Investigation of the central nervous system as a potential HIV reservoir during combination antiretroviral therapy.

Investigation of the central nervous system as a potential HIV reservoir during combination antiretroviral therapy.

Project

The major obstacle to HIV cure is presence of a stable reservoir of latently infected cells. Specific targeting and elimination of these cells is essential for HIV eradication, yet many basic questions about the composition of the latent reservoir are unanswered. As such, HIV infection of long-lived macrophages and microglia in the central nervous system (CNS) may present a major barrier to eradication strategies. This study uses unique material obtained from the CNS of patients on combination antiretroviral therapy (cART) and highly innovative brain cell culture systems, never before employed in parallel, to investigate if the CNS can serve as a potential reservoir for HIV. By whole genome deep-sequencing we will characterize the viral population as present in cerebral spinal fluid (CSF) obtained from patients on cART with undetectable plasma viral RNA. Furthermore, HIV will be characterized in CSF and brain biopsies from patients who received a stem cell transplantation. Replication potential of these characterized viruses will be analyzed in brainderived macrophages, microglia, T-cells and brain slice cultures. Outcome of this study will provide novel insights in the role of the CNS as an HIV reservoir and will help to target future HIV eradication strategies.

Project details

Time frame
31 August 2016 - 14 April 2021
Budget
€ 264,470
Active in
Netherlands

Objectives

This study uses unique material obtained from the CNS of patients on combination antiretroviral therapy (cART) and highly innovative brain cell culture systems, never before employed in parallel, to investigate if the CNS can serve as a potential reservoir for HIV.
The research questions are:
1. Does HIV reside in the CNS during cART? We will identify and genetically characterize HIV in the CNS during cART in a group of patients with detectable HIV RNA in the CSF and an undetectable viral load (<50 c/ml) in a paired plasma sample.
2. Does HIV reside in the CNS after stem cell transplantation? We will identify and genetically characterize HIV in the CNS in a group of stem cell transplantation patients on cART (EpiStem cohort). We have collected blood samples and CSF and in some cases we have obtained post-mortem brain biopsies.
3. Is HIV in the CNS replication competent? Genetic characterization of viral sequences in the CNS is a first indication that this compartment may serve as an HIV reservoir. A critical aspect is however to demonstrate that these sequences represent replication competent virus.
5. In which cells can HIV reside during cART? We will investigate in which cell populations the replication competent viruses may reside. In addition to cell lines, we will use brain-derived microglia, macrophages and T-cells as well as brain slices to investigate the origin of the virus.
Outputs are scientific publications and an integrated database. In addition, sequences will be submitted to GenBank.

Community groups

scientific community including the IAS workinggroup Cure

Background

Since the identification of HIV as the causative agent for AIDS, this retrovirus has claimed the lives of more than 30 million patients. At the moment, 37 million adults and children are estimated to be living
with HIV and need access to combination ntiretroviral therapy (cART). Implementation of cART has substantially reduced AIDSrelated morbidity and mortality. However, cART does not eliminate HIV that persists as a latent infection in cellular reservoirs and viremia rapidly resumes if therapy is interrupted. Consequently, HIV infected individuals must commit to expensive, life-long therapies and must tackle problems associated with uninterrupted cART and
chronic infection, including continuous clinical and laboratory monitoring, drug toxicities and chronic immune activation/inflammation, together resulting in increased incidence of co-morbidities and mortality compared to non-infected individuals.
There is an emerging interest worldwide (1) and among HIV-infected individuals from the Netherlands in particular
(http://www.aidsmap.com/What-do-people-living-with-HIV-think-aboutthe-
prospect-of-a-cure/page/2446375/), in developing safe and affordable curative strategies that would eliminate the need for lifelong therapy while improving their health, reducing viral transmission and HIV-related stigma and discrimination.

There is currently no HIV cure. The major obstacle to HIV cure is presence of a stable reservoir of latently infected cells. Specific targeting and elimination of these cells is essential for HIV eradication, yet many basic questions about the composition of the latent reservoir are unanswered. As such, HIV infection of long-lived macrophages and microglia in the central nervous system (CNS) may present a major barrier to eradication strategies.

Goals

A cure for HIV
100%
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