HIV-1 genetic variation in clinical disease progression
One line of investigation within the laboratory is focused on studying the impact of genetic variation on HIV-1 and SIV replication and pathogenesis. Studies in this line of investigation are focused on understanding if genetic variation that occurs throughout a patient’s course of disease can be utilized as a diagnostic or predictive marker of peripheral or neurologic disease progression. This study is being performed utilizing patients enrolled in a longitudinal study in Drexel's CNS AIDS Research and Eradication Study (CARES) Cohort. These patients are recruited to this cohort from the Partnership Comprehensive Care Practice at Drexel. As these markers are identified, the laboratory then focuses on understanding the functional implications these variations may have on HIV-1 replication and pathogenesis. These studies are currently focused on two areas of the HIV genome: Tat and the long terminal repeat (LTR).
The studies on Tat are currently focused on genetic variants that may alter the many pathogenic functions of the protein. These are currently focused on secretion from various cell types, neuronal and astrocyte dysfunction and LTR transactivation.
The HIV-1 promoter or LTR studies are being conducted in a long-term collaboration with Dr. Wigdahl’s laboratory. These studies span examining the effect of LTR variation on transcriptional control of the virus, as well as designing novel “cure” therapeutics. These currently focus on using the CRISPR/cas9 system for excision of the HIV provirus from cells.
HIV/HBV coinfection in cancer
The hypothesis of this work is that in an HIV/HBV co-infection, the effects of Tat, as an extracellular protein or in combination with other cellular macromolecules from HIV-infected Kupffer cells (KCs), enhance HBx-driven cellular signals that regulate HBV replication and/or apoptosis, leading to an elevated risk for liver disease, including HCC, as compared to mono-infection. The goal of this work is to determine whether cooperative HBx and Tat activities affect HBV replication and apoptosis in HBV-infected hepatocytes and define mechanisms underlying cooperative effects.
Impact of HIV-1 and drugs of abuse on the CNS
Another line of investigation the laboratory focuses on is the impact of drugs of abuse, especially opioids, in combination with HIV-1, on blood-brain barrier (BBB) structure and function. The integrity of the BBB is compromised by the actions of the HIV-1 virions, viral proteins, and host cytokines and chemokines from both sides of this barrier alone and in combination with drugs of abuse. This compromise results in disruption and dysregulation of the normal function of the BBB. Changes in BBB permeability following HIV-1 infection are likely the result of multiple intracellular and intercellular events involving several cell types in addition to both viral and host proteins. Cells actively infected with HIV-1 exhibit changes in cytokine expression, produce virions, and secrete viral proteins. Damage to the BBB allows increased cell migration from peripheral circulation, increasing the access of virus-infected cells, viral proteins, and free virus to the CNS. The laboratory is currently using in vitro BBB models to assess these alterations in structure and function to understand the full impact of HIV-1 and drugs of abuse on the BBB.
The studies in the Nonnemacher laboratory are funded by National Institutes of Health (NIH)’s Martin Delaney Collaboratories for HIV Cure Research Program, an NINDS R01 and several developmental awards.