Brain health disorders (BHDs), such as depression, anxiety, and cognitive impairment, affect a substantial proportion of the 39 million people with HIV (PWH) even when the virus is suppressed with antiretroviral therapy (ART). Despite two decades of research and clinical trials, no effective therapeutic strategies or biological targets yet exist to manage many of these disorders, primarily due to their heterogeneity. Leveraging NIH’s investment in current and past cohorts and research projects to better understand the range of pathology and identify new therapies is essential. This will require collecting, harmonizing, and analyzing data from the diverse protocols performed in the U.S. and in international settings. The purpose of this contract is to support a consortium project to understand the heterogeneity of BHDs in PWH on suppressive ART using data from established cohorts. The results will advance the field, support development of personalized medicine, and lead to improvements in brain health outcomes in PWH.

The mission of the International NeuroHIV Cure Consortium (INHCC) is to provide cutting-edge investigation and expertise in central nervous system (CNS) aspects of HIV infection relevant to pathogenesis, treatment, and HIV remission, or 'cure.'  Beginning with our first project in 2009 to evaluate the neurological implications of acute HIV infection, the group has grown to now encompass investigation into a broad array of early infection and cure strategy work. The consortium was established in 2014 to facilitate scientific exchange among investigators in a diverse array of fields and to leverage all aspects of the research portfolio  through multidisciplinary studies during acute and chronic HIV infection and HIV remission studies.​ Learn more at: https://www.inhcc.net/.

This study will leverage an unprecedented opportunity to overcome limitations of previous studies of early stage HIV neuropathogenesis. We will examine brain integrity within weeks of initial viral exposure and prior to initiation of combination antiretroviral therapy (cART). Our preliminary data reveals normal brain structure and function during the acute infection period, with new evidence of progressive brain disruption that corresponds to monocyte subpopulations and CSF markers of brain damage. The proposed study will determine the link between these progressive brain impairments within the context of cART using a mixed-model design. Evidence of persistent neural injury despite cART instituted during acute infection will highlight the importance of adjuvant treatment to improve neurological outcomes regardless of HIV disease stage.

An estimated 3.4 million children are living with HIV globally. As more children with perinatally-acquired HIV survive, understanding the impact of HIV on cognition and behavior in children is increasingly important. This project addresses potential viral and host factors that underlie neurocognitive impairment in these children. The study will take place in Myanmar where HIV+ and HIV- children live in separate orphanages with identical socioeconomic conditions and HIV +children are on a similar treatment protocol nationally. An understanding of viral (subtype, p-Proviral DNA, HIV-1 tat gene, co-receptor usage) and host (immune status) determinants is critical, as those factors may better inform the initiation of combined antiretroviral therapy, selection of drugs with greater penetration into the central nervous system with less neurotoxic effect, and targeted therapy related to viral determinants.

The proposed project will build on our successful work completed in Phase 1 to enhance mental health research capacity in Cambodia. In this Phase 2 program, we will work with government and academic leaders to enrich the professional opportunities and generate innovative mental health research programs relevant to the needs of Cambodian citizens. Mixed methods analyses will examine the feasibility and acceptability of trauma informed care, and a randomized clinical trial will examine the effectiveness of a novel, evidence-based treatment for post-traumatic stress, depression, anxiety, and substance use. Outcomes from the integrated program will lay the groundwork to scale and sustain mental health research and clinical care driven by in-country leaders and US partners dedicated to changing the current trajectory of mental health equity in Cambodia.

This randomized controlled trial is  the first to examine the efficacy of an evidence-based Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) treatment for altering microbiome-gut-brain (MGB) axis pathways in depressed people with HIV (PWH) receiving effective anti-retroviral therapy. Leveraging an evidence-based CBT-AD treatment as an experimental probe will advance our basic understanding of the MGB axis pathways whereby decreasing depression potentiates alterations in key neurobehavioral substates relevant to depression in PWH. Examining MGB axis moderators and mediators using multi-level, high dimensional data will support efforts to identify subgroups of individuals who may be most responsive to CBT-AD as well as inform the development of a new generation of pharmacologic and behavioral treatments for depression targeting the MGB axis in PWH. Dr. Paul serves as MPI on this R01 with Dr. Adam Carrico at Florida International University and Dr. Roger McIntosh at University of Miami.

Since early in the COVID-19 pandemic, some patients have described neurological symptoms during acute COVID-19 and lingering nervous system syndromes following acute infection. People with HIV (PWH) may be especially vulnerable to nervous system complications of COVID-19, including inflammation and injury in the brain as well as cognitive and mood sequelae. We propose to leverage the opportunity to analyze pre- and post-COVID-19 data in a unique cohort of virologically-suppressed, early treated PWH with longitudinal multimodal nervous system phenotyping to provide key information regarding the combined effects of SARS-CoV-2 and HIV on the brain. Dr. Paul serves as MPI on this study with Dr. Serena Spudich at Yale University.

Our proposal takes advantage of an established infrastructure to evaluate mental health disorders and cognition in HIV+ individuals on long-term ART in Uganda. Our investigations will improve our understanding of the causal mechanisms of these central nervous system complications in both the US and Africa that could potentially lead to improved interventions to treat mental health disorders in HIV infection which may be of benefit worldwide. Dr. Paul serves as MPI on this R01 with Dr. Leah Rubin at Johns Hopkins University.