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Life Sciences

Volume 88, Issues 21–22, 23 May 2011, Pages 980-986
Life Sciences

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Molecular mechanisms of HIV-1 mother-to-child transmission and infection in neonatal target cells

https://doi.org/10.1016/j.lfs.2010.09.023Get rights and content

Abstract

HIV-1 mother-to-child transmission (MTCT) occurs mainly at three stages, including prepartum, intrapartum and postpartum. Several maternal factors, including low CD4+ lymphocyte counts, high viral load, immune response, advanced disease status, smoking and abusing drugs have been implicated in an increased risk of HIV-1 MTCT. While use of antiretroviral therapy (ART) during pregnancy has significantly reduced the rate of MTCT, selective transmission of ART resistant mutants has been reported. Based on HIV-1 sequence comparison, the maternal HIV-1 minor genotypes with R5 phenotypes are predominantly transmitted to their infants and initially maintained in the infants with the same properties. Several HIV-1 structural, regulatory and accessory genes were highly conserved following MTCT. In addition, HIV-1 sequences from non-transmitting mothers are less heterogeneous compared with transmitting mothers, suggesting that a higher level of viral heterogeneity influences MTCT. Analysis of the immunologically relevant epitopes showed that variants evolved to escape the immune response that influenced HIV-1 MTCT. Several cytotoxic T-lymphocyte (CTL) epitopes were identified in various HIV-1 genes that were conserved in HIV-1 mother–infant sequences, suggesting a role in MTCT. We have shown that HIV-1 replicates more efficiently in neonatal T-lymphocytes and monocytes/macrophages compared with adult cells, and this differential replication is influenced at the level of HIV-1 gene expression, which was due to differential expression of host factors, including transcriptional activators, signal transducers and cytokines in neonatal than adult cells. In addition, HIV-1 integration occurs in more actively transcribed genes in neonatal compared with adult cells, which may influence HIV-1 gene expression. The increased HIV-1 gene expression and replication in neonatal target cells contribute to a higher viral load and more rapid disease progression in neonates/infants than adults. These findings may identify targets, viral and host, for developing strategies for HIV-1 prevention and treatment.

Introduction

Mother-to-child transmission (MTCT) of HIV-1 occurs at a rate of 30% without any antiretroviral treatment and accounts for 90% of all HIV-1 infections in children (Ahmad, 2005, Ahmad, 2008a). While antiretroviral therapy in HIV-infected pregnant women has significantly reduced the rate of MTCT in developed countries, HIV-1 infection in children is still a major concern because approximately 500,000 new HIV-1 infected infants are born every year worldwide. In addition, more women in childbearing age group continue to be infected with HIV-1 worldwide increasing the risk of MTCT. More importantly, HIV-1 infected infants born to these infected mothers develop a higher viral load and progress to AIDS more rapidly than infected adults and their own infected mothers, including differences seen in clinical manifestations (Little et al., 2007). However, the molecular mechanisms of HIV-1 MTCT and differential infection in neonates/infants remain poorly understood. This article describes the characteristics of HIV-1 associated with and lack of MTCT and molecular mechanisms of differential HIV-1 infection in neonatal and adult target cells.

Section snippets

Overview of HIV-1 mother-to-child transmission

HIV-1 MTCT occurs mainly at three stages: prepartum (transplacental passage), intrapartum (exposure of infants skin and mucus membrane to maternal blood and vaginal secretions), and postpartum (breast milk) (Ahmad, 2005, Ahmad, 2008b). Several studies have demonstrated the infection of placentas or fetuses, including the capability of HIV-1 to pass through an intact placental barrier maintained ex vivo (Bawdon et al., 1994). The intrapartum transmission occurs in more than 50% of the cases due

Characteristics of HIV-1 associated with and lack of mother-to-child transmission

Characterization of the molecular and biological properties of HIV-1 variants that are associated with and lack of MTCT has been performed by our and several other groups, with the idea that the strategies for prevention and treatment should be targeted at the properties of transmitted viruses. We and others have shown that a minor genotype, subtype or variant of maternal virus from a genetically heterogeneous virus population was transmitted to the infant based on HIV-1 envelope gp120

Characteristics of HIV-1 genes associated with and lack of mother-to-child transmission

We have characterized several HIV-1 genes, including the structural genes (gag, pol and env), regulatory (tat and rev) and accessory (vif, vpr, vpu and nef) genes from mother–child pairs. Since these genes are essential for viral replication and pathogenesis, molecular analysis should provide relevant information for developing strategies for prevention and treatment. The frequencies of the coding potential of gag p17 and NC, pol RT, env (V3 region) and gp41, tat, rev, vif, vpr, vpu and nef

Analysis of immunologically relevant epitopes associated with HIV-1 mother-to-child transmission

One of the major challenges in containing HIV-1 is the evasion of the host cytotoxic T-lymphocytes (CTL) response because of mutations in the key epitopes. While the immune responses against HIV-1 are generally effective, generation of HIV-1variants expose CTL to a large number of mutants that impairs the efficacy of the CTL. Escape mutants can arise early or late in HIV-1 infection and can also be transmitted (Goulder et al., 2001). Analysis of immunologically relevant mutations in HIV-1

Mechanisms of HIV-1 infection in neonatal target cells

Neonates and infants infected with HIV-1 have a higher viral load and progress to symptomatic AIDS more rapidly than infected adults and their own infected mothers, including differences seen in clinical manifestations (Little et al., 2007). HIV-1 infected children commonly experiment recurrent bacterial infections, otitis media, sinusitis, viral respiratory infections, bacterial pneumonia, meningitis, lymphocyte interstitial pneumonitis, encephalopathy, neurological, and physical growth

Drugs of abuse and HIV-1 mother-to-child transmission and neonatal infection

Drugs of abuse, including cocaine, heroin, opiates, methamphetamine, and others taken during pregnancy increases the risk of HIV-1 MTCT (Bulterys et al., 1997, Rodriguez et al., 1996). These studies have suggested that drugs of abuse modulated immunity and increased incidence of preterm births and therefore increased the risk of HIV-1 MTCT. Several studies have shown that drugs of abuse, including cocaine, heroin, methamphetamine and others enhance HIV-1 replication, modulate immune functions

Conclusion and future prospective

While the use of ART during pregnancy has been significantly reduced the risk of HIV-1 MTCT in developed countries, this treatment is not readily available in developing countries where most of the HIV-1 MTCT cases occur. In addition, MTCT of ART and multi-drug resistant HIV-1 has been reported. There is also a major concern regarding the long-term effect of ART/HHART on the development of uninfected children born to these mothers. Several factors, including drugs of abuse may influence HIV-1

Conