Projects
Acute HIV-1 infection
Viral evolution and innate immune responses during acute adult HIV-1 infection and their association with disease pathogenesis
It has been suggested that different virological and immunological events during the very early stages of HIV infection may determine the rate of the future disease course of the individual patient. Previous studies by us and others have suggested that differences in disease progression rate may be associated with both viral parameters, such as diversity or infecting subtype and host immune responses. Moreover, differences in clinical symptoms during the acute HIV-1 infection may be driven by both viral factors and innate immune responses. The detailed underlying mechanisms that determine differences in disease progression and clinical presentation of acute HIV infection (AHI) are largely unknown. The main goal of this project is to dissect the relationship between HIV-1 viral diversity, evolutionary dynamics, innate immune responses, and acute retroviral syndrome during acute HIV-1 infection, and how they contribute to disease pathogenesis during the acute and chronic stages of infection.
Leading Researchers: Amin S. Hassan, Eduard Sanders, Joakim Esbjörnsson
Main collaborators: IAVI, Kamini Gounder, Thumbi Ndung’u, Per Björkman, Sarah Rowland-Jones
Methods paper: Single Genome Amplification
In-depth analysis of how HIV evolutionary dynamics in diversity and divergence as well as adaptation to host immune responses require methods that enable large-scale and thorough dissection of the HIV quasispecies. We have developed a single-genome amplification platform that makes this possible. This project aims to describe our experiences of the challenges and benefits of using such a methodology.
Leading Researchers: Amin S. Hassan, Jamirah Nazziwa, Sara Karlson, Joakim Esbjörnsson
Main collaborators: IAVI, Eduard Sanders, Thumbi Ndung’u, Per Björkman
Viral evolution and innate immune responses during acute infant HIV-1 infection and their association with disease pathogenesis
Clear differences in the natural history of acute HIV-1 infection exist between adults and infants both clinically and with respect to viral population dynamics and the nature of the immune response. Where adults on average progress to AIDS over 8-10 years if untreated, infants experience extremely rapid progression, with 50% of African infants dying before they are two years old. The main goal of this project is to dissect the relationship between HIV-1 viral diversity, evolutionary dynamics, and innate immune responses during acute infant HIV-1 infection, and how they contribute to disease pathogenesis during the acute and chronic stages of infection.
Leading Researchers: Joakim Esbjörnsson, Jamirah Nazziwa
Main collaborators: Sarah Rowland-Jones, Jennifer A. Slyker, Grace C. John-Stewart
Quantification of the blood proteome during acute HIV-1 infection
Recent advances in the sensitivity of proteomic analysis techniques have made it possible to simultaneously quantify and trace the anatomic origin of more than 800 blood plasma proteins from less than 10 μl blood plasma. In this study, we plan to analyse samples that has been collected during acute HIV-1 infection (AHI) from a total of 115 participants (74 from the International AIDS Vaccine Initiative [IAVI, http://www.iavi.org/, samples from Kenya, Uganda, Zambia, Rwanda], 26 from Sweden, and 15 from South Africa).
Leading Researchers: Jamirah Nazziwa, Joakim Esbjörnsson
Main collaborators: IAVI, Amin S. Hassan, Eduard Sanders, Thumbi Ndung’u, Johan Malmström
Associating viral replicative capacity close to HIV-1 transmission during adult acute HIV- 1 infection
The HIV-1 gag and env genes amplified from blood plasma samples of a unique cohort of acute HIV-1 infections are analyzed in this project with the aim to assess virus adaptations during acute HIV-1 infection and how these relates to the replicative capacity of the virus. This is done by a combination of state-of-the-art virus replicative capacity assays and statistics.
Leading Researchers: George Nduva, Eduard Sanders, Amin S. Hassan, Joakim Esbjörnsson
Main collaborators: IAVI, Kamini Gounder, Thumbi Ndung’u
Disentangling differences between adult and infant acute HIV-1 infection in secondary lymphoid tissue using single-cell transcriptomics
Thirty-seven million individuals are currently infected with the human immunodeficiency virus (HIV) worldwide. Curbing the HIV epidemic represents one of the biggest challenges of our time and although combination antiretroviral therapy can control the infection, HIV infection remains incurable. Interestingly, the disease progression rate can vary considerably between individuals (with time to AIDS ranging between months to decades), and the immune specificity against HIV infection has been suggested to only explain about 22% of the most reliable predictor of when AIDS will develop? Importantly, this implies that up to 78% of the variation in HIV disease progression rate between patients remains to be explained. In addition, clear differences in the natural history of acute HIV-1 infection exist between adults and infants both clinically and with respect to viral population dynamics and the nature of the immune response. Where adults on average progress to AIDS over 8-10 years if untreated, infants experience extremely rapid progression, with 50% of African infants dying before they are two years old. Despite the uncontrolled viral replication and high mortality rates associated with vertical HIV-1 transmission, a proportion of infants experience delayed clinical and immunological progression in the absence of antiretroviral therapy that can persist into childhood and even adolescence. The mediators of infant immunity that contribute to slow progression in pediatric HIV-1 infection remain largely unknown.
The objective of this project is to determine and compare key virus-host regulators of disease progression rate in adults and infants. To do this, human cell-cell and virus-cell interactions are studied in the context of the complex tissue cytoarchitecture in secondary lymphoid tissue. The infected secondary lymphoid tissue will be monitored longitudinally and virus-cell interactions will be dissected by single-cell transcriptomics using the Drop-seq platform.
Leading Researchers: Joakim Esbjörnsson
Main collaborators: IAVI, Eduard Sanders, Thumbi Ndung’u, Sarah Rowland-Jones, Jennifer A. Slyker, Grace C. John-Stewart
HIV-1 and HIV-2 interactions
Development of HIV-1 and HIV-2 gene-specific chimeric viruses
The aim of this study is to develop vectors for an optimized generation of gene-specific chimeric viruses, including inserts of gag, pol, env and nef amplicons into HIV-1 and HIV-2 backbones containing the full genomes (except for the targeted genes). Chimeric virus particles are produced after transfection and titres and replicative capacities of infectious chimeric viruses are determined by infection of GFP-expressing indicator cells.
Leading Researchers: Emil Johansson, Marianne Jansson, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group, Kamini Gounder, Thumbi Ndung’u, Mark Brockman, Zabrina Brumme
Analysis of infectivity and replicative capacity of HIV-1 and HIV-2 isolates and chimeric viruses in lymphoid cells and tissue
In this project, we will analyze the infectivity and replicative capacity of HIV-1 and HIV-2 isolates and chimeric viruses, developed in a related project and belonging to different progressor groups. The infectivity and replicative capacity of viruses are assessed in different cell types and in lymphoid tissue (tonsils), with the aim to identify viral genes linked to the pathogenesis of HIV-1 and HIV-2.
Leading Researchers: Emil Johansson, Joakim Esbjörnsson, Marianne Jansson
Main collaborators: SWEGUB CORE group, Cecilia Ahlström-Emanuelsson
Identification of mechanisms behind HIV-2 interference with HIV-1 replication in dual infections of lymphoid cells and tissue
On the basis of the epidemiological finding that the HIV-2 delays HIV-1 driven disease progression in those being dually infected, the aim of this project is to study mechanisms of interference between these viruses in different infection models. HIV-1 and/or HIV-2 isolates and chimeric viruses, in dual and single infection setups of lymphoid cells and tonsil tissue, are studied using viral RNA and DNA readout. Soluble and intracellular markers are correlated with single and dual-infections.
Leading Researchers: Emil Johansson, Marianne Jansson, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group, Cecilia Ahlström-Emanuelsson
Characterization of HIV-2 cell tropism and reservoirs, compared to HIV-1, in lymphoid tissue
lThe cell tropism and reservoir have been well characterized for HIV-1, where different CD4+ memory T cell subsets constitute the main pool of latently infected cells. The knowledge on the tropism and latent reservoir in HIV-2 infection is, however, much less studied. The aim of this project is to use FACS analysis to study the latently infected reservoir of cells in a lymphoid tissue model using isolates and chimeric viruses.
Leading Researchers: Emil Johansson, Joakim Esbjörnsson, Marianne Jansson
Main collaborators: SWEGUB CORE group, Cecilia Ahlström-Emanuelsson
Determination of HIV-1 and HIV-2 interactions with host immune cells in secondary lymphoid tissue using single-cell transcriptomics
Thirty-seven million individuals are currently infected with the human immunodeficiency virus (HIV) worldwide. Curbing the HIV epidemic represents one of the biggest challenges of our time and although combination antiretroviral therapy can control the infection, HIV infection remains incurable. Two HIV virus types exist HIV-1 and HIV-2. Although HIV-1 and HIV-2 are closely related, share transmission routes, cellular targets, and AIDS-defining symptomatology, HIV-2 infection is characterized by lower transmission rates, a slower decline in CD4+ T-cells, longer asymptomatic stage, and lower mortality rates. Until recently, a common perception was that HIV-2 infection often is characterized by a normal life span, reflected by bimodal survival characteristics on the population level (i.e. some individuals progress to HIV-related disease whereas others do not). We recently demonstrated that HIV-1 and HIV-2 have identical disease trajectories, but that the disease-free time on average is more than twice as long in HIV-2 infection (Esbjörnsson, Lancet HIV, 2018), a result that has been described as “a game-changer to the prevailing view of HIV-2”. However, the underlying mechanisms for the slower disease progression in HIV-2 infection are not known, and unraveling these mechanisms hold the potential of discovering novel targets for treatment or prevention against the more widespread HIV-1. As a proof-of-concept, we previously showed that HIV-2 inhibits HIV-1 disease progression in humans in vivo, resulting in almost twice as long time to AIDS and mortality among HIV-1/HIV-2 dual-infected individuals compared with HIV-1 single-infected individuals (Esbjörnsson, N Engl J Med, 2012; AIDS, 2014). This indicates that the mechanisms responsible for the slower disease progression in HIV-2 infection likely can be exploited to control the more aggressive HIV-1 infection.
The objective of this project is therefore to study key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection. To do this, human cell-cell and virus-cell interactions are studied in the context of the complex tissue cytoarchitecture in secondary lymphoid tissue. The infected secondary lymphoid tissue will be monitored longitudinally and virus-cell interactions will be dissected by single-cell transcriptomics using the Drop-seq platform.
Leading Researchers: Nordine Bakouche, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group
HIV-1 coreceptor tropism in HIV-1 and HIV-2 dual-infection
HIV enters target cells via interactions with CD4 and a coreceptor, usually one of the chemokine receptors CCR5 or CXCR4. Whereas CCR5-using strains usually are present throughout the complete disease course, CXCR4-using strains generally emerge in late-stage disease, close to the AIDS onset, and is almost invariably associated with a subsequent increase in the rate of CD4+ T-cell decline, accelerated disease progression, and a poor prognosis for survival. In this study, we investigate differences in HIV-1 coreceptor tropism and genetics between HIV-1 single and HIV-1 and HIV-2 dual-infection.
Leading Researchers: Joakim Esbjörnsson, Patrik Medstrand
Main collaborators: SWEGUB CORE group
HIV molecular epidemiology and drug resistance
Tracing the HIV-1 molecular epidemiology in Kenya: origin, demography and geographical spread
In this project, the molecular epidemiology of HIV-1 is assessed by the analysis of 3,698 sequences from the HIV-1 pol region collected 1986-2017, whereof 865 constitute sequences determined specifically for this project. The new sequences have been selected to represent both the general population and key populations (e.g. MSM and
FSW), available through an established collaboration between key stakeholders in Kenya. This project employs molecular biology techniques to determine new virus sequences from blood plasma samples and phylodynamic and phylogeographic approaches to determine and characterize epidemiologically important transmission clusters of the most common HIV-1 strains that are circulating in Kenya.
Leading Researchers: George Nduva, Amin S. Hassan, Eduard Sanders, Joakim Esbjörnsson
Main collaborators: Fredrick Otieno, Joshua Kimani, Maxwel Majiwa, Gaudensia Mutua, Omu Anzala, Kimberly D McCarthy, Lyle R. McKinnon, Lawrence Gelmon, Susan Graham, Robert C.Bailey
Prevalence and time trends of transmitted drug resistance among HIV-1 infected patients in Kenya
This study builds on the sequence dataset generated in another project of the molecular epidemiology of HIV-1 in Kenya. The aim is to dissect the current prevalence of transmitted HIV-1 drug resistance both in general and key populations. Trend analysis are performed to assess how transmitted drug resistance changes with time with the aim to forecast the number of HIV-1 infected individuals that will fail first-line treatment regimen during the following decade, and if there will be differences in first-line treatment failure between general and key population groups.
Leading Researchers: George Nduva, Eduard Sanders, Joakim Esbjörnsson, Amin S. Hassan
Main collaborators: Fredrick Otieno, Joshua Kimani, Maxwel Majiwa, Gaudensia Mutua, Omu Anzala, Kimberly D McCarthy, Lyle R. McKinnon, Lawrence Gelmon, Susan Graham, Robert C. Bailey
HIV-2 molecular epidemiology of HIV-2 in Guinea-Bissau
The aim of this study is to dissect the molecular epidemiology of HIV-2 in Guinea-Bissau. Previously published and new HIV-2 env sequences are analyzed by state-of-the-art phylodynamic and phylogeographic approaches to estimate growth rates, number of effective infections, and the timing of the origin and dispersal of HIV-2 in Guinea-Bissau.
Leading Researchers: Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group
HIV-1 molecular epidemiology in Pakistan
The aim of this study is to dissect the molecular epidemiology of HIV-1 in Pakistan. Previously published and new HIV-1 pol sequences are analyzed by state-of-the-art phylodynamic and phylogeographic approaches to estimate growth rates, number of effective infections, and the timing of the origin and dispersal of HIV-1 in Pakistan. A thorough comparison between the HIV-1 subtype A-strains specific for Pakistan vs. Kenya.
Leading Researchers: Uroosa Tariq, Hani Abidi, Joakim Esbjörnsson
Virus evolution and disease pathogenesis
Linking HIV-1 disease progression with virus escape mechanisms and immune selection
In this project, we analyze 1351 clonal HIV-1 env V1-V3 amplicons (approximately 940 bp) generated from two or more time-points throughout the disease course of 33 study participants. The study participants will be stratified by disease progression rate based on CD4+ T-cell dynamics and analyzed by so-called hierarchical phylogenetic models to link virus diversity, evolution and selection with disease progression rate. The results will further our understanding of virus-host interactions and virus escape mechanisms during HIV-1 pathogenesis.
Leading Researchers: Jamirah Nazziwa, Patrik Medstrand, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group
Intra-host evolution of HIV-2 capsid and associations with disease progression
In this project, we aim to (1) describe amino acid sequence variation in the HIV-2 quasispecies in 12 patients and map how these sequence variants change over time, (2) measure site-specific selection pressure in intrahost evolution, and (3) compare evolutionary rates in p24 between fast and slow disease progressors.
Leading Researchers: Michael Boswell, Sarah Rowland-Jones, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group
The impact of TRIM22 genotype on disease outcomes of HIV-1 infected children and adolescents
In this project, we aim to (1) characterize genetic diversity, defined as the number and frequencies of SNPs, in TRIM5 and TRIM22 in HIV-1 infected children and adolescents from Zimbabwean cohorts, and (2) perform SNP association studies with clinical outcomes of HIV-1 infection in this population.
Leading Researchers: Michael Boswell, Joakim Esbjörnsson, Rashida Ferrand, Sarah Rowland-Jones
The impact of TRIM22 genotype on disease progression of HIV-2 infected individuals
In this project, we aim to (1) determine TRIM5 and TRIM22 genotype by sequencing their coding regions and identify which SNPs are present in HIV-2 infected patients from the Police Cohort, (2) determine if SNPs in TRIM5 and TRIM22 associated with relevant clinical outcomes using both cross-sectional and longitudinal analyses, and (3) determine if genotype frequencies of the identified SNPs vary between fast and slow disease progressors as determined by the combined coefficient.
Leading Researchers: Michael Boswell, Sarah Rowland-Jones, Joakim Esbjörnsson
Main collaborators: SWEGUB CORE group