The Genetic Bottleneck in Vertical Transmission of Subtype C HIV-1 Is Not Driven by Selection of Especially Neutralization-Resistant Virus from the Maternal Viral Population

Abstract

Subtype C human immunodeficiency virus type 1 (HIV-1C) continues to cause the majority of new cases of mother-to-child transmission (MTCT), and yet there are limited data on HIV-1C transmission. We amplified env from plasma RNA for 19 HIV-1C MTCT pairs, 10 transmitting in utero (IU) and 9 transmitting intrapartum (IP). There was a strong genetic bottleneck between all mother-infant pairs, with a majority of transmission events involving the transmission of a single virus. env genes of viruses transmitted to infants IP, but not IU, encoded Env proteins that were shorter and had fewer putative N-linked glycosylation sites in the V1-V5 region than matched maternal sequences. Viruses pseudotyped with env clones representative of each maternal and infant population were tested for neutralization sensitivity. The 50% inhibitory concentration of autologous serum was similar against both transmitted (infant) and nontransmitted (maternal) viruses in a paired analysis. Mother and infant Env proteins were also similar in sensitivity to soluble CD4, to a panel of monoclonal antibodies, and to heterologous HIV-1C sera. In addition, there was no difference in the breadth or potency of neutralizing antibodies between sera from 50 nontransmitting and 23 IU and 23 IP transmitting HIV-1C-infected women against four Env proteins from heterologous viruses. Thus, while a strong genetic bottleneck was detected during MCTC, with viruses of shorter and fewer glycosylation sites in env present in IP transmission, our data do not support this bottleneck being driven by selective resistance to antibodies.

Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

“…It is possible that MBL in vaginal secretions traps or neutralizes virus in a way that is enhanced by higher glycosylation density. This model is consistent with the recent observation of a reduced glycosylation count in viruses transmitted intrapartum but not intrauterine (81). Alternatively, differences in Langerhans cells (LCs) in the male epithelium and the female epithelium (such as the differences observed between skin and vaginal LCs [82]) could result in either enhancement of trans-infection of T cells by underglycosylated viruses or inhibition of trans-infection of T cells by viruses that bind surface lectins too tightly due to higher levels of glycosylation.…”

Neutralizing Antibody Escape during HIV-1 Mother-to-Child Transmission Involves Conformational Masking of Distal Epitopes in Envelope

“…These studies suggest that variants with certain properties may be selected during transmission, and similar findings have been obtained in cases of heterosexual transmission (59). In support of this, variants that are transmitted from mother to child have been found to possess fewer potential N-linked glycosylation sites than variants found in the index case in some studies (58,77). Vertically transmitted viruses also have been reported to have enhanced replication kinetics (27) and fitness (28) compared to nontransmitted viruses.…”

“…MTCT studies were the first to illustrate the concept of an HIV-1 transmission bottleneck (76); despite a heterogeneous population in the chronically infected mother, only one variant is typically transmitted to the infant (1,29,58,63,69,77,82). These studies suggest that variants with certain properties may be selected during transmission, and similar findings have been obtained in cases of heterosexual transmission (59).…”

“…This has not been observed in all studies (24,58,67), and it is unclear if these different findings represent methodological differences of the type noted above or immunological differences that are specific to different populations or routes of MTCT. In our study of 12 breastfeeding infants infected postpartum, regular infant testing and longitudinal sample collection allowed for the analysis of maternal and infant viruses very close to the time of transmission (77).…”

HIV-1 Pathogenesis: The Virus

“…Finally, multiple cells could become infected at the site of transmission, but only one variant succeed in establishing a systemic infection. There are rare examples in which the initially observed virus is not the same as the transmitted virus Russell et al 2011). However, in the setting of low frequency infection in humans, transmission of a single variant appears to be the norm (Shaw and Hunter 2011).…”