| 1. |
- Abidi, Syed Hani, et al.
(author)
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Phylogenetic and Drug-Resistance Analysis of HIV-1 Sequences From an Extensive Paediatric HIV-1 Outbreak in Larkana, Pakistan
- 2021
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In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 12
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Journal article (peer-reviewed)abstract
- Introduction: In April 2019, an HIV-1 outbreak among children occurred in Larkana, Pakistan, affecting more than a thousand children. It was assumed that the outbreak originated from a single source, namely a doctor at a private health facility. In this study, we performed subtype distribution, phylogenetic and drug-resistance analysis of HIV-1 sequences from 2019 outbreak in Larkana, Pakistan. Methods: A total of 401 blood samples were collected between April–June 2019, from children infected with HIV-1 aged 0–15 years recruited into a case-control study to investigate the risk factors for HIV-1 transmission. Partial HIV-1 pol sequences were generated from 344 blood plasma samples to determine HIV-1 subtype and drug resistance mutations (DRM). Maximum-likelihood phylogenetics based on outbreak and reference sequences was used to identify transmission clusters and assess the relationship between outbreak and key population sequences between and within the determined clusters. Bayesian analysis was employed to identify the time to the most recent common recent ancestor (tMRCA) of the main Pakistani clusters. Results: The HIV-1 circulating recombinant form (CRF) 02_AG and subtype A1 were most common among the outbreak sequences. Of the treatment-naïve participants, the two most common mutations were RT: E138A (8%) and RT: K219Q (8%). Four supported clusters within the outbreak were identified, and the median tMRCAs of the Larkana outbreak sequences were estimated to 2016 for both the CRF02_AG and the subtype A1 clusters. Furthermore, outbreak sequences exhibited no phylogenetic mixing with sequences from other high-risk groups of Pakistan. Conclusion: The presence of multiple clusters indicated a multi-source outbreak, rather than a single source outbreak from a single health practitioner as previously suggested. The multiple introductions were likely a consequence of ongoing transmission within the high-risk groups of Larkana, and it is possible that the so-called Larkana strain was introduced into the general population through poor infection prevention control practices in healthcare settings. The study highlights the need to scale up HIV-1 prevention programmes among key population groups and improving infection prevention control in Pakistan.
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| 2. |
- Andersson, E., et al.
(author)
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Increase in transmitted drug resistance in migrants from sub-Saharan Africa diagnosed with HIV-1 in Sweden
- 2018
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In: AIDS. - 0269-9370. ; 32:7, s. 877-884
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Journal article (peer-reviewed)abstract
- Objective: To study the trends of transmitted drug resistance (TDR) in HIV-1 patients newly diagnosed in Sweden, 2010-2016. Design: Register-based study including all antiretroviral therapy-naive patients ≥18 years diagnosed with HIV-1 in Sweden 2010-2016. Methods: Patient data and viral pol sequences were extracted from the national InfCareHIV database. TDR was defined as the presence of surveillance drug resistance mutations (SDRMs). A CD4+ T-cell decline trajectory model estimated time of infection. Phylogenetic inference was used for cluster analysis. Chi-square tests and logistic regressions were used to investigate relations between TDR, epidemiological and viral factors. Results: One thousand, seven hundred and thirteen pol sequences were analyzed, corresponding to 71% of patients with a new HIV-1 diagnosis (heterosexuals: 53%; MSM: 34%). The overall prevalence of TDR was 7.1% (95% CI 5.8-8.3%). Nonnucleoside reverse transcriptase inhibitor (NNRTI) TDR increased significantly from 1.5% in 2010 to 6.2% in 2016, and was associated to infection and/or origin in sub-Saharan Africa (SSA). An MSM transmission cluster dating back to the 1990s with the M41L SDRM was identified. Twenty-five (1.5%) patients exhibited TDR to tenofovir (TDF; n = 8), emtricitabine/lamivudine (n = 9) or both (n = 8). Conclusion: NNRTI TDR has increased from 2010 to 2016 in HIV-1-infected migrants from SSA diagnosed in Sweden, mirroring the situation in SSA. TDR to tenofovir/emtricitabine, used in preexposure prophylaxis, confirms the clinical and epidemiological need for resistance testing in newly diagnosed patients.
