Effects of Drugs of Abuse on Latent HIV Reservoirs in the CNS (R01)
Department of Health and Human Services
National Institutes of Health
In response to the recently issued research priorities for AIDS funding, (NOT-OD-15-137), NIDA is interested in high-priority basic and systems-level approaches for advancing our understanding of CNS HIV latency and reservoirs in the context of substance abuse and addiction.
One of the major barriers to eradication of HIV-1 is the persistence of the latently-infected cells located in the different regions of the body. Viral latency is most likely governed by transcriptional silencing of the viral promoter. While the predominant viral reservoir is thought to be resting CD4(+) T cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbor persistently infected cellular reservoirs of HIV-1. While ART has been successful in controlling viral replication, leading to undetectable viremia in patients, it does not affect latent virus integrated into host cell DNA. Researchers have employed various strategies to eradicate viral reservoirs, but to date, none have been successful. In order to improve and refine strategies for the eradication of HIV reservoirs it is important to fully understand the characteristics of HIV latency, and to understand the effects of drugs of abuse on the molecular mechanisms underlying latency.
Current research suggests that latent viral reservoirs are present in the CNS, but many questions remain. The CNS has several unique features compared to other reservoirs. There are no resident T cells in the brain; the virus resides in macrophages, microglia, and astrocytes where the viral infection is non-cytopathic; the virus evolves in the brain; and since the turnover rate of these cells is low, the virus has the potential to reside in these cells for several decades and possibly for the life of the individual. In addition, despite the use of ART for long periods of time, low levels of viral replication, immune activation, and inflammation persist in the CNS and these factors may be responsible for the development of asymptomatic and/or mild neurocognitive impairments reported in HIV-infected patients even with ART. Importantly, drugs of abuse have been shown to exacerbate pathogenesis of neurocognitive impairments in HIV-infected patients. Therefore, a clear understanding of the cell types in which the virus resides in the CNS, the mechanisms of viral persistence, restricted replication and latency, the turnover rate of the infected cells, and how drugs of abuse affect these parameters is critical to develop strategies to treat and eradicate CNS HIV reservoirs or induce irreversible suppression of viral DNA transcription in drug-abusing populations.
It has been proposed that during early infection HIV enters the CNS but it is important to know how soon HIV enters the brain as timing of viral entry may impact the initiation of viral latency. Although transmigration of HIV-infected monocytes through the blood-brain barrier (BBB) is a generally accepted mechanism of HIV CNS entry, the exact mechanisms of viral entry into CNS are not clear. Do other peripheral immune cells participate in the transport of HIV into the CNS? Is the CNS initially colonized by free virus or by infected cells which subsequently release virus into CNS and CSF? Integrated HIV-1 provirus has been detected in perivascular macrophages, microglia, and astrocytes; productive HIV infection occurs in perivascular macrophages and microglia, but in astrocytes the infection is restricted and does not give rise to new viral particles.
Drugs of abuse add another layer of complexity in our understanding of CNS HIV latency as they have potential to impact HIV latency directly or indirectly at different stages of HIV infection and progression, including initiation, establishment, and maintenance. Drugs of abuse can affect BBB permeability, which may modulate the timing and extent of viral CNS entry. Substance abuse has been shown to decrease adherence to ART drugs and consequently impair their efficacy in the suppression of viral replication. Various substances of abuse can impact systemic and localized inflammation. For example, cocaine and methamphetamine can trigger inflammatory changes in macrophages and microglia and opioids may stimulate inflammation in brain and gut. Thus, abused substances could have an impact on the size and distribution of HIV reservoirs.
Proposed projects MUST include the following:
- A focus on HIV latency and viral reservoirs in the CNS. Proposed projects may be conducted in humans, animals, or in vitro model systems
- At least one aim or sub-aim must involve exposure to substances of abuse, such as including analysis of samples from exposed subjects or animals or drug studies using in vitro model systems.
