HIV-1 Subtype C Mother-to-Child Transmission: Genetic and Immunologic Correlates Public Deposited

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  • March 22, 2019
Creator
  • Russell, Elizabeth S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Mother-to-child transmission (MTCT) of human immunodeficiency virus-1 (HIV-1) infects over 300,000 infants each year. This transmission can occur in utero (IU), intrapartum (IP), or post-partum through breastfeeding (PP). One feature of transmission from mother to child is a reduction (or 'bottleneck') in viral genetic diversity, particularly within the envelope (env) gene. A heteroduplex tracking assay was used to examine env diversity in women whose infants remained uninfected at least through 6 weeks, and in mother-infant IU and IP transmission pairs. Maternal diversity was similar regardless of transmission status. We confirmed a bottleneck in subtype C IU and IP transmission. We further found that infants infected IU had fewer variants than those infected IP, and that these variants transmitted IU were major variants in the maternal populations more often than variants transmitted IP. Also, minor maternal variants were transmitted with a frequency that demonstrates neither IU nor IP transmission is stochastic. Shorter env sequences and fewer glycosylation sites, ie more 'compact' viruses, have been associated with greater neutralization sensitivity, and compact subtype C viruses are often transmitted through horizontal infection. env genes from a subset of IU and IP transmission pairs were sequenced and showed that compact maternal variants were transmitted IP, but not IU. env sequences from 3 mother-infant pairs where transmission occurred through breastfeeding were also analyzed and we found reductions in genetic diversity, sequence length, and glycosylation. These results demonstrate selection occurs in MTCT, and mechanisms may vary with the timing of transmission. High titers of neutralizing antibodies (NAB) have been correlated with lower rates of horizontal and vertical transmission in animal models, and in some small studies of human transmission. Because we identified selection had occurred in these transmission pairs, we next tested sera from non-transmitting, IU-, and IP-transmitting women for neutralizing activity against virus pseudotyped with heterologous subtype B and C Env proteins. Though non-transmitting women more often had NAB titers against multiple Envs, NAB titer to any one Env did not correlate to transmission status. Thus, we cannot attribute vertical transmission or a lack of transmission to different levels of neutralizing antibodies in the context of subtype C HIV-1 transmission events.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Medicine (Microbiology and Immunology)
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  • Swanstrom, Ronald
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