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| 3. |
- Andrews, Sophie M., et al.
(author)
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Analysis of HIV-1 envelope evolution suggests antibody-mediated selection of common epitopes among Chinese former plasma donors from a narrow-source outbreak
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- The HIV-1 envelope mutates rapidly to evade recognition and killing, and is a major target of humoral immune responses and vaccine development. Identification of common epitopes for vaccine development have been complicated by genetic variation on both virus and host levels. We studied HIV-1 envelope gp120 evolution in 12 Chinese former plasma donors infected with a purportedly single founder virus, with the aim of identifying common antibody epitopes under immune selection. We found five amino acid sites under significant positive selection in ≥50% of the study participants, and 22 sites consistent with antibody-mediated selection. Despite strong selection pressure, some sites housed a limited repertoire of amino acids. Structural modelling revealed that most of the variable amino acid sites were located on the exposed distal edge of the Gp120 trimer, whilst invariant sites clustered within the centre of the protein complex. Two sites, flanking the V3 hypervariable loop, represent novel antibody sites. Analysis of HIV-1 evolution in hosts infected with a narrow-source virus may provide insight and novel understanding of common epitopes under antibody-mediated selection. If verified in functional studies, such epitopes could be suitable as targets in vaccine development.
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| 4. |
- Boswell, Michael T., et al.
(author)
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TRIM22 genotype is not associated with markers of disease progression in children with HIV-1 infection
- 2021
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In: AIDS (London, England). - 1473-5571. ; 35:15, s. 2445-2450
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Untreated perinatal HIV-1 infection is often associated with rapid disease progression in children with HIV (CWH), characterized by high viral loads and early mortality. TRIM22 is a host restriction factor, which directly inhibits HIV-1 transcription, and its genotype variation is associated with disease progression in adults. We tested the hypothesis that TRIM22 genotype is associated with disease progression in CWH. DESIGN: ART-naive CWH, aged 6-16 years, were recruited from primary care clinics in Harare, Zimbabwe. We performed a candidate gene association study of TRIM22 genotype and haplotypes with markers of disease progression and indicators of advanced disease. METHODS: TRIM22 exons three and four were sequenced by Sanger sequencing and single nucleotide polymorphisms were associated with markers of disease progression (CD4+ T-cell count and HIV viral load) and clinical indicators of advanced HIV disease (presence of stunting and chronic diarrhoea). Associations were tested using multivariate linear and logistic regression models. RESULTS: A total of 241 children, median age 11.4 years, 50% female, were included. Stunting was present in 16% of participants. Five SNPs were analyzed including rs7935564, rs2291842, rs78484876, rs1063303 and rs61735273. The median CD4+ count was 342 (IQR: 195-533) cells/μl and median HIV-1 viral load 34 199 (IQR: 8211-90 662) IU/ml. TRIM22 genotype and haplotypes were not associated with CD4+ T-cell count, HIV-1 viral load, stunting or chronic diarrhoea. CONCLUSION: TRIM22 genotype was not associated with markers of HIV disease progression markers or advanced disease in CWH.
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| 5. |
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| 6. |
- Ederth, Josefine, et al.
(author)
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Molecular characterization of HCV in a Swedish county over 8 years (2002-2009) reveals distinct transmission patterns.
- 2016
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In: Infection ecology & epidemiology. - : Informa UK Limited. - 2000-8686. ; 6
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Journal article (peer-reviewed)abstract
- Hepatitis C virus (HCV) is a major public health concern and data on its molecular epidemiology in Sweden is scarce. We carried out an 8-year population-based study of newly diagnosed HCV cases in one of Sweden's centrally situated counties, Södermanland (D-county). The aim was to characterize the HCV strains circulating, analyze their genetic relatedness to detect networks, and in combination with demographic data learn more about transmission.
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| 7. |
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| 8. |
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| 9. |
- Esbjörnsson, Joakim, et al.
