Laboratory of HIV Molecular Pathogenesis and Prevention

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Mary Klotman, MD is the chair of the Department of Medicine at Duke University Medical Center.  The Klotman laboratory joined the Duke Human Vaccine Institute in December 2010.  The laboratory includes Andrea Cara, Donatella Negri, and Bala.  

The primary focus of Dr. Klotman’s research efforts is understanding fundamental host-viral interactions that provide insights into pathogenesis and approaches to prevention of Human Immunodeficiency Virus 1 (HIV-1) infection.  A long-standing project is focused on HIV-associated nephropathy (HIVAN) as part of a multi-project NIH-funded initiative to understand the cell biology, virology and genetically determined host factors involved in disease pathogenesis.  Recent important observations made by the Klotman lab include the demonstration that HIV resides in and evolves separately in kidney cells, that virus persists in renal cells despite therapy, and the viral proteins Nef and Vpr play significant roles in renal pathology.  Current work is focused on defining the efficiency and consequences of cell-associated (compared to cell-free) HIV infection of renal tubule epithelial (RTE) cells via the virologic synapse;  defining the mechanism by which specific viral genes, particularly HIV Vpr, induce pathologic changes in RTECs that are characteristic of HIVAN and characterization of the renal compartment as a long-term reservoir for HIV.  

An additional focus in the laboratory is understanding the role of the genital mucosa and associated host proteins that protect or, in the context of a second sexually transmitted disease, might enhance HIV transmission.  Ultimately, the goal of the latter work is to devise safe strategies for prevention, particularly around topical microbicides that might be applied directly to the genital mucosa to block sexual transmission.  This work is presently focused on establishing in vitro models to study vaginal transmission and topical microbicides including genital cell monolayers and genital tissue explant models.  

Lastly, through a long-standing collaboration with Drs. Andrea Cara and Donatella Negri, the laboratory has defined the viral RNA and protein expression potential and stability of non-integrated closed circular forms of HIV DNA.  This work formed the basis of subsequent work focused on the generation of integrase defective HIV-1 based vectors to be used as a vaccine delivery vehicle for HIV as well as other infections.  Drs. Cara and Negri recently arrived from Italy to join the Klotman laboratory.  They have been working together for many years and finally decided to continue their scientific collaboration in the wonderful setting that is Duke.  Their work is centered on the development of a new vaccine strategy based on integrase-defective lentiviral vector (IDLV) as a delivery system.  The idea is to exploit the ability of a safety modified HIV-based vector for stably transducing non-dividing antigen presenting cells, such as dendritic cells and macrophages.  They have demonstrated that this vector is effective in inducing long-term antigen-specific immune responses in small animal models after a single immunization and they are working on improving both safety and efficiency for a potential use of the vector in non-human primate models of AIDS.