Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies - PubMed (original) (raw)

Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies

Q Mao et al. J Virol. 2001 Apr.

Abstract

When chronic hepatitis C virus (HCV) infections are complicated by acquisition of human immunodeficiency virus (HIV), liver disease appears to accelerate and serum levels of HCV RNA may rise. We hypothesized that HIV might affect the HCV quasispecies by decreasing both complexity (if HIV-induced immunosuppression lessens pressure for selecting HCV substitutions) and the ratio of nonsynonymous (d(N)) to synonymous (d(S)) substitutions, because d(N) may be lower (if there is less selective pressure). To test this hypothesis, we studied the evolution of HCV sequences in 10 persons with chronic HCV infection who seroconverted to HIV and, over the next 3 years, had slow or rapid progression of HIV-associated disease. From each subject, four serum specimens were selected with reference to HIV seroconversion: (i) more than 2 years prior, (ii) less than 2 years prior, (iii) less than 2 years after, and (iv) more than 2 years after. The HCV quasispecies in these specimens was characterized by generating clones containing 1 kb of cDNA that spanned the E1 gene and the E2 hypervariable region 1 (HVR1), followed by analysis of clonal frequencies (via electrophoretic migration) and nucleotide sequences. We examined 1,320 cDNA clones (33 per time point) and 287 sequences (median of 7 per time point). We observed a trend toward lower d(N)/d(S) after HIV seroconversion in 7 of 10 subjects and lower d(N)/d(S) in those with rapid HIV disease progression. However, the magnitude of these differences was small. These results are consistent with the hypothesis that HIV infection alters the HCV quasispecies, but the number of subjects and observation time may be too low to characterize the full effect.

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Figures

FIG. 1

FIG. 1

Hypothetical course of HIV-1 seroconverter to show study conventions. For example, pre-SC1 refers to the first serum specimen in which the HCV quasispecies was studied. Pre-HIV refers to sequence evolution before HIV-1 seroconversion, as measured at pre-SC1 and pre-SC2. HIV seroconversion was estimated as the midpoint between the last HIV antibody (Ab)-negative and first HIV antibody-positive specimens.

FIG. 2

FIG. 2

HCV RNA levels (ovals) and CD4 lymphocyte counts (squares) with respect to HIV seroconversion. Subjects are identified at the left as designated in Table 1. The four visits at which the HCV quasispecies was assessed correspond to HCV RNA determinations.

FIG. 2

FIG. 2

HCV RNA levels (ovals) and CD4 lymphocyte counts (squares) with respect to HIV seroconversion. Subjects are identified at the left as designated in Table 1. The four visits at which the HCV quasispecies was assessed correspond to HCV RNA determinations.

FIG. 3

FIG. 3

Clonotype ratios in 10 HIV seroconverters. Each point represents a unique subject visit. Slow and rapid progressors are identified by designations used in Table 1.

FIG. 4

FIG. 4

Overall dN/dS of envelope sequences at the amino acid positions in the HCV-1 polyprotein according to HIV progression status (5). Results were calculated comparing pre-SC1 with post-SC2 sequences using VarPlot configured with a 30-amino-acid sliding window centered on HVR1, as previously described (27). Similar plots were generated using a 10-amino-acid window and analysis of dN alone (not shown).

FIG. 5

FIG. 5

Pre- and post-HIV dN/dS in rapid and slow progressors. (A) Sequences determined from cDNA clones representing at least 70% of 33 clones examined from each serum specimen, based on HDA+SSCP. (B) Sequences determined by direct sequencing of reverse transcription-PCR products. Relationship of pre-HIV and post-HIV to HIV seroconversion is as defined in the legend to Fig. 1.

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