(author)
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Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa
- 2010
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In: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 7
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Journal article (peer-reviewed)abstract
- Background: HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease. Results: We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%). Conclusions: The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.
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| 10. |
- Esbjörnsson, Joakim
(author)
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HIV-1 evolution, disease progression and molecular epidemiology of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals in Guinea-Bissau
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- The two genetically related human lentiviruses known today, HIV-1 (which is pandemic) and HIV-2 (which mainly is confined to West Africa), are the causative agents of AIDS. Progressive immune dysfunction and AIDS develop in most cases of untreated HIV-1 infection, but only in approximately 25-30% of HIV-2 infected individuals. The V1-V3 region of the HIV-1 env gp120 is important for HIV-1 coreceptor use, and represents an informative region for both molecular epidemiology and intrapatient phylogenetic analyses due to high level of genetic variation. In this doctoral dissertation, HIV-1 V1-V3 sequences in combination with clinical disease markers were used to investigate HIV-1 evolution, disease progression, coreceptor tropism and molecular epidemiology of HIV-1. All sequences were derived from single (HIV-1 only) or dual-infected (HIV-1 and HIV-2) individuals from Guinea-Bissau, West Africa. The main findings was that CRF02_AG represents the most common form of HIV-1 in Guinea-Bissau, and that HIV-1 was introduced into the country on at least six different occasions between 1976 and 1981. Dual-infected individuals had a 46% lower mortality rate and a 53% longer progression-time to AIDS compared to single-infected individuals. CD4+ T cell counts were higher at corresponding time-points after infection among dual-infected individuals, reflecting the slower disease progression rate at the cellular immune level. In addition, CD8+ T cell counts were increasing at a faster rate in single than in dual-infected individuals. Stratified analyses showed that these observations were most prominent among the subgroup of dual-infected individuals that became HIV-1 infected after an established HIV-2 infection. Moreover, the HIV-1 genetic diversity was significantly lower in dual than in single-infected individuals at comparable time-points after infection. HIV-1 coreceptor tropism was investigated in late-stage disease by the use of a recombinant virus phenotypic assay that were confirmed to accurately predict the coreceptor tropism of HIV-1 subtype A and CRF02_AG. CXCR4 tropism has been coupled to an increased HIV-1 disease progression rate in late-stage disease. We found that HIV-1 CRF02_AG CXCR4 tropism was frequent (86%) and increased over time on the population level, indicating an evolving epidemic. In addition, a literature analysis showed a similar evolving epidemic for HIV-1 subtype C. Genotypic analysis suggested that the total number of charged amino acids could be important in predicting HIV-1 CRF02_AG coreceptor tropism. Finally, HIV-1 CXCR4-tropism was more common in single (79%) than in dual-infected individuals (35%). Understanding the underlying mechanisms responsible for the inhibitory effects exerted by HIV-2 against HIV-1 could be important for the development of future HIV-1 vaccines and therapeutics.
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| 11. |
- Esbjörnsson, Joakim, et al.
(author)
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HIV-1 Molecular Epidemiology in Guinea-Bissau, West Africa: Origin, Demography and Migrations
- 2011
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2
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Journal article (peer-reviewed)abstract
- The HIV-1 epidemic in West Africa has been dominated by subtype A and the recombinant form CRF02_AG. Little is known about the origins and the evolutionary history of HIV-1 in this region. We employed Maximum likelihood and Bayesian methods in combination with temporal and spatial information to reconstruct the HIV-1 subtype distribution, demographic history and migration patterns over time in Guinea-Bissau, West Africa. We found that CRF02_AG and subsubtype A3 were the dominant forms of HIV-1 in Guinea-Bissau and that they were introduced into the country on at least six different occasions between 1976 and 1981. These estimates also corresponded well with the first reported HIV-1 cases in Guinea-Bissau. Migration analyses suggested that (1) the HIV-1 epidemic started in the capital Bissau and then dispersed into more rural areas, and (2) the epidemic in Guinea-Bissau was connected to both Cameroon and Mali. This is the first study that describes the HIV-1 molecular epidemiology in a West African country by combining the results of subtype distribution with analyses of epidemic origin and epidemiological linkage between locations. The multiple introductions of HIV-1 into Guinea-Bissau, during a short time-period of five years, coincided with and were likely influenced by the major immigration wave into the country that followed the end of the independence war (1963-1974).
