Notice of Special Interest (NOSI): Evaluation of sex differences on HIV-associated comorbidities in the context of stimulant use
Notice Number:

Key Dates

Release Date:

September 9, 2021

First Available Due Date:
February 05, 2022
Expiration Date:
January 08, 2025

Related Announcements

PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-184 – NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

Issued by

National Institute on Drug Abuse (NIDA)



The goal of this Notice is to encourage applications focusing on the understanding of the biological basis of sex differences in HIV neuropathogenesis and the comorbidity of HIV with misuse of stimulants, including amphetamine, methamphetamine, cocaine, and nicotine. Studies at single cell and CNS circuits levels and in live behaving animals are encouraged.


HIV is incorporated into host cell genomes in humans after infection. Even with persistent treatment using combined antiretroviral therapy (cART), many infected brain cells retain HIV in a latent state resulting in prolonged neuropathology, and the likelihood of virus reactivation and infection of new cells within the CNS. Stimulants synergize with HIV, exacerbating neurodegeneration and neurocognitive dysfunction of people living with HIV (PLWH). Stimulant misuse can also lessen the effectiveness of treatments for HIV and/or other substance use disorders (SUD). In addition, stimulants may influence HIV latency and reactivation in the presence or absence of cART, although the mechanism is unknown.

Growing evidence suggests that there are distinct sex differences in both HIV-associated neurocognitive impairments and in the characteristics of CNS stimulant use disorders. First, HIV acquisition, pathogenesis, treatment response and prospects for cure have all been reported to differ between men and women. Factors that may differ based on sex include risky behaviors, microbiome, inflammatory mediators, and sex hormones, which also influence viral reservoir dynamics. Women living with HIV have also been reported to have greater neurocognitive impairments, including memory loss, deterioration in information processing speed and motor function. Stimulant use and its consequences also differ between males and females with respect to:the age of initiation ; patterns of use; severity of dependence; use of other addictive substances; and response to treatments. Additionally, there have been reported sex differences in stimulant-induced gene transcription and gene regulation in neurons and glia, in cortical and subcortical connectivity, and neurotransmitter release, and in immune cell activation.

Currently studies are lacking on the cellular and molecular mechanisms of sex differences in stimulant use disorders and how such differences may influence HIV and health outcomes in PLWH.

Because HIV does not infect non-human hosts, animal models have been limited to studying the expression of HIV proteins in transgenic animals, infection with pseudotyped HIV virus, or SIV in non-human primates. Mechanistic studies of HIV infection in the CNS in vivo in animal models have been critically lacking.

Recent technological advancements provide powerful tools to advance our knowledge of the basis for sex differences in HIV neuropathology and stimulant misuse. These tools range from advanced functional genomics and gene editing, single-cell omics and structural biology, and advanced electron microscopy for subcellular cell biology. Furthermore, the emerging research platforms of human cell-based organ-chip technologies, cerebral organoids and human cell-mice chimeric animals have allowed studying the comorbidity of HIV and drugs in conditions that mimic live brain environments.

Research areas responsive to this Notice include but are not limited to:

  • Research to understand molecular mechanisms underlying sex differences in HIV neuropathogenesis and in the establishment and maintenance of viral latency and reservoirs.
  • Studies exploring the genetic, epigenetic, and cellular mechanisms underlying sex differences in synaptodendritic growth, pruning, and regulation in response to HIV infection and stimulants concomitantly or separately.
  • Analysis of sex differences in HIV-specific adaptive and innate immune responses, and the influence of stimulants on these responses.
  • Studies to identify the sex-dependent effects of HIV and the effect of stimulants on brain development.
  • Research on sex difference in the effects of HIV, with and without the presence of stimulants, on behavior and cognitive function.
  • Development and validation of novel, alternative approaches to achieving HIV infection in a non-human animal model removing host-restriction factors.

Application and Submission Information

This notice applies to due dates on or after February 5, 2022 and subsequent receipt dates through May 8, 2024. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required)
  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-184 – NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-DA-21-020” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed funding opportunity announcements.

Scientific/Research Contact(s)

Da-Yu Wu, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-4649

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