CAPT Network News

Finding the Keys to Help the Immune System Protect Itself from HIV

With its world-class laboratories, excellent infrastructure and state of the art equipment, the National Institute for Communicable Diseases (NICD) in South Africa stands out in the field of immunology. “The unit also has a critical mass of researchers, which strengthens its capacity to conduct clinical and experiential research,” says Dr. Clive Gray, Chief Specialist Scientist and Head of HIV Immunology, AIDS Research Unit, NICD. The HIV Research Unit is the largest unit at the NICD. Its main focus is on the virology and pathogenesis of HIV. Scientists and post graduate students, both local and from other African countries, undergo training at the unit. The unit collaborates with many networks including CAPT Network, HIV Vaccine Trials Network, and WHO Regional HIV/AIDS Public Health Laboratory Network.

Dr. Gray’s discussions with Dr. Rafick-Pierre Sékaly, from the University of Montreal, and Dr. Catherine Riou, led to the development of an ambitious project on T cell immunity and cell signaling. “More clinical studies are needed that focus on what immune cells lead to, what switches them on and how to modulate cellular immunity,” says Dr. Gray. “That could lead to new kinds of vaccine intervention.”

Dr. Riou came to NICD to engage in this major research study, for which the CAPT Network awarded her a fellowship. The study will monitor HIV specific responses in HIV infected individuals and compare them to cytomegalovirus (CMV) responses in uninfected individuals.

“It is now well established that HIV-specific T cells are defective in their ability to produce cytokines,” says Dr. Riou. “However, less is known about the capacity of these cells to respond to cytokines.” Her study is focused on understanding the role played by cytokine signaling in the course of HIV infection. The goal is to define the phosphorylation profiles of T-cells in response to exogenous cytokine engagement and identify signaling cascades and target genes associated with efficient or impaired immune responses.

By comparing the phosphorylation profiles of CMV- and HIV-specific T cells, the study will establish the phospho-signatures that are associated with a successful immune response (CMV) and establish the potential defects of cytokine induced phosphorylation in HIV-specific cells. These markers will allow the research team to develop biomarkers associated with protective immune response. Furthermore, this project will allow the development of novel immune-monitoring assays for measuring possible protective HIV vaccine responses and provide a better understanding of the mechanisms of HIV pathogenesis.

Fifty discordant couples have been enrolled in the study. The first part of the study (analyzing cytokine responses in different T cells subsets) is currently going on and the data are expected to be ready for analysis within 4 to 5 months. For the second part, dealing with cytokine responses in HIV and CMV-specific cells, tetramers are currently under production and the experiments will be starting in about six months. The initial results are expected to be available in February 2009 and by July 2009 the project should be completed.

Analyzing the profiles of cytokine responses in HIV negative and HIV-positive individuals, and more specifically in HIV and CMV-specific cells, will allow the team to define the intrinsic capacity of T cell populations to respond to specific stimuli. They expect to identify activation, or lack of, in certain signaling pathways associated with protective immune response.

“Once these pathways have been identified,” says Dr. Riou, “an extended analysis will be needed to understand the impact of defective responsiveness on cell functions such as their survival, proliferation and cytotoxic abilities. Moreover it will be important to define if these phosphorylation signatures can be extended to clinical HIV vaccine trials, which would be a natural follow-up study, and hopefully identify new immunogenicity markers.”

Ms. Netty Malatsi, a young South African doctoral fellow is collaborating with Dr. Riou on this project. Participation in the project will strengthen Ms. Malatsi’s knowledge on T cell immunity and cell signaling. The project will also allow her to complete her PhD under Dr. Riou’s mentorship, and enable Ms. Malatsi to launch her scientific career. In addition, Dr. Riou is training staff members on multi-parameter flow-cytometry using the NICD’s 18-color capacity LSRII flow cytometer. She also actively participates in other research projects in the group to develop and reinforce work plans and analysis of data.

In addition to Dr. Riou’s study, the CAPT Network is also involved in other groundbreaking research projects at Dr. Gray’s site. One other example is a study by Dr. Tumelo Mashishi, looking at the correlation between IL-4 secreting CTL responses and disease progression.


Dr. Catherine Riou and Netty Malasti