Neuroglial-specific factors and the regulation of retrovirus transcription.

Retroviruses have been implicated as causative agents of a variety of human diseases including malignancy, immune system dysfunction, and neurologic disorders. Despite the isolation of various retroviral agents from patients suffering from malignant neoplasias and neurologic disorders, only the human T-cell lymphotropic virus type I (HTLV-I) and the human immunodeficiency virus (HIV) have been definitively accepted as etiologic agents of human disease (Hjelle, 1991; Gessain and Gout, 1992; Rosenblatt, 1993). Because of their increasingly defined roles in disease progression, the replication of HTLV-I and HIV is an important focus for understanding the pathogenic processes resulting from viral infection. Of particular interest are the molecular mechanisms by which expression of retroviral genomes is regulated by their regulatory units, the long terminal repeats (LTR), in a manner specific to the cellular targets which they infect.

Persistence of multiple maternal genotypes of human immunodeficiency virus type I in infants infected by vertical transmission.

The extent of nucleotide variation within the HIV-1 env hypervariable domains serves as a marker of virus genotypes within infected individuals and as a means to track transmission of the virus between individuals. We analyzed env V1 and V2 sequences in longitudinal samples from two HIV-1-infected mothers, each with three children infected by maternal transmission of the virus. Sequences in samples that were obtained from two infants at 2 d and 4 wk after birth displayed more variation in V1 and V2 than maternal samples obtained at the same times. Multiple HIV-1 genotypes were identified in each mother. In each family, multiple maternal HIV-1 genotypes were transmitted to the infants. Specific amino acid residues in the hypervariable domains were conserved within sequences from each family producing a family-specific amino acid signature pattern in V1 and V2. Viruses that were highly related to maternal viruses in signature pattern persisted for as long as 4 yr in the older children. Results support a model of transmission involving multiple HIV-1 genotypes with development of genetic variation from differential outgrowth and accumulation of genetic changes within each individual.

Independent variation and positive selection in env V1 and V2 domains within maternal-infant strains of human immunodeficiency virus type 1 in vivo.

Multiple targets for immune recognition and cellular tropism are localized to the V1 and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gp120env. We have assessed genetic diversity in env V1 and V2 hypervariable domains in vivo within epidemiologically related strains of HIV-1. Our strategy was to analyze longitudinal samples from two seropositive mothers and multiple children infected by perinatal transmission. Although the V1 and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in V1 and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in V1 and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env V1 and V2 peptides in the mothers and in two older children but was not generally apparent in HIV-1 sequences in infants. An excess of nonsynonymous over synonymous substitutions indicated that there is positive selection for independent genetic variation in the V1 and V2 domains in vivo. It is likely that there are host responses to complex determinants in the V1 or V2 hypervariable domain of HIV-1 gp120.