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| 12. |
- Esbjörnsson, Joakim, et al.
(author)
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HIV-2 as a model to identify a functional HIV cure
- 2019
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In: AIDS Research and Therapy. - : Springer Science and Business Media LLC. - 1742-6405. ; 16:1
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Research review (peer-reviewed)abstract
- Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-Term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.
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| 13. |
- Esbjörnsson, Joakim, et al.
(author)
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Increased survival among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals
- 2014
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In: AIDS. - 1473-5571. ; 28:7, s. 949-957
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Journal article (peer-reviewed)abstract
- Objective: To compare survival times of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. Design: Prospective open cohort study. Methods: We analysed data from 259 HIV-1-seroincident cases (either HIV-1 single or HIV-1 and HIV-2 dual-infected) from a cohort with long follow-up (similar to 20 years) in order to study the influence of type of infection and infection order on mortality. Sex and age at HIV-1 infection date was controlled for in a Cox proportional-hazards model. Results: Dual-infected individuals had a 42% longer time from HIV-1 infection to death compared with single-infected individuals, adjusting for age asymmetries between groups. Dual-infected individuals with an HIV-2 infection preceding the HIV-1 infection had a more than two-fold lower mortality risk during follow-up than HIV-1 single-infected individuals. Conclusion: Survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. This natural inhibition could have implications for the development of future HIV-1 vaccines and therapeutics.
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| 14. |
- Esbjörnsson, Joakim, et al.
(author)
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Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection.
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:3, s. 224-232
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Journal article (peer-reviewed)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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| 15. |
- Esbjörnsson, Joakim, et al.
(author)
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Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau : a prospective open cohort study
- 2019
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In: The Lancet HIV. - : The Lancet Publishing Group. - 2405-4704 .- 2352-3018. ; 6:1, s. E25-E31
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Journal article (peer-reviewed)abstract
- BACKGROUND: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2.METHODS: We did a prospective open cohort study. We included all police officers with regular employment from police stations in both urban and rural areas of Guinea-Bissau since Feb 6, 1990. We continued to include participants until Sept 28, 2009, and follow-up of HIV-1-positive and HIV-2-positive individuals continued until Sept 28, 2013. We collected blood samples at enrolment and at scheduled annual follow-up visits at police stations. We analysed longitudinal data from individuals infected with HIV-1 and HIV-2 according to time to AIDS, time to death, and T-cell dynamics. Time of HIV infection was estimated as the mid-timepoint between last HIV-seronegative and first HIV-seropositive sample. Data from an additional 2984 HIV-uninfected individuals from the same population were analysed to assess the effect of natural mortality on HIV-related mortality.FINDINGS: 872 participants tested HIV positive during the 23-year study period: 408 were infected with HIV-1 (183 infected before and 225 infected after enrolment) and 464 were infected with HIV-2 (377 before and 87 after enrolment). The median time from HIV infection to development of AIDS was 6·2 years (95% CI 5·4-7·1) for HIV-1 infection and 14·3 years (10·7-18·0) for HIV-2 infection (p<0·0001). The median survival time after HIV infection was 8·2 years (95% CI 7·5-8·9) for HIV-1 infection and 15·6 years (12·0-19·2) for HIV-2 infection (p<0·0001). Individuals who were infected with HIV-1 or HIV-2 before enrolment showed similar results. Comparison with uninfected individuals indicated limited confounding contribution from natural mortality. Mean CD4 percentages were higher in individuals with HIV-2 than in those with HIV-1 during early infection (28·0% [SE 1·3] vs 22·3% [1·7]; p=0·00094) and declined at a slower rate (0·4% [0·2] vs 0·9% [0·2] per year; p=0·028). HIV-2-infected individuals developed clinical AIDS at higher mean CD4 percentages (18·2%, IQR 7·2-25·4) than HIV-1-infected individuals (8·2%, 3·0-13·8; p<0·0001).INTERPRETATION: Our results show that both HIV-1-infected and HIV-2-infected individuals have a high probability of developing and dying from AIDS without antiretroviral treatment.
