Our group’s work is focused on the South African HIV epidemic. Although the group is based in Oxford, we have over the past 20 years developed strong collaborations in Durban and Kimberley, South Africa. Our group’s major focus is on HIV-infected children; specifically: (1) the impact of differences in the immune response in adults and children on HIV disease and HIV cure/remission potential in children; and (2) the impact of sex differences in the immune response, from conception through adolescence, on HIV disease and HIV cure/remission potential in children.
HIV infects CD4+ T-cells, causes a decline in CD4 count and immunodeficiency, ultimately resulting in AIDS. An estimated 78 million people have been infected with HIV to date, of whom ~36m are living with HIV today. Approximately 15% of HIV infections are in children. So far, only two people with HIV infection have been cured.
- Defining the role of CTL escape and viral replicative capacity in immune control and in HIV disease: Viral escape normally precipitates loss of immune control and hastens disease progression. However, selection of escape mutations that reduce viral replicative capacity may actually facilitate control by other immune responses. Transmission of viruses with low replication capacity means that disease progression is slower in the transmission recipient.
- Defining mechanisms of HLA-mediated control of HIV: Protective HLA class I molecules such as HLA-B*27, B*57, B*58:01, B*81:01 all appear to mediate immune control of HIV in part through immunodominant p24 Gag-specific CTL responses. Even in the absence of protective HLA, a broad Gag-specific CTL response is protective against HIV disease progression. Multiple other factors contribute in addition. Although close to 50% of elite controllers (ART-naïve individuals who maintain viral loads of <50 copies/ml) express HLA-B*57, only 2-5% of people with HLA-B*57 achieve elite control. Other factors include the KIR and LILRB2 interactions with HLA-B molecules, and the HLA-A and HLA-C molecules expressed. Genetic factors are estimated to account for ~25% of variation in viral load.
- Impact of viral adaptation at the population level to protective CTL responses: Transmission of escape mutants results in their accumulation at the population level, and a diminution in the protective effect of HLA molecules that depend on those epitopes for mediation of immune control. In Botswana and South Africa, the two countries worst-affected by the global epidemic, the accumulation of escape mutants has been associated with a significant reduction in viral replication capacity (‘virulence’) over the past 10-20 years.
- The impact of differences in the adult and paediatric immune response: The paediatric response is highly regulated and tolerogenic, whereas the adult response is characteristically much more aggressive. The result is that ART-naïve children typically progress much more rapidly to HIV disease than adults, and elite control is substantially rarer among children. However, viraemic non-progressors, who, like the natural hosts of SIV, maintain normal for age CD4 counts despite persistent high viraemia, are much more common among children. The potential for post-treatment control (cure/remission) may also be higher in paediatric HIV.
- The impact of sex differences in the immune response: Adult females have lower viral setpoints but progress faster for a given viral load than males. Among children, females tend to have lower viral loads and, as in adult infection, elite controllers are much more commonly female (5:1 and 10:1, respectively). However, females are also more susceptible to in utero HIV infection (2:1) for reasons unknown. The mechanisms behind this female susceptibility to in utero infection and the impact of these sex differences on HIV disease progression and cure/remission potential are current studies highlighted below.
- bnAbs to accelerate cure/remission in paediatric HIV infection: It is unlikely that ART alone will achieve cure/remission other than in exceptional cases. However, in children who have received ART very early (within 48hrs of birth), the size and diversity of the viral reservoir is very low. Recent studies in the SIV macaque model suggest that the addition of bnAbs in this setting has the potential to achieve cure/remission. We are currently planning to undertake a number of clinical trials using combination bnAbs to determine whether cure/remission can be achieved in very early treated children.
Paediatric HIV Research Clinic Team, Ithembalabanthu Clinic, Umlazi
Goulder has received funding from the Wellcome Trust from 2002-2015 through Senior Clinical Fellowships and since 2015 through a Wellcome Trust Investigator Award, 2015-2020. He has also received RO1 support from the National Institutes of Health since 2000 (most recent RO1 award 2017-2022).
In the news ...
Thumbi Ndung’u - Principal Investigator, Durban, South Africa
Pat Mbatha - Clinical Coordinator, Durban, South Africa
Manjeetha Jaggernath - Research Clinician, Durban, South Africa
Pieter Jooste - Principal Investigator, Kimberley, South Africa
Samantha Daniels - Research Technician, Kimberley, South Africa
Thea Brits - Research Technician, Kimberley, South Africa
Joris Hemelaar - Clinical Lecturer, Nuffield Department of Obstetrics and Gynaecology, University of Oxford