Genetic variation of the human immunodeficiency virus type 1 long terminal repeat.

摘要

The long terminal repeat plays a crucial role in the HIV life cycle by regulating viral gene expression. As promoter strength may influence viral load and replicative capacity, we have chosen to focus our investigations on this non-coding, but functionally relevant region of the viral genome. A comparative study of the long terminal repeats from HIV-1 subtypes B, C, and E showed subtype-specific sequence changes among LTRs. These differences resulted in divergent activation of the LTR in response to several cellular and viral transcription activators, and they may have important implications for the transmission and pathogenesis of HIV-1 subtypes. HIV may additionally increase its adaptive potential through recombination; however, no data are available on intersubtype recombination within the long terminal repeat. We analyzed the 5′ LTR from HIV-infected infants from Tanzania and found several LTR recombination patterns. In another study, mother-infant pairs were analyzed for intrapatient variation in both the LTR and env regions. Results showed that intrapatient LTR variation within infants was significantly less than that of mothers for most pairs. These data suggest that non-immune selection pressures, such as transcriptional fitness, may restrict LTR variation during perinatal transmission. A case-control study was used to assess potential differences in perinatal transmission of HIV-1 subtypes. We have provided the first evidence that determinants associated with perinatal transmission of HIV-1 may be contained within the LTR.;This thesis has addressed several aspects of genetic diversity of the long terminal repeat. Variation within the LTR increases the adaptive potential of HIV-1 and may dramatically impact viral transmission and pathogenesis.