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

Abstract

Multiple targets for immune recognition and cellular tropism are localized to the Vi and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gpl20e`v. We have assessed genetic diversity in env Vl 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 Vi and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in Vl and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in Vl and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env Vl 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 Vl and V2 domains in vivo. It is likely that there are host responses to complex determinants in the Vi or V2 hypervariable domain of HIV-1 gpl20. Genetic variability within the human immunodeficiency virus type 1 (HIV-1) genome is most pronounced in env, in which nucleotide substitutions, duplications, and deletions produce extensive amino acid diversity within five hypervariable domains in the envelope glycoprotein (7). The hypervariable domains, designated Vi through V5, are interspersed with conserved regions along the gp120 molecule (42, 44, 70). Sequence variation in env can affect an array of functional parameters of the virus in vivo and in culture (8, 9, 14, 16, 28, 52, 57, 59, 61, 62, 74). Major determinants critical for HIV-1 tropism, for cytopathology in culture, and for host immunological responses to HIV-1 infection have been mapped to the carboxyl half of gp120, where V3, V4, and V5 are localized (14, 15, 24, 35). The V3 hypervariable region in particular encodes the principal neutralizing domain in gp120 (25). Nucleotide variability in the V3 loop is characterized by a high proportion of nonsynonymous substitutions indicative of positive genetic selection (1, 60, 71). A principal mechanism contributing to evolution of genetic variability in the V3 domain of gp120 is the host immune response (6, 21, 30, 39). Complex functional determinants are not restricted to the V3 region of gpl20. Sequences associated with HIV-1 tropism for macrophages (49, 69) or encoding targets for immune recognition (13, 17, 26, 32, 67) are also localized in

Genetic variability of the V1 and V2 env domains of SIVcpz‐ant and neutralization pattern of plasma viruses in a chimpanzee infected naturally

“…The same V2 length variant is found in both month 22 and 33 isolates (n 47 nucleic acids, in bold). genome to another, indicating that recombination events are occuring as have been described for HIV-1 [Howell et al, 1991;Lamers et al, 1993;Morris et al, 1999]. This was further supported by evidence that part of the V1 region (amino acid residues 135 to 155, gray highlights) of month 1 and the entire V2 region of month 22 recombined in the month 33 isolate.…”

Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: recognition of autologous virus sequences within a conserved immunodominant epitope.

“…Serial nested deletions of the HIV-1Hm envelope gp160 were expressed in vectors vAbT271, vAbT299, vAbT294, vAbT295, vAbT296, and vAbT364. The aa within gp160 which have been deleted from each vector are as follows (numbered according to LAI sequence in Myers et al [19]): vAbT271, none; vAbT299, [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]vAbT294,vAbT295,vAbT296,vAbT364,. Vaccinia vectors expressing the complete envelope glycoproteins of the RF (vAbT272 [25,26]) and MN (MN462) strains of HIV-1 were also used in some assays.…”

Study of the dynamics of neutralization escape mutants in a chimpanzee naturally infected with the simian immunodeficiency virus SIVcpz-ant

“…If we consider the midpoints of the clusters of isolates (0, 14.5, and 29 months), we find that they are separated by about 15-month intervals. If we look at the midpoints of the groups of sera (8,22, and 37 months), we also find that they are separated by intervals of about 15 months. Furthermore, the differences in time between the midpoints of the clusters of isolates and the groups of sera that are positively specific for them amount to about 8 months.…”

“…Amino acid sequences of the envelope variable regions of SIVcpz-ant consecutive isolates. Sequence numbers 1 to 10 denotes isolates taken at months 0, 1,7,15,18,22,25,29,33, and 38, respectively. Variation in V1, V2, and V4 is characterized by mostly nonsynonymous nucleotide substitutions, together with insertions and deletions, both involving the creation and deletion of potential N-glycosylation sites.…”

“…The suggestion that broadening of the immune response to a particular region results in an increased rate of sequence evolution for that region implies that regions of HIV-1 envelope may evolve at differential rates. There is experimental evidence for differential rates of evolution between hypervariable regions from longitudinal studies of envelope sequence variation (21,22,43). In our study, based on the polygram analysis, the largest number of amino acid quadruplets specific for a particular isolate neutralization cluster was situated in the V4 region (seven quadruplets) followed by V1 (three), gp40 (three), V2 (one), C2 (one), and the region between CD4 (one) and V5 (one).…”