier BV. - 2405-8440. ; 3:7
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Journal article (peer-reviewed)abstract
- Background: The HIV-1 spread in the Middle East and North Africa (MENA) has not been previously characterised using the phylogenetic approach. The aim of the current study was to investigate the genetic diversity and domestic transmission of HIV-1 in the MENA. Methods: A total of 2036 HIV-1 sequences available in Genbank and collected in the MENA during 1988–2016 were used together with 715 HIV-1 reference sequences that were retrieved from Genbank based on genetic similarity with the MENA sequences. The REGA and COMET tools were used to determine HIV-1 subtypes and circulating recombinant forms. Maximum Likelihood and Bayesian phylogenetic analyses were used to identify and date HIV-1 transmission clusters. Results: At least 21 HIV-1 subtypes and recombinant forms were prevalent in the MENA. Subtype B was the most common variant (39%), followed by CRF35_AD (19%) and CRF02_AG (14%). The most common genetic region was pol, and 675 partial pol sequences (average of 1005 bp) were eligible for detailed phylogenetic analysis. Fifty-four percent of the MENA sequences formed HIV-1 transmission clusters. Whereas numerous clusters were country-specific, some clusters indicated transmission links between countries for subtypes B, C and CRF02_AG. This was more common in North Africa compared with the Middle East (p < 0.001). Recombinant forms had a larger proportion of clustering compared to pure subtypes (p < 0.001). The largest MENA clusters dated back to 1991 (an Algerian CRF06_cpx cluster of 43 sequences) and 2002 (a Tunisian CRF02_AG cluster of 48 sequences). Conclusions: We found an extensive HIV-1 diversity in the MENA and a high proportion of sequences in transmission clusters. This study highlights the need for preventive measures in the MENA to limit HIV-1 spread in this region.
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| 5. |
- Fenyö, Eva Maria, et al.
(author)
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Human immunodeficiency virus type 1 biological variation and coreceptor use: from concept to clinical significance.
- 2011
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In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 270, s. 520-531
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Journal article (peer-reviewed)abstract
- There is ample evidence for intra-patient evolution of the human immunodeficiency virus type 1 (HIV-1) biological phenotype during the pathogenic process. Evolution often involves switch of coreceptor use from CCR5 to CXCR4, but change to more flexible use of CCR5 occurs over time even in patients with maintained CCR5 use. The increasing use of entry inhibitors in the clinic, often specific for one or the other HIV-1 coreceptor or with different binding properties to CCR5, calls for virus testing in patients prior to treatment initiation. Cell lines expressing CCR5/CXCR4 chimeric receptors are tools for testing viruses for mode of CCR5 use. It is conceivable that small-molecule entry inhibitors that differentially bind to CCR5 can be matched for best effect against HIV-1 with different modes of CCR5 use, thereby allowing an individualized drug choice specifically tailored for each patient.
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| 6. |
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| 7. |
- Johansson, Emil, et al.
(author)
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Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection
- 2022
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In: Cells. - : MDPI. - 2073-4409. ; 11:19
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Journal article (peer-reviewed)abstract
- Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.
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| 8. |
- Karlsson, Ulf, et al.
(author)
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Mode of coreceptor use by R5 HIV type 1 correlates with disease stage: a study of paired plasma and cerebrospinal fluid isolates.
- 2009
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In: AIDS research and human retroviruses. - : Mary Ann Liebert Inc. - 1931-8405 .- 0889-2229. ; 25:12, s. 1297-1305
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Journal article (peer-reviewed)abstract
- Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF) isolates from 28 HIV-1-infected individuals. Furthermore, selected R5 isolates, with varying chimeric receptor use, were tested for sensitivity to inhibition by the CCR5 antagonist TAK-779. Discordant CSF/plasma virus coreceptor use was found in 10/28 patients. Low CD4+ T cell counts correlated strongly with a more flexible mode of R5 virus CCR5 usage, as disclosed by an increased ability to utilize chimeric CXCR4/CCR5 receptors, specifically receptor FC-2. Importantly, an elevated ability to utilize chimeric receptors correlated with a reduced susceptibility to inhibition by TAK-779. Our findings show that a discordant CSF and plasma virus coreceptor use is not uncommon. Furthermore, we provide support for an emerging paradigm, where the acquisition of a more flexible mode of CCR5 usage is a key event in R5 virus pathogenesis. This may, in turn, negatively impact the efficacy of CCR5 antagonist treatment in late stage HIV-1 disease.