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| 16. |
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| 17. |
- 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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| 18. |
- Fwambah, Lynn, et al.
(author)
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Exposure to common infections may shape basal immunity and potentially HIV-1 acquisition amongst a high-risk population in Coastal Kenya
- 2023
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In: Frontiers in Immunology. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Introduction: The impact of exposure to endemic infections on basal immunity and susceptibility to HIV-1 acquisition remains uncertain. We hypothesized that exposure to infections such as cytomegalovirus (CMV), malaria and sexually transmitted infections (STIs) in high-risk individuals may modulate immunity and subsequently increase susceptibility to HIV-1 acquisition. Methods: A case-control study nested in an HIV-1 negative high-risk cohort from Coastal Kenya was used. Cases were defined as volunteers who tested HIV-1 positive during follow-up and had a plasma sample collected 3 ± 2 months prior to the estimated date of HIV-1 infection. Controls were individuals who remained HIV-1 negative during the follow-up and were matched 2:1 to cases by sex, age, risk group and follow-up time. STI screening was performed using microscopic and serologic tests. HIV-1 pre-infection plasma samples were used to determined exposure to CMV and malaria using enzyme-linked immunosorbent assays and to quantify forty-one cytokines and soluble factors using multiplexing assays. Multiplexing data were analyzed using principal component analysis. Associations between cytokines and soluble factors with subsequent HIV-1 acquisition were determined using conditional logistic regression models. Results and discussion: Overall, samples from 47 cases and 94 controls were analyzed. While exposure to malaria (p=0.675) and CMV (p=0.470) were not associated with HIV-1 acquisition, exposure to STIs was (48% [95% CI, 33.3 – 63] vs. 26% [95% CI, 17.3 – 35.9]. Ten analytes were significantly altered in cases compared to controls and were clustered into four principal components: PC1 (VEGF, MIP-1β, VEGF-C and IL-4), PC2 (MCP-1, IL-2 and IL-12p70), PC3 (VEGF-D) and PC4 (Eotaxin-3). PC1, which is suggestive of a Th2-modulatory pathway, was significantly associated with HIV-1 acquisition after controlling for STIs (adjusted odds ratio, (95% CI), p-value: 1.51 [1.14 – 2.00], p=0.004). Elevation of Th2-associated pathways may dampen responses involved in viral immunity, leading to enhanced susceptibility to HIV-1 acquisition. Immunomodulatory interventions aimed at inhibiting activation of Th2-associated pathways may be an additional strategy to STI control for HIV-1 prevention and may reduce dampening of immune responses to vaccination.
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| 19. |
- Hassan, Amin S, et al.
(author)
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A Stronger Innate Immune Response During Hyperacute HIV-1 Infection is associated with ACUTE retroviral syndrome
- 2021
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1537-6591 .- 1058-4838. ; 73:5, s. 832-841
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Journal article (peer-reviewed)abstract
- BACKGROUND: Acute retroviral syndrome (ARS) is associated with HIV-1 subtype and disease progression, but the underlying immunopathological pathways are poorly understood. We aimed to elucidate associations between innate immune responses during hyperacute HIV-1 infection (hAHI) and ARS.METHODS: Plasma samples obtained from volunteers (≥18.0 years) before and during hAHI, defined as HIV-1 antibody negative and RNA or p24 antigen positive from Kenya, Rwanda, Uganda, Zambia and Sweden were analysed. Forty soluble innate immune markers were measured using multiplexed assays. Immune responses were differentiated into volunteers with stronger and comparatively weaker responses using principal component analysis. Presence or absence of ARS was defined based on eleven symptoms using latent class analysis. Logistic regression was used to determine associations between immune responses and ARS.RESULTS: Of 55 volunteers, 31 (56%) had ARS. Volunteers with stronger immune responses (n=36 [65%]) had increased odds of ARS which was independent of HIV-1 subtype, age, and risk group (adjusted odds ratio, 7.1 [95% CI: 1.7-28.8], p=0.003). IP-10 was fourteen-fold higher during hAHI, elevated in seven of the eleven symptoms, and independently associated with ARS. IP-10 threshold >466.0 pg/mL differentiated stronger immune responses with a sensitivity of 84.2% (95% CI: 60.4-96.6) and specificity of 100.0% (95% CI: 90.3-100.0).CONCLUSIONS: A stronger innate immune response during hAHI was associated with ARS. Plasma IP-10 may be a candidate biomarker of stronger innate immunity. Our findings provide further insights on innate immune responses in regulating ARS and may inform the design of vaccine candidates harnessing innate immunity.
