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Drug discovery for eradication of HIV-1 infection. Uncovering the mechanisms that rule HIV-1 latency.

Sofiya Micheva
M.S. 1996
Sofia University
Sofia, Bulgaria

Thesis Advisor: Joseph Dougherty, Ph.D.
Graduate Program in Molecular Genetics, Microbiology & Immunology


Wednesday, March 19, 2008
11:00 a.m.


Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus that specifically targets CD4+ T-lymphocytes leading to their dramatic decline. HIV-1 patients must adhere to a highly active antiretroviral therapy (HAART) to avoid developing acquired immunodeficiency syndrome (AIDS). The current treatment inhibits viral replication, but does not eradicate the disease; therefore, it has to be applied for the entire life of the patient. HAART can be combined with novel class of antiviral agents, capable of specific elimination of the population of latently infected cells, which could lead to eradication of the infection. To address this problem, we have initiated a project aiming at the discovery of novel compounds capable of elimination of latent HIV. A highly sensitive and robust cell-based assay that models HIV-1 latency has been developed and applied in high throughput screening (HTS) of a chemical library. The HTS resulted in identification of small molecules that recovered replication competent virus from resting CD4+T cells isolated from HIV-1 patients successfully treated with HAART. Our preliminary studies indicated that some of the novel compounds activated latent HIV trough mechanisms that differ from those of the known HIV activators and thus may establish a novel class of HIV latency antagonists.

A clear understanding of the mechanisms involved in establishing and maintaining HIV-1 latency is needed in order to develop efficient strategies for elimination of HIV-1 infection. Current hypotheses describe the phenomenon of HIV-1 latency as one ruled by the conditions specific to the host cell and do not suggest an active participation of the virus in the process. It has been reported that HIV-1, similar to other retroviruses such as HTLV and FIV, produces negative strand transcripts that originate both from 5íLTR and 3íLTR. Naturally occurring antisense transcripts (NAT) are known to regulate gene expression on transcriptional and posttranscriptional level. We have developed an assay that monitors the real-time accumulation of HIV-1 sense and antisense transcripts in a single cell. Data obtained from this assay demonstrated that accumulation of HIV NAT at early stage viral infection predisposes the establishment of latent provirus resistant to reactivation stimuli and thus, provided evidence that HIV can actively participate in the process of establishment and maintenance of non-productive replication.

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