The introduction of combined antiretroviral therapy, or cART, transformed HIV from a death sentence to a chronic disease with several comorbid complications, the most notable of which is HIV-associated neurocognitive disorders, or HAND. Despite cART, HAND affects approximately 18 to 50 percent of HIV infected individuals and its prevalence is expected to increase as the HIV-infected population ages. This underscores the need to better define cellular and molecular mechanisms driving HIV-mediated neuropathogenesis to devise novel strategies to prevent and/or treat HAND. Further,
HIV latency and/or residual low-level of HIV replication continue to be an impediment to the eradication of HIV.
Our work
The lab of Lena Al-Harthi, PhD, is focused on understanding mechanism(s) driving HAND and HIV latency in the central nervous system. Specifically, we study the role of astrocytes in HAND and HIV latency. Astrocytes are the most abundant cell type in the brain. They perform vital functions to maintain neuronal homeostasis, blood-brain barrier and immune regulation. In a number of neurodegenerative diseases, including HAND, reactive/activated astrocyte is a hallmark feature of the disease. These reactive astrocytes undergo morphologic and biochemical changes that compromise their protective properties and lead to harmful neuroinflammatory processes. We study how alteration in the Wnt/β-catenin pathway in astrocytes changes their function leading to profound changes in neurons, culminating in neuronal injury. We showed that triggers (e.g. IFNγ, HIV, drugs of abuse) that diminish β-catenin signaling in astrocytes induce HIV productive replication and perturb astrocyte function. We continue to probe the dynamic cross-talk between Wnt/β-catenin signaling in astrocytes, inflammatory mediators, and HIV as they impact astrocyte/neuronal communication and homeostasis in the brain.
We also study the role of astrocytes in HIV latency. HIV latency and/or residual low-level of HIV replication is a major obstacle towards an HIV cure. Drug intensification alone has not been able to alter the size of the latent reservoir pool. Much attention, rightly so, is focused on understanding mechanisms of HIV latency in CD4+ resting T cells. However, other cellular reservoirs and sanctuary sites for HIV remain including the CNS. HIV invades the brain within weeks of infection, persists in the CNS at a steady state despite cART, and undergoes compartmentalization as indicated by the evolution of HIV genetic sequences in the CNS that are distinct from those in plasma and lymphoid tissue. Our lab studies the epigenetic mechanisms driving HIV latency in astrocytes and contribution of astrocytes to HIV latency/residual low-level HIV repliation.
We have been a leading lab in describing a unique subset of CD8+ T cells that co-express CD4 on their surface. These cells are known as CD4dimCD8bright T cells and exhibit potent antiviral responses. We showed that migration of CD8+ T cells into the CNS in context of HIV gives rise to CD4dimCD8bright T cells, in a Wnt signaling -dependent manner. These CNS CD4dimCD8bright T cells exhibit highly potent anti-HIV responses and correlate with HIV control in the CNS. Given that T cell responses in the brain must be balanced to clear a brain infection without excessive inflammation, disrupting the otherwise quiescent microenvironment of the brain, we are actively pursuing the consequence of CD4dimCD8bright T cells control of HIV replication in the CNS as well as their role in HIV neuroinvasion and potentially latency in the CNS.
Impact of work
Our lab theme will collectively provide the following:
- A paradigm shift in mechanism(s) driving neuronal injury that focus on astrocyte dysregulation in context of HAND. There is a concerted effort within the field of HAND/neuroAIDS and other neurodegenerative diseases to focus on dysfunction of neurons to understand their role in the disease process. Little information, however, is available on cross-talk between astrocytes and neurons, from a mechanistic perspective, that drives neuronal injury. Our lab continues to focus on the consequence of astrocyte dysregulation as it relates to neuronal injury in HAND. Understanding the details of the astrocyte/neuronal axis of communication through a mechanistic perspective (Wnt/β-catenin signaling) will shed some light on critical process that can be exploited for therapeutic intervention.
- A broader applicability to understand mechanisms of neurodegenerative disease beyond HAND: β-catenin is dysregulated in a number of neurodegenerative diseases including AD, PD, ALS and in neuropsychdisorders such as schizophrenia. Studying the role of Wnt/ β-catenin signaling in astrocytes may have broader implications beyond HAND to understand the role of Wnt/β-catenin signaling in neurodegeneration mediated by dysregulation in Wnt/β-catenin signaling.
- A path for translational studies: Our studies could define a novel biomarker for HAND. To date there are no biomarkers that can identify HAND. The markers that have been proposed correlate better with HIV-E, which by then patients have outward clinical symptoms. Our studies will explore parts of the Wnt/β-catenin pathway as potential biomarker for early stage HAND.
Technology
We use leading-edge, multidisciplinary tools to conduct our research. Molecular biology techniques include cloning, real-time PCR, gain and loss of function studies using siRNAs, CRISP-PAR; transduction, transfection, reporter assays, and chromatin immunoprecipitation assay (ChiP). We also use 12-color flow cytometry, ELISAs, Western blot, immunofluorescence, immunohistochemistry, and laser capture microdissection. We use two animal models, NOD/SCID/IL-2rcγ-/- mice reconstituted with human PBMCs (NSG-huPBMC) and HIV-Tg rats.
Funding
We are grateful to the NIH for funding our scientific work. This includes the following current grants:
- R01 DA033966-05: Title: Mechanisms of HIV and drug abuse pathogenesis in CNS. The goal of this project is to determine the impact of HIV verotoxins and psychostimulants (Methamphetamine) on β-catenin activity and neuropathogenesis
- R25 GM109421-04: Title: Integrated scientific and professional PhD training program in biomedical science. A PhD training grant to maximize the development of underrepresented minority students (URMs) seeking a PhD degree in basic sciences at Rush Graduate college
- R01 MH100628-05: Title: HIV latency in astrocytes. The goal of this project is to assess the role of astrocytes in HIV latency and establish the extent of HIV compartmentalization within astrocytes
- R01 MH113425-02: Title: Neuroimmune axis in HAND and HIV persistence in the brain.
- NIH R01 NS0606032-09: Title: Interplay between neuroprotective pathways, HIV, and astrocytes. The goal of this grant is to determine the biologic consequences of modulation of neuroprotective signaling pathways as they impact HIV-associated neurologic disease
- NIH R01 NS0606032-09S1: Title: Interplay between neuroprotective pathways, HIV, and astrocytes.
Our team
Faculty
- Hemil Gonzalez, MD, Assistant Professor (Infectious Diseases)
Staff scientists
- Arundhati Jana, PhD
- Srinivasa Narasipura, PhD
Postdoctoral fellow
- Amber Virdi PhD, PhD
Graduate students
- Jekzaly Arellano, PhD Candidate
- Ishwarya Venkatesh, PhD Candidate
Technician
- Margaret Byrne, Research Lab Tech 2
- Leannie Olivares, Research Lab Tech 3
Contact us
We welcome inquiries about our research, collaborations and funding. Please contact Lena Al-Harthi, PhD.