HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CELLULAR RNA LOAD AND SPLICING PATTERNS PREDICT DISEASE PROGRESSION IN A LONGITUDINALLY STUDIED COHORT

We report the results of a longitudinal study of RNA splicing patterns in 31 early stage human immuno deficiency virus disease patients with an average follow-up time of 3 years. Eighteen patients showed no evi dence for disease progression, whereas 13 patients either showed a gre ater than or equal to 50% reduction in baseline CD4 count or developed opportunistic infections. Levels of unspliced, tat, rev, and nef mRNA s in peripheral blood mononuclear cells were measured by a reverse tra nscriptase quantitative, competitive PCR assay. Viral RNA was detected in all patients at ah time points. Ah 13 rapid progressors had viral RNA loads that were greater than or equal to 1 log unit greater than t hose of the slow progressors. In addition, seven of the rapid progress ors showed a reduction of more than threefold in the ratio of spliced to unspliced RNA over the 3 years of follow-up. Conversely, two Slow p rogressors with intermediate levels of viral RNA showed no splicing sh ift. These results confirm earlier observations that viral RNA is unif ormly expressed in early-stage patients. We further show that cellular RNA viral load is predictive of disease progression. Importantly, the shift from a predominately spliced or regulatory viral mRNA pattern t o a predominately unspliced pattern both is associated with disease pr ogression and adds predictive utility to measurement of either RNA cla ss alone.