Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa

Abstract

More than 80% of the world's HIV-infected adults live in sub-Saharan Africa, where heterosexual transmission is the predominant mode of spread. The virologic and immunologic correlates of female-to-male (FTM) and male-to-female (MTF) transmission are not well understood. A total of 1022 heterosexual couples with discordant HIV-1 serology results (one partner HIV infected, the other HIV uninfected) were enrolled in a prospective study in Lusaka, Zambia and monitored at 3-month intervals. A nested case-control design was used to compare 109 transmitters and 208 nontransmitting controls with respect to plasma HIV-1 RNA (viral load, VL), virus isolation, and CD4(+) cell levels. Median plasma VL was significantly higher in transmitters than nontransmitters (123,507 vs. 51,310 copies/ml, p < 0.001). In stratified multivariate Cox regression analyses, the risk ratio (RR) for FTM transmission was 7.6 (95% CI: 2.3, 25.5) for VL > or = 100,000 copies/ml and 4.1 (95% CI: 1.2, 14.1) for VL between 10,000 and 100,000 copies/ml compared with the reference group of <10,000 copies/ml. Corresponding RRs for MTF transmission were 2.1 and 1.2, respectively, with 95% CI both bounding 1. Only 3 of 41 (7%) female transmitters had VL < 10,000 copies/ml compared with 32 of 93 (34%) of female nontransmitters (p < 0.001). The transmission rate within couples was 7.7/100 person-years and did not differ from FTM (61/862 person-years) and MTF (81/978 person-years) transmission. We conclude that the association between increasing plasma viral load was strong for female to male transmission, but was only weakly predictive of male to female transmission in Zambian heterosexual couples. FTM and MTF transmission rates were similar. These data suggest gender-specific differences in the biology of heterosexual transmission.

Figures

FIG. 1

Epidemiological linkage analysis for a subset of putative HIV-1 transmission pairs. A phylogenetic tree was constructed from partial gp41 sequences (consensus length, 389 bp), using the neighbor-joining method and the Kimura two-parameter model. Horizontal branches are drawn to scale (the scale bar indicates 1% sequence divergence); vertical separation is for clarity only (the tree was rooted with A_U455). The bootstrap values at each node represent the percentage of 1000 bootstrap replicates that support the branching order (only values of 80% or higher are shown). Newly derived sequences from 22 different individuals (11 couples) are shown (boxed), along with 11 subtype C reference sequences (http://hiv-web.lanl.gov/HTML/alignments.html) from the Los Alamos sequence database (M and F indicate sequences derived from male and female partners, respectively). Viruses from seven couples (highlighted) are closely related to one other (0.5-2.7% nucleotide sequence diversity) and cluster together with significant bootstrap values (100%), thus indicating epidemiological linkage. By contrast, viruses from four other couples (boxed) do not cluster together and their range of within-couple diversity (5.9-10.1%) is comparable to that of the reference sequences (4.4-11.6%), thus making viral transmission between partners highly unlikely.

FIG. 2

Plasma HIV RNA levels (copies/ml) of transmitters and nontransmitters stratified by gender: Male transmitters (triangles), female transmitters (circles), male nontransmitters (open triangles), female nontransmitters (open circles). Median plasma HIV RNA levels for each group are indicated by a solid line.