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| 20. |
- Hassan, Amin S., et al.
(author)
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Defining HIV-1 transmission clusters based on sequence data : a systematic review and perspectives
- 2017
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In: AIDS. - 0269-9370. ; 31:9, s. 1211-1222
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Research review (peer-reviewed)abstract
- Understanding HIV-1 transmission dynamics is relevant to both screening and intervention strategies of HIV-1 infection. Commonly, HIV-1 transmission chains are determined based on sequence similarity assessed either directly from a sequence alignment or by inferring a phylogenetic tree. This review is aimed at both nonexperts interested in understanding and interpreting studies of HIV-1 transmission, and experts interested in finding the most appropriate cluster definition for a specific dataset and research question. We start by introducing the concepts and methodologies of how HIV-1 transmission clusters usually have been defined. We then present the results of a systematic review of 105 HIV-1 molecular epidemiology studies summarising the most popular methods and definitions in the literature. Finally, we offer our perspectives on how HIV-1 transmission clusters can be defined and provide some guidance based on examples from real life datasets.
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| 21. |
- Hassan, Amin S., et al.
(author)
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HIV-1 subtype diversity, transmission networks and transmitted drug resistance amongst acute and early infected MSM populations from Coastal Kenya
- 2018
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Journal article (peer-reviewed)abstract
- Background HIV-1 molecular epidemiology amongst men who have sex with men (MSM) in sub-Saharan Africa remains not well characterized. We aimed to determine HIV-1 subtype distribution, transmission clusters and transmitted drug resistance (TDR) in acute and early infected MSM from Coastal Kenya. Methods Analysis of HIV-1 partial pol sequences from MSM recruited 2005–2017 and sampled within six months of the estimated date of infection. Volunteers were classified as men who have sex with men exclusively (MSME) or with both men and women (MSMW). HIV-1 subtype and transmission clusters were determined by maximum-likelihood phylogenetics. TDR mutations were determined using the Stanford HIV drug resistance database. Results Of the 97 volunteers, majority (69%) were MSMW; 74%, 16%, 9% and 1% had HIV-1 subtypes A1, D, C or G, respectively. Overall, 65% formed transmission clusters, with substantial mixing between MSME and MSMW. Majority of volunteer sequences were either not linked to any reference sequence (56%) or clustered exclusively with sequences of Kenyan origin (19%). Eight (8% [95% CI: 4–16]) had at least one TDR mutation against nucleoside (n = 2 [2%]) and/or non-nucleoside (n = 7 [7%]) reverse transcriptase inhibitors. The most prevalent TDR mutation was K103N (n = 5), with sequences forming transmission clusters of two and three taxa each. There were no significant differences in HIV-1 subtype distribution and TDR between MSME and MSMW. Conclusions This HIV-1 MSM epidemic was predominantly sub-subtype A1, of Kenyan origin, with many transmission clusters and having intermediate level of TDR. Targeted HIV-1 prevention, early identification and care interventions are warranted to break the transmission cycle amongst MSM from Coastal Kenya.
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| 22. |
- Hønge, Bo L., et al.
(author)
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T-cell and B-cell perturbations are similar in ART-naive HIV-1 and HIV-1/2 dually infected patients
- 2019
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In: AIDS. - 0269-9370. ; 33:7, s. 1143-1153
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Journal article (peer-reviewed)abstract
- BACKGROUND: HIV-2 may slow progression of a subsequently acquired HIV-1 infection through cross-neutralizing antibodies and polyfunctional CD8 T cells. We hypothesized that HIV-1/2 dually infected patients compared with HIV-1-infected patients had more preserved immune maturation subsets and less immune activation of T and B cells. METHODS: ART-naive patients with HIV-1 (n = 83) or HIV-1/2 dual (n = 27) infections were included in this cross-sectional study at an HIV clinic in Guinea-Bissau. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry according to T-cell maturation and activation, regulatory T-cell fraction, and B-cell maturation and activation. RESULTS: HIV-1/2 dually infected patients had lower levels of HIV-1 RNA compared with patients with HIV-1 infection, but the levels of total HIV RNA (HIV-1 and HIV-2) were similar in the two patient groups. T-cell maturation, and proportions of regulatory T cells (FoxP3+) were also similar in the two groups. HIV-1/2 dually infected patients had higher proportions of CD4 and CD8 T cells positive for the activation marker CD38, but there was no difference in other T-cell activation markers (CD28, CTLA-4, PD-1). HIV-1/2 dually infected patients also had higher proportions of IgM-only B cells and plasmablasts. CONCLUSION: HIV-1/2 was not associated with less immune perturbations than for HIV-1 infection.
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| 23. |
- James, Katherine L., et al.
(author)
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Low-Bias RNA Sequencing of the HIV-2 Genome from Blood Plasma
- 2019
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In: Journal of Virology. - 1098-5514. ; 93:1
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Journal article (peer-reviewed)abstract
- Accurate determination of the genetic diversity present in the HIV quasispecies is critical for the development of a preventative vaccine: in particular, little is known about viral genetic diversity for the second type of HIV, HIV-2. A better understanding of HIV-2 biology is relevant to the HIV vaccine field because a substantial proportion of infected people experience long-term viral control, and prior HIV-2 infection has been associated with slower HIV-1 disease progression in coinfected subjects. The majority of traditional and next-generation sequencing methods have relied on target amplification prior to sequencing, introducing biases that may obscure the true signals of diversity in the viral population. Additionally, target enrichment through PCR requires a priori sequence knowledge, which is lacking for HIV-2. Therefore, a target enrichment free method of library preparation would be valuable for the field. We applied an RNA shotgun sequencing (RNA-Seq) method without PCR amplification to cultured viral stocks and patient plasma samples from HIV-2-infected individuals. Libraries generated from total plasma RNA were analyzed with a two-step pipeline: (i) de novo genome assembly, followed by (ii) read remapping. By this approach, whole-genome sequences were generated with a 28× to 67× mean depth of coverage. Assembled reads showed a low level of GC bias, and comparison of the genome diversities at the intrahost level showed low diversity in the accessory gene vpx in all patients. Our study demonstrates that RNA-Seq is a feasible full-genome de novo sequencing method for blood plasma samples collected from HIV-2-infected individuals.IMPORTANCE An accurate picture of viral genetic diversity is critical for the development of a globally effective HIV vaccine. However, sequencing strategies are often complicated by target enrichment prior to sequencing, introducing biases that can distort variant frequencies, which are not easily corrected for in downstream analyses. Additionally, detailed a priori sequence knowledge is needed to inform robust primer design when employing PCR amplification, a factor that is often lacking when working with tropical diseases localized in developing countries. Previous work has demonstrated that direct RNA shotgun sequencing (RNA-Seq) can be used to circumvent these issues for hepatitis C virus (HCV) and norovirus. We applied RNA-Seq to total RNA extracted from HIV-2 blood plasma samples, demonstrating the applicability of this technique to HIV-2 and allowing us to generate a dynamic picture of genetic diversity over the whole genome of HIV-2 in the context of low-bias sequencing.
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| 24. |
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| 25. |
- 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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