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Characterization of Vertically Transmitted Subtype C HIV during Acute Infection
Laura Heath*1, S Conway2, K Nakamura3, K Semrau4, D Thea4, L Kuhn5, J Mullins1, and G Aldrovandi2
1Univ of Washington, Seattle, US; 2Children`s Hosp Los Angeles and Univ of Southern California, US; 3Children`s Hosp Los Angeles and Keck Sch of Med, Univ of Southern California, US; 4Boston Univ Sch of Publ Hlth, MA, US; and 5Columbia Univ, New York, NY, US
Background: Mother-to-child transmission (MTCT) of
HIV-1 remains an important source of new infections, especially in the
developing world. Heterosexual subtype C transmission is associated with HIV
envelopes (Env) with shorter variable loops and fewer potential N-linked
glycosylation (PNG) sites compared to strains in the infecting donor. Here we
sought parallel insight into the mechanisms of HIV-1 subtype C infection due to
MTCT.
Methods: The gp120 env sequence from 15 women and
their HIV-infected infants participating in the Zambia Exclusive Breastfeeding
Study were analyzed. Proviral DNA and plasma RNA were collected from women
shortly before birth, and infant proviral DNA was obtained at the first
positive sample. To avoid resampling, multiple independent polymerase chain
reaction (PCR) amplifications were performed before cloning and sequencing. A
total of 223 clones from peripheral blood mononuclear cells (PBMC), 95 from
plasma and 83 from breast milk RNA were derived. We calculated pairwise
distances and evaluated PNG and length in V1 to V5. Diversity comparison
p-values were obtained using Gilbert, Rossini, and Shankarappa's 2-sample test
for comparing intra-individual genetic sequence diversity between populations,
and PNG and length comparisons were made using a GEE model for aggregate
comparisons.
Results: Diversity was significantly lower in
infants than in mothers (mean corrected infant diversity, 0.00647; mean
corrected mother diversity, 0.0617; p <0.001). Of 14 infant viral
populations, 9 were composed of an extremely homogeneous viral population,
indicative of a genetic bottleneck. When making an aggregate comparison of PNG
of all infants and mothers, infants had significantly fewer PNG (p
<0.001). The lengths of sequences exhibited the same trend; when making an
aggregate comparison, infants had shorter sequences than mothers (p
<0.0001). To address the potential effects a mucosal transmitting
compartment might have on these characteristics, we examined plasma RNA and
breast milk RNA in 9 transmitting women and found that there was no difference
in the number of PNG between plasma and breast milk (p = 0.71) or in
gene length (p = 0.88).
Conclusions: Our results indicate that an overall
loss of variable loop length and potential N-linked glycosylation sites
typically occurs during vertical transmission of subtype C HIV-1.
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