Evolution of sequences encoding the principal neutralization epitope of human immunodeficiency virus 1 is host dependent, rapid, and continuous.

Abstract

The principal neutralization epitope of human immunodeficiency virus 1 is localized in the third variable (V3) domain of the external envelope and has been shown to bind isolate-specific antibodies. Therefore, the extent of variation within the nucleic acid sequence encoding this epitope was studied in DNA directly obtained from peripheral blood mononuclear cells of six children and their plasma donor. This revealed that the quasi-species distribution of sequences obtained after cloning varied from recipient to recipient and that the distance from the donor sequences increased over time. V3 nucleotide evolution rates averaged 9.5 X 10-3 per site per year for silent sites and 11.4 X 10-per site per year for nonsilent sites (vs. 9.7 and 9.8 x 10-3 per site per year for a control region 5' adjacent to the V3 region) and, although individual differences were observed, did not correlate with the serum antigen levels or disease progression. Sequences of both the epitope coding region itself (V3) and the control region upstream diverted more from the donor sequence among children not progressing to AIDS than among children progressing to AIDS. The evolution of V3 sequences is apparently host dependent, rapid, and independent of the level of antigen expression.The third hypervariable region (V3) of the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gpl20 contains a neutralization epitope that is highly antigenic (1-4). Antibodies binding to the amino acid stretch between amino acids 307 and 321 exhibit isolate-specific virus-neutralizing and cell fusion-inhibiting activities (1-7). Moreover, Takahashi et al. (8,9) showed that the V3 region encompasses a major histocompatibility complex class I-restricted isolatespecific determinant for cytotoxic T lymphocytes (CTLs

Analysis of HIV-1envgene sequences reveals evidence for a low effective number in the viral population

“…A phylogenetic analysis of the sequence data has been published (21). A total of 77 sequences of the V3 region, 231 bp long, were obtained; the overall level of variation was similar to that observed in other studies (22,23). Only plasma viral sequences were included to ensure that the sample represented the recently replicated viral population; it has been shown that the proviral population in peripheral blood is heterogeneous, containing both recently replicated and older variants (9).…”

Transition between Stochastic Evolution and Deterministic Evolution in the Presence of Selection: General Theory and Application to Virology

“…Equation 79 is necessary for convergence of the integral in equation 78. It reflects the fact that f(t) never crosses its steadystate level (see the previous subsection).…”

“…HIV displays a remarkable extent of genetic variation concurrent with a high speed of evolution: in the most variable region of the genome (env), individual genomes within a population from an infected person can vary by as much as 3 to 5% (2,43,78); substitutions in env accumulate at a rate of approximately 1% per year (71), 50 million times faster than in the small subunit of rRNA (61). This variation has important consequences.…”

Rapid selection for an N-linked oligosaccharide by monoclonal antibodies directed against the V3 loop of human immunodeficiency virus type 1

“…The hypervariable V3 loop of gp 120 constitutes an important neutralizing determinant for strains of HIV-1 adapted to T cell lines (Goudsmit et al, 1988;Javaherian et al, 1989;Rusche et al, 1988). Variability within this loop is observed both inter-and intra-individually (Balfe et al,, 1990;Hahn et al, 1986;LaRosa et al, 1990;Wolfs et al, 1990). The emergence in vivo of variants resistant to neutralization is correlated with mutations within this loop (Arendrup et al, 1993).…”