Longitudinal analysis of human immunodeficiency virus type 1 nef/long terminal repeat sequences in a cohort of long-term survivors infected from a single source

Abstract

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) in a cohort of long-term survivors infected with an attenuated strain of HIV-1 acquired from a single source. Although the cohort members experienced differing clinical courses, we demonstrate similar evolution of HIV-1 nef/long-terminal repeat (LTR) sequences, characterized by progressive sequence deletions tending toward a minimal nef/LTR structure that retains only sequence elements required for viral replication. The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome.

FIG. 1.

Analysis of SBBC nef/LTR sequence. (A) Schematic representation of nef/LTR sequence deletions of HIV-1 cloned from the earliest available PBMC samples. The data shown represent a consensus of at least 20 independent nef/LTR sequences cloned from each PBMC sample. The genomic structures are compared to wild-type HIV-1 (NL4-3). Numbers refer to nucleotide positions in NL4-3. Black blocks represent intact sequence, and gaps represent deletions. Gray blocks represent the sequence area containing duplicated and rearranged NF-κB and Sp-1 binding sites in the LTR. The dates shown represent the times when PBMC were collected for analysis. (B) More-detailed analysis of the LTR, depicting transcription factor binding sites. PPT, polypurine tract; NRE, negative regulatory element.

FIG. 2.

Evolution of SBBC nef/LTR sequence deletions. Schematic representation of nef/LTR sequence deletions of HIV-1 cloned from longitudinally collected PBMC samples from SBBC long-term nonprogressors (A) and slow progressors (B). The data shown represent a consensus of at least 20 independent nef/LTR sequences cloned from each PBMC sample. The genomic structures are compared to wild-type HIV-1 (NL4-3). Numbers refer to nucleotide positions in NL4-3. Black blocks represent intact sequence, and gaps represent deletions. Gray blocks represent the sequence area containing duplicated and rearranged NF-κB and Sp-1 binding sites in the LTR. The dates shown represent the times when PBMC were collected for analysis. PPT, polypurine tract; NRE, negative regulatory element.

FIG. 3.

Convergent evolution of SBBC nef/LTR sequences to a minimal nef/LTR structure. Comparisons of the genomic structures of nef/LTR sequences cloned from the earliest available and most recently obtained PBMC samples are shown. The genomic structures are compared to those of wild-type HIV-1 (NL4-3). Numbers refer to nucleotide positions in NL4-3. Black blocks represent intact sequence, and gaps represent deletions. Gray blocks represent the sequence area containing duplicated and rearranged NF-κB and Sp-1 binding sites in the LTR. The dates shown represent the times when PBMC were collected for analysis. PPT, polypurine tract; NRE, negative regulatory element.