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| 9. |
- Palm, Angelica A., et al.
(author)
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Interferon Alpha-Inducible Protein 27 Expression Is Linked to Disease Severity in Chronic Infection of Both HIV-1 and HIV-2
- 2022
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In: Frontiers in Virology. - : Frontiers Media SA. - 2673-818X. ; 2
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Journal article (peer-reviewed)abstract
- Disease progression is slower in HIV-2, as compared with HIV-1 infection, in accordance with low or undetectable plasma viremia at viral setpoint. However, it is unclear why most HIV-2 infected individuals are still at risk of developing AIDS. To explore if specific host responses are linked to HIV disease severity, we have compared blood gene expression profiles between HIV seronegative and HIV-1, HIV-2 or dually HIV-1/HIV-2 infected individuals. In this study the gene encoding Interferon alpha-inducible protein 27 (IFI27) was found to be the most differentially expressed. Detailed expression analysis revealed significantly higher IFI27 expression in HIV infected individuals compared with seronegative individuals, irrespectively of HIV type. Moreover, IFI27 expression was higher in HIV-1 than in HIV-2 infected individuals. Multiple linear regression analysis, adjusting for age and sex, showed also that plasma viral load was the strongest predictor of IFI27 expression, followed by CD4% and HIV type. In line with this, IFI27 expression was found to be higher in HIV-2 viremic, compared with HIV-2 aviremic individuals. Still, HIV-2 aviremic individuals displayed elevated IFI27 expression compared with seronegative individuals. Furthermore, in HIV-2 infected individuals, IFI27 expression was also correlated with plasma markers previously linked to inflammation and disease progression in HIV infection. Taken together, our findings suggest that sustained elevation of type I interferon signaling, here reflected by elevated IFI27 expression in the chronic infection phase, is a key pathogenic feature of both HIV-1 and HIV-2
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| 10. |
- Palm, Angelica A., et al.
(author)
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Low Postseroconversion CD4+ T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection
- 2019
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In: mBio. - 2161-2129. ; 10:1
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Journal article (peer-reviewed)abstract
- A positive correlation between virus evolutionary rate and disease progression has been shown for human immunodeficiency virus type 1 (HIV-1) infection. Much less is known about HIV-2, the second causative agent of AIDS. We analyzed 528 HIV-2 env V1-C3 sequences generated from longitudinal plasma samples that were collected from 16 study participants during a median observation time of 7.9 years (interquartile range [IQR], 5.2 to 14.0 years). Study participants were classified as faster or slower disease progressors based on longitudinal CD4+ T-cell data. The HIV-2 evolutionary rate was significantly associated with CD4+ T-cell levels and was almost twice as high among the faster progressors as among the slower progressors. Higher evolutionary rates were accounted for by both synonymous and nonsynonymous nucleotide substitutions. Moreover, slow disease progression was associated with stronger positive selection on HIV-2/SIVsm (simian immunodeficiency virus infecting sooty mangabey) surface-exposed conserved residues. This study demonstrated a number of previously unknown characteristics linking HIV-2 disease progression with virus evolution. Some of these findings distinguish HIV-2 from HIV-1 and may contribute to the understanding of differences in pathogenesis.IMPORTANCE The relationship between HIV evolution and disease progression is fundamental to our understanding of HIV immune control and vaccine design. There are no clear definitions for faster and slower HIV-2 disease progression and for the relationship of the rate of progression with HIV-2 evolution. To address the hypothesis that viral evolution is correlated with disease progression in HIV-2 infection, we determined faster and slower disease progression based on follow-up data from a prospective cohort of police officers in Guinea-Bissau. The analysis showed that although the CD4+ T-cell level and the decline in the level were independently associated with progression to AIDS, only the CD4+ T-cell level or a combined CD4+ T-cell level/decline stratification was associated with the rate of HIV-2 evolution. The HIV-2 evolutionary rate was almost twice as high among the faster progressors as among the slower progressors. Importantly, this report defines previously unknown characteristics linking HIV-2 disease progression with virus evolution.
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