Genotypic and phenotypic characterization of long terminal repeat sequences from long-term survivors of human immunodeficiency virus type 1 infection

Abstract

Human immunodeficiency virus type 1 (HIV-1)-infected individuals who remain asymptomatic despite prolonged infection present a unique opportunity to understand virologic and immunologic factors involved in the pathogenesis of AIDS. We have previously identified a group of long-term survivors (LTS) who are clinically healthy and immunologically normal despite 13 to 15 years of HIV-1 infection. In this study, we examined the 5' long terminal repeat (5' LTR) sequences in eight of these LTS. A total of 29 nucleotide sequences were obtained from their peripheral blood mononuclear cells (PBMC). Analysis of these sequences revealed no gross deletions within the 5' LTR. Seven of the eight subjects shared nearly identical consensus sequences in the binding sites for NF-kappaB, Sp1, and the viral trans-activator Tat. In multiple samples from one individual (Pt 5), however, G-to-A hypermutations were found throughout the entire region, suggesting a genetically defective 5' LTR. The effects of the observed genetic variations on LTR transcription were studied by transient transfection of an LTR-driven luciferase reporter gene and by infection with a full-length recombinant HIV-1 containing a luciferase reporter (HIVHXBLTRluc). A wide range of basal and Tat-induced transcriptional activities was found among the 5' LTR from seven of the eight LTS in both transfected 293 cells and donor PBMC, suggesting a functionally intact 5' LTR in these individuals. It is therefore unlikely that defects in the 5' LTR are the underlying explanation for the benign clinical course associated with these seven individuals. However, functional abnormalities were found in the LTR from Pt 5 in directing both heterologous and viral gene expression, providing a possible genetic explanation for the low viral load and prolonged asymptomatic state of this individual. Last, a similar overall degree of genetic diversity was found among viruses from the LTS compared to those from patients with AIDS, reinforcing the notion that a strong correlation between the degree of genetic diversity and the rate of disease progression is unlikely.