Notice Number: NOT-MH-16-008
Release Date: April 14, 2016
This Notice is to update the research community on the availability of clinical samples for research towards an HIV cure from the National NeuroAIDS Tissue Consortium (NNTC).
The NNTC is funded by NIMH and NINDS and manages a collection of high quality brain specimens and data resources (and was supported through RFA-MH-13-070 and RFA-MH-13-071). The NNTC provides resources to scientific investigators engaged in NeuroAIDS research and research towards an HIV cure. The NNTC cohort is currently comprised of 596 late stage HIV-positive participants and 31 HIV-negative participants who have indicated a willingness to participate in organ donation. Comprehensive neuromedical, neuropsychological, psychiatric and virological data are collected in life and following death, the collected post mortem samples and clinically annotated data sets are maintained in the repository. The NNTC ensures that scientific investigators have access to the available data (clinical, laboratory and research) and specimens of the repository including 899 HIV-positive brains and 249 HIV-negative brains as well as peripheral nervous system tissue, heart, lung, liver, kidney, lymph nodes, cerebral spinal fluid and blood.
The NNTC has recently defined criteria for a unique subset of samples that are available for use. This subset includes 44 HIV-positive participants of the NNTC cohort who were on suppressive antiretroviral therapy (ART) in life and who participated in organ donation. Brain and other tissue samples from this unique subset of the NNTC repository are entitled, "Virally Suppressed Cases." The samples are de-identified and therefore do not meet the criteria for human subjects research. These NNTC Cohort enrollees consented to future use and the samples are accompanied with a code that matches clinical and laboratory with research data. For additional details on the criteria used by the NNTC to create this distinct collection of samples, and to determine the availability or to request samples, please contact the NNTC at the following website: www.nntc.org.
This Notice encourages supplemental and new applications to propose use of the NNTC samples from the NNTC subset of "Virally Suppressed Cases" to further characterize HIV-1 latency in the cells and tissues of the central nervous system (CNS) and to assess the potential for HIV-1 rebound from the brain upon cessation of Anti-Retroviral Therapy (ART). Please see the research objectives below.
Only requests for Administrative Supplements will be considered for FY2016 funding and all such requests must be received by June 4, 2016, 5 pm local time of the applicant organization. All administrative supplement applications should be preceded by consultation with the NIMH Program Staff associated with the parent grant to discuss the potential supplement request.
ART suppresses HIV-1 RNA levels in plasma and cerebral spinal fluid, yet it does not completely eliminate the virus. Resting memory CD4 positive T cells latently infected with HIV-1 are considered the primary source of resurgent virus upon cessation of ART. Other potential cellular reservoirs under investigation include monocyte-derived macrophages, microglial cells, and astrocytes. HIV-1 is also sequestered in anatomic tissue reservoirs such as gut-associated lymphoid tissue and the brain. Whether cells resident in the central nervous system (CNS) such as macrophages and microglia contribute to the HIV-1 reservoir is a matter of debate. Despite a significant number of studies on HIV-1 reservoirs and latency, there is a gap in our understanding of CNS HIV-1 reservoirs due to lack of credible evidence that CNS derived cells of ART-suppressed patients contain replication-competent HIV-1 genomes that are potentially capable of causing rebound viremia.
Suggested areas of research using this subset of NNTC samples include, yet are not limited to, the following:
1) Identify innovative strategies to discover potential CNS reservoirs that harbor intact HIV-1 provirus capable of replication using state-of-the art techniques involving PCR amplification and sequencing of full length HIV genome. Further, use of technologies such as laser capture micro dissection and multiplexed DNA and/or RNA in situ hybridization/amplification (DNAscope and RNAscope) are encouraged;
2) Quantify the level of replication of competent provirus in the CNS compartment using validated assays;
3) Delineate the presence of ART drugs in specific regions of the brain and determine the impact on viral reservoirs;
4) Compare and contrast the phylogenetic signatures of HIV isolated from cells and tissues of the CNS with those of the circulating virus in the periphery to identify CNS escape and compartmentalization of viral variants;
5) Define the relationship between chronicity of infection and aging to the nature and size of the CNS reservoir;
6) Elucidate the mechanisms involved in persistence of HIV-1-infected cells in the CNS despite the presence of suppressive ART and identify mechanisms used to escape the immune response;
7) Identify novel cellular markers that can be used to detect latently infected cells in the CNS.
The funding opportunities that may be used to submit research applications proposing the use of samples from the NNTC subset of "Virally Suppressed Cases" include, but are not limited, to the following announcements:
Please direct inquiries regarding NIH Administrative Supplements to the NIH Program Staff affiliated with the parent award.
Please contact the following NIH Staff members for general inquires related to this Notice:
National Institute of Mental Health (NIMH)
National Institute of Neurological Disorders and Stroke (NINDS)