Other application considerations:
- Newly-formed collaborations to foster sharing of expertise between the fields of HIV/AIDS and drug abuse, and other relevant fields are encouraged.
- This FOA utilizes the R01 mechanism and is appropriate for projects that can support the proposed aims either with appropriate preliminary data or relevant related work by the investigative team. Applicants lacking significant preliminary data may wish to de-risk the proposed project by submitting an R01 application of shorter duration (e.g. 2-3 years) commensurate with the higher risk of such a project.
Topics appropriate for this FOA include but not are limited to the following:
- Investigate how soon HIV enters CNS after initial infection, what are the mechanisms of viral entry, and how drugs of abuse influence these parameters.
- Investigate whether CNS is initially colonized by free virus or by infected cells which subsequently release virus into CNS and CSF. Can drugs of abuse modulate these parameters?
- Identify which CNS cells harbor latent HIV in different anatomical compartments (e.g., dopamine rich vs. dopamine deficient) in the presence and absence of drugs of abuse
- Determine the turnover rates of CNS cells harboring latent HIV in different compartments. Do drugs of abuse modulate turnover rates of these cells?
- Understanding the underlying molecular mechanisms of the initiation, establishment, and maintenance of HIV latency in CNS cells and do they differ in different cells and different CNS compartments?
- Do drugs of abuse interfere with the initiation, establishment and maintenance of the latent HIV in the CNS? If yes, what are the mechanisms?
- How is viral latency established in the CNS? Factors such as reduced basal transcriptional activity of viral promoters and increased expression of transcriptional repressors have been proposed to contribute to viral latency but confirmation is required.
- Does CNS harbor functional HIV reservoirs defined as those hosting replication-competent virus capable of producing new virus particles that can infect new susceptible cells? Using in vivo and in vitro techniques, investigate the presence of functional CNS HIV reservoirs.
Use of novel methods for studying the mechanisms of HIV latency in the context of drugs of abuse:
- Develop biomarkers to identify and quantify CNS HIV reservoirs
- Real time monitoring of viral reservoirs using imaging techniques
- Use genome editing tools (e.g., CRISPR, TALEN, Zinc Finger) to determine how drugs of abuse alter mechanisms of viral latency
|Posted Date:||Dec 8, 2015|
|Creation Date:||Dec 8, 2015|
|Original Closing Date for Applications:||Mar 3, 2016|
|Current Closing Date for Applications:||Mar 3, 2016|
|Archive Date:||Apr 3, 2016|
|Estimated Total Program Funding:||$3,000,000|
Others (see text field entitled “Additional Information on Eligibility” for clarification)
For profit organizations other than small businesses
Public and State controlled institutions of higher education
City or township governments
Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education
Native American tribal governments (Federally recognized)
Special district governments
Private institutions of higher education
Independent school districts
Native American tribal organizations (other than Federally recognized tribal governments)
Public housing authorities/Indian housing authorities
Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education
|Additional Information on Eligibility:||Other Eligible Applicants include the following: Alaska Native and Native Hawaiian Serving Institutions; Asian American Native American Pacific Islander Serving Institutions (AANAPISISs); Eligible Agencies of the Federal Government; Faith-based or Community-based Organizations; Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Indian/Native American Tribal Governments (Other than Federally Recognized); Non-domestic (non-U.S.) Entities (Foreign Organizations); Regional Organizations; Tribally Controlled Colleges and Universities (TCCUs) ; U.S. Territory or Possession.|
|Agency Name:||National Institutes of Health|
|Description:||The purpose of this FOA is to promote research to investigate the underlying molecular mechanisms by which HIV latency is initiated, established, and maintained in the CNS and to determine how drugs of abuse modulate HIV latency and the size and persistence of CNS HIV reservoirs. The ultimate goal is to obtain information for developing new or improved therapies for HIV treatment in drug-abusing populations.|
|Link to Additional Information:||http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-16-014.html|
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