Molecular epidemiology of human immunodeficiency virus type 1 transmission in a heterosexual cohort of discordant couples in Zambia - PubMed (original) (raw)
Molecular epidemiology of human immunodeficiency virus type 1 transmission in a heterosexual cohort of discordant couples in Zambia
Stanley A Trask et al. J Virol. 2002 Jan.
Abstract
Most human immunodeficiency virus type 1 (HIV-1) transmissions in sub-Saharan Africa are believed to occur between married adults who are discordant for their HIV-1 infection status; however, no studies to date have investigated the molecular epidemiology of such transmission events. Here we report the genetic characterization of HIV-1 strains from 149 transmission pairs that were identified prospectively in a cohort of discordant couples in Lusaka, Zambia. Subgenomic gag, gp120, gp41, and/or long terminal repeat regions were amplified by PCR analysis of uncultured blood samples from both partners and sequenced without interim cloning. Pairwise genetic distances were calculated for the regions analyzed and compared to those of subtype-specific reference sequences as well as local controls. Sequence relationships were also examined by phylogenetic tree analysis. By these approaches, epidemiological linkage was established for the majority of transmission pairs. Viruses from 129 of the 149 couples (87%) were very closely related and clustered together in phylogenetic trees in a statistically highly significant manner. In contrast, viruses from 20 of the 149 couples (13%) were only distantly related in two independent genomic regions, thus ruling out transmission between the two partners. The great majority (95%) of transmitted viruses were of subtype C origin, although representatives of subtypes A, D, G, and J were also identified. There was no evidence for extensive transmission networks within the cohort, although two phylogenetic subclusters of viruses infecting two couples each were identified. Taken together, these data indicate that molecular epidemiological analyses of presumed transmission pairs are both feasible and required to determine behavioral, virological, and immunological correlates of heterosexual transmission in sub-Saharan Africa with a high level of accuracy.
Figures
FIG. 1.
HIV-1 subgenomic regions utilized for epidemiological linkage analysis. A schematic representation of the HIV-1 genome is shown, with brackets denoting the subgenomic gag, gp120, gp41, and LTR fragments that were amplified for diagnostic PCR analysis. Overlapping gag and gp120 regions are denoted by capital letters (gagA to -H; gp120A to -C) and are referred to in Tables 2 to 4.
FIG. 2.
Within-group diversity among linked and unlinked Zambian transmission pairs and corresponding reference sequences. Subtype C reference sequences (n = 15) from the Los Alamos HIV/SIV Sequence Database (Table 1) were subjected to pairwise sequence comparisons in the region corresponding to the PCR-amplified gp41 fragment shown in Fig. 1. Pairwise sequence distances were also calculated for 66 subtype C transmission pairs classified as linked and 15 subtype C transmission pairs classified as unlinked in the same genomic region. The distribution of distance values for these three different groups is depicted as boxes, with the lower and upper limits of the box delineating the 25th and 75th percentiles and the bars indicating the 10th and 90th percentiles, respectively. The median distance of the linked viral group (median = 1.5) was significantly different from that of both the unlinked viral group (median distance = 8.8) and the reference sequence group (median distance = 8.2) (P < 0.0001, one-sided Mann-Whitney test [17]). In contrast, the median sequence distance of the unlinked viral group was not statistically different from that of the reference sequence group (_P_ > 0.05, Mann-Whitney test).
FIG. 3.
Molecular linkage analysis for a subset of putative HIV-1 transmission pairs. A phylogenetic tree was constructed from partial gp41 sequences (consensus length, 276 bp) by using the neighbor-joining method (34) and the Kimura two-parameter model (22). Horizontal branch lengths are drawn to scale (the scale bar represents 0.05 nucleotide substitutions per site); vertical separation is for clarity only. Asterisks indicate bootstrap values in which the cluster to the right is supported in >80% replicates (out of 1,000). Newly derived sequences from 42 transmission pairs (84 individuals) are shown, along with 26 reference sequences from the Los Alamos Sequence Database (
http://hiv-web.lanl.gov/HTML/alignments.html
). Viruses from 36 couples are closely related to one another and cluster together with significant bootstrap values, indicating that they are epidemiologically linked (highlighted in red and denoted by dots). Viruses from six couples do not cluster together and exhibit a range of within-couple diversity that is similar to that of the reference sequences (highlighted in blue and denoted by triangles), indicating that they are epidemiologically unlinked. Two small brackets denote viral subclusters, each involving viruses from two sets of couples (see text for details). Brackets on the far right indicate major group M sequence subtypes.
FIG. 4.
Transmission networks within the ZUHRP cohort. Phylogenetic trees were constructed from gp41 sequences of viruses infecting four different transmission pairs putatively classified as linked by pairwise sequence analysis. Couple identifiers are indicated in red (F, female partner; M, male partner). Horizontal branch lengths are drawn to scale (the scale bar represents 0.05 nucleotide substitutions per site); vertical separation is for clarity only. Values at nodes indicate the percentage of bootstraps in which the cluster to the right was found; only values of ≥80% are shown. Representative subtype C (left) and subtype G (right) reference sequences are included in each tree. Donor partners are underlined.
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