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A Restriction Enzyme Based Cloning Method to Assess the In vitro Replication Capacity of HIV-1 Subtype C Gag-MJ4 Chimeric Viruses
Published on: August 31, 2014
Restricted genetic diversity of HIV-1 subtype C envelope glycoprotein from perinatally infected Zambian infants
Hong Zhang1, Damien C Tully, Federico G Hoffmann
1Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska, United States of America.
Insights
Mother-to-child transmission of HIV-1 subtype C involves a severe genetic bottleneck, with infants infected by a single founder virus. This transmitted virus has a less glycosylated envelope, suggesting preferential transmission of these variants.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Mother-to-child transmission of Human Immunodeficiency Virus type 1 (HIV-1) remains a critical global health issue, particularly in resource-limited settings.
- Understanding the initial stages of HIV-1 transmission and the genetic characteristics of the founder virus is crucial for developing effective interventions.
Purpose of the Study:
- To analyze the genetic features of the HIV-1 env quasispecies in mother-infant pairs.
- To characterize the genetic attributes of the envelope glycoprotein that may influence perinatal transmission of HIV-1 subtype C.
Main Methods:
- Analysis of the V1-V5 region of the HIV-1 env gene from six mother-infant transmission pairs (MIPs).
- Sequencing of 334 DNA samples and phylogenetic analysis to identify founder viruses.
- Comparison of genetic diversity, N-linked glycosylation sites, and variable loop lengths between transmitted and non-transmitted viruses.
Main Results:
- A significant genetic bottleneck was observed during perinatal HIV-1 subtype C transmission, evidenced by low sequence diversity in infants.
- Phylogenetic analysis strongly suggested a single founder virus established infection in each infant.
- Transmitted viruses exhibited fewer N-linked glycosylation sites and shorter variable loops in the Env V1-V5 region compared to non-transmitted viruses.
Conclusions:
- Perinatal transmission of HIV-1 subtype C is characterized by a severe genetic bottleneck, with a single viral variant typically initiating infection.
- The transmitted viruses show reduced glycosylation of the envelope glycoprotein, indicating preferential transmission of less glycosylated variants.
- Purifying selection plays a predominant role in shaping the early evolution of HIV-1 subtype C envelope sequences within hosts.
Background:
Mother-to-child transmission of HIV-1 remains a significant problem in the resource-constrained settings where anti-retroviral therapy is still not widely available. Understanding the earliest events during HIV-1 transmission and characterizing the newly transmitted or founder virus is central to intervention efforts. In this study, we analyzed the viral env quasispecies of six mother-infant transmission pairs (MIPs) and characterized the genetic features of envelope glycoprotein that could influence HIV-1 subtype C perinatal transmission.
Methodology And Findings:
The V1-V5 region of env was amplified from 6 MIPs baseline samples and 334 DNA sequences in total were analyzed. A comparison of the viral population derived from the mother and infant revealed a severe genetic bottleneck occurring during perinatal transmission, which was characterized by low sequence diversity in the infant. Phylogenetic analysis indicates that most likely in all our infant subjects a single founder virus was responsible for establishing infection. Furthermore, the newly transmitted viruses from the infant had significantly fewer potential N-linked glycosylation sites in Env V1-V5 region and showed a propensity to encode shorter variable loops compared to the nontransmitted viruses. In addition, a similar intensity of selection was seen between mothers and infants with a higher rate of synonymous (dS) compared to nonsynonymous (dN) substitutions evident (dN/dS<1).
Conclusions:
Our results indicate that a strong genetic bottleneck occurs during perinatal transmission of HIV-1 subtype C. This is evident through population diversity and phylogenetic patterns where a single viral variant appears to be responsible for infection in the infants. As a result the newly transmitted viruses are less diverse and harbored significantly less glycosylated envelope. This suggests that viruses with the restricted glycosylation in envelope glycoprotein appeared to be preferentially transmitted during HIV-1 subtype C perinatal transmission. In addition, our findings also indicated that purifying selection appears to predominate in shaping the early intrahost evolution of HIV-1 subtype C envelope sequences.
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