Human immunodeficiency virus type 1 (HIV-1) causes a slowly progressive deterioration of the immune system, resulting in the acquired immunodeficiency syndrome (AIDS). The mean period of time between infection with the virus and the onset of AIDS is eight to ten years. A major contributing factor to this long clinical latency period is likely to be related to latent or persistent states of the virus. When HIV-1 infects quiescent T-lymphocytes, virus is not produced until the cell is subsequently stimulated by mitogen or antigen. Thus, a latent form of the virus appears to exist in these cells. I have previously shown, using a quantitative polymerase chain reaction (PCR) technique, that reverse transcription of HIV-1 is arrested in quiescent T- lymphocytes. The objective of this proposal is to more fully understand the pathogenesis of HIV-1 by exploring the viral and cellular mechanisms responsible for the arrest of reverse transcription in quiescent T- lymphocytes. This work will: 1) further define the structure of the partial HIV-1 reverse transcripts in quiescent T-lymphocytes, and determine their role in pathogenesis; 2) determine the role of T-cell activation in reverse transcription; and 3) determine the mechanism of action responsible for the arrest of reverse transcription in quiescent T-lymphocytes. As more than 90% of circulating T-lymphocytes in vivo are in the quiescent state, these studies are of critical importance for understanding HIV-1 pathogenesis, and may identify novel approaches to test therapeutically.
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