8th International AIDS Conference Amsterdam, Netherlands — July 19-24, 1992

Int Conf AIDS 1992 Jul 19-24; 8:We45 (abstract no. WeA 1005)
Pavlakis GN, Felber BK, Schwartz S, D'Agostino DM, Campbell M, Korneyeva M; Human Retrovirus Section, NCI-FCRDC, Md 21702.

OBJECTIVES: To characterize the transcriptional and posttranscriptional regulatory mechanisms of HIV-1 gene expression. RESULTS AND CONCLUSIONS: The study of the molecular properties of HIV-1 shows that it is a highly complex regulated system. These studies have provided important insights in the function of HIV, and are also important for the development of effective antiviral strategies. Two important regulatory proteins, Tat and Rev have been characterized in all lentiviruses. Previous results in tissue culture have indicated that Tat protein is necessary for HIV-1 propagation. The study of Tat-negative viruses indicates that in certain cell types Tat is not necessary for virus production. This indicates a role for tat-defective genomes during infection. According to this hypothesis, Tat-defective genomes may be dormant for a long period of time. A change in the cellular status may result in Tat-independent expression and efficient virus production. The produced virus may revert to Tat-positive and propagate more efficiently. The study of Rev protein indicates that it is necessary for virus production and it is needed to counteract defects on the viral mRNAs. HIV-1 and the other lentiviruses contain potent signals able to down-regulate their expression. These signals act at different levels during gene expression. We have studied the inhibitory signals that prevent the expression of the structural mRNAs of HIV-1. These mRNAs are defective and require the function of Rev protein in order to be transported to the cytoplasm and translated efficiently. The reason for the mRNA defect is the presence of inhibitory sequences named INS or CRS. Genetic analysis indicated that the inhibitory sequences are located throughout the HIV-1 genome, in the gag, pol and env regions. The INS or CRS elements prevent HIV-1 expression in the absence of Rev and constitute a prerequisite for Rev regulation. We have removed the negative elements from the gag region of HIV-1 by mutagenesis. This resulted in constitutive high gag expression. The observations that the inhibitory sequences act in the absence of any other viral proteins and that they can be inactivated by mutagenesis suggest that these elements may be targets for the binding of cellular factors that interact with the mRNA and inhibit posttranscriptional steps of gene expression. The interaction of HIV-1 mRNAs with such factors may cause nuclear retention, resulting in either further splicing or rapid degradation of the mRNAs. The presence of such negative elements within the coding sequences of HIV and other lentiviruses is a unique characteristic, not found in other retroviruses such as Rous sarcoma virus. Their role in the virus life cycle may be to lower the levels of expression under certain conditions and to promote the long association of the virus with the host. The positive and negative regulatory elements present in HIV-1 allow for complex interactions with the host and may provide several advantages, including the ability to enter a state of low or latent expression and the ability for rapid and high activation of expression. Research sponsored by the National Cancer Institute, under contract NO. N01-CO-74101 with ABL.

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