Immunological and genetic correlates of delayed HIV disease progression in children with perinatally-acquired HIV-1 infection, Harare, Zimbabwe

Project Overview

Before the widespread availability of anti-retroviral treatment (ART) to treat HIV-infected children in Africa, perinatally-acquired HIV infection (PHIV) led to very rapid disease progression[1, 2], leading to the assumption that survival of children with PHIV to older childhood and adolescence would be rare. However, as the HIV epidemic has matured, recent studies from southern Africa now demonstrate that up to one third of perinatally-infected children are slow progressors and a substantial number of older children are presenting late to health services with undiagnosed/untreated PHIV[3-6]. Many of these older survivors of PHIV present with multiple and often irreversible complications from long-standing HIV infection[5, 7]: however, a minority remain healthy with preserved CD4+ T cell counts and undetectable viral loads. The rates of HIV disease progression differ significantly between adults and children, but the reasons for these differences are not well understood[1, 8, 9]. Understanding how some children have managed to keep HIV replication under control for years without treatment should provide new insights into HIV immunity and immunopathogenesis.

 

The aim of this project is to investigate whether specific host immune and genetic factors are associated with delayed PHIV disease progression. The study will utilize archived samples from two cohorts of older children and adolescents with PHIV in Harare, Zimbabwe, established by Professor Rashida Ferrand (co-supervisor of this project). The ZENITH cohort recruited 400 newly-diagnosed (hence previously untreated) children aged 6-15 years from primary health care clinics in Harare, who were then enrolled in HIV care, treated with ART according to national guidelines and followed for 2 years [10, 11]. The INHALE cohort recruited 200 older children and adolescents with PHIV, on ART for at least 6 months, to study the natural history of chronic lung and heart disease [12]. Samples are also available from 200 age and sex-matched controls from the same ethnic group.

We propose to investigate immunogenetic factors associated with delayed disease progression, focusing on Human Leucocyte Antigen (HLA), Killer Immunoglobulin-like Receptor (KIR) and tapasin genes. In adults there are clear HLA and KIR associations with HIV disease outcome [13], but it is not clear how important these factors are in PHIV in children [14]. Our previous HLA data from an observational study of older children with PHIV in Harare revealed a novel association between HLA-C alleles and slow disease progression[15]. The cell-surface expression of HLA-C molecules is strongly associated with delayed disease progression in adults [16], but has not been investigated in children. If significant associations between HLA and KIR genotypes and HIV disease progression are identified, we will investigate potential immunological mechanisms, looking at HIV-specific cytotoxic T-lymphocyte (CTL) responses, Natural Killer cell responses and surface expression of HLA molecules.

References:

1. Barnhart HX, Caldwell MB, Thomas P, Mascola L, Ortiz I, Hsu HW, et al. Natural history of human immunodeficiency virus disease in perinatally infected children: an analysis from the Pediatric Spectrum of Disease Project. Pediatrics 1996; 97(5):710-716.

2. Mok JY. Vertical transmission. Baillieres Clin Obstet Gynaecol 1992; 6(1):85-100.

3. Ferrand RA, Corbett EL, Wood R, Hargrove J, Ndhlovu CE, Cowan FM, et al. AIDS among older children and adolescents in Southern Africa: projecting the time course and magnitude of the epidemic. AIDS 2009; 23(15):2039-2046.

4. Bernays S, Jarrett P, Kranzer K, Ferrand RA. Children growing up with HIV infection: the responsibility of success. Lancet 2014; 383(9925):1355-1357.

5. Ferrand RA, Luethy R, Bwakura F, Mujuru H, Miller RF, Corbett EL. HIV infection presenting in older children and adolescents: a case series from Harare, Zimbabwe. Clin Infect Dis 2007; 44(6):874-878.

6. Ferrand RA, Munaiwa L, Matsekete J, Bandason T, Nathoo K, Ndhlovu CE, et al. Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe. Clin Infect Dis 2010; 51(7):844-851.

7. Ferrand RA, Bandason T, Musvaire P, Larke N, Nathoo K, Mujuru H, et al. Causes of acute hospitalization in adolescence: burden and spectrum of HIV-related morbidity in a country with an early-onset and severe HIV epidemic: a prospective survey. PLoS Med 2010; 7(2):e1000178.

8. Ofori-Mante JA, Kaul A, Rigaud M, Fidelia A, Rochford G, Krasinski K, et al. Natural history of HIV infected pediatric long-term or slow progressor population after the first decade of life. Pediatr Infect Dis J 2007; 26(3):217-220.

9. Goulder PJ, Jeena P, Tudor-Williams G, Burchett S. Paediatric HIV infection: correlates of protective immunity and global perspectives in prevention and management. Br Med Bull 2001; 58:89-108.

10. McHugh G, Rylance J, Mujuru H, Nathoo K, Chonzi P, Dauya E, et al. Chronic morbidity among older children and adolescents at diagnosis of HIV infection. J Acquir Immune Defic Syndr 2016.

11. Simms V, Dauya E, Dakshina S, Bandason T, McHugh G, Munyati S, et al. Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey. PLoS Med 2017; 14(7):e1002360.

12. Rylance J, McHugh G, Metcalfe J, Mujuru H, Nathoo K, Wilmore S, et al. Chronic lung disease in HIV-infected children established on antiretroviral therapy. AIDS 2016.

13. Carrington M, Martin MP, van Bergen J. KIR-HLA intercourse in HIV disease. Trends Microbiol 2008; 16(12):620-627.

14. Adland E, Paioni P, Thobakgale C, Laker L, Mori L, Muenchhoff M, et al. Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection. PLoS Pathog 2015; 11(6):e1004954.

15. Shepherd BL, Ferrand R, Munyati S, Folkard S, Boyd K, Bandason T, et al. HLA Correlates of Long-Term Survival in Vertically Infected HIV-1-Positive Adolescents in Harare, Zimbabwe. AIDS research and human retroviruses 2015; 31(5):504-507.

16. Apps R, Qi Y, Carlson JM, Chen H, Gao X, Thomas R, et al. Influence of HLA-C expression level on HIV control. Science 2013; 340(6128):87-91.

Training Opportunities

This project offers the student an excellent opportunity for training in a multi-disciplinary range of skills, including project management, statistics and genetic epidemiology, state-of-the-art molecular techniques for genotyping of immunogenetic loci (including HLA, KIR, and Tapasin), such as the use of long-range mon-allelic sequencing and next generation sequencing. Training will also be provided in cellular immunology, including flow cytometry and functional assays of CTL, NK cell and viral inhibition activity. Additional training on scientific writing and dissemination of research findings will be available to the student, as he/she will be encouraged to prepare and present his/her work during regular weekly meetings/scientific presentations and national/international conferences. The student will be encouraged to visit the project sites in Zimbabwe and visit the laboratories of our collaborator (Prof Mary Carrington, NCI, USA) to gain specific skills as may be needed for the project.

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 959

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Sarah L Rowland-Jones Target Discovery Institute Oxford University, NDM Research Building GBR sarah.rowland-jones@ndm.ox.ac.uk
Professor Rashida Ferrand London School of Hygiene and Tropical medicine ZWE Rashida.Ferrand@lshtm.ac.uk
Dr Louis-Marie Yindom NDM Oxford University GBR louis-marie.yindom@ndm.ox.ac.uk

There are no publications listed for this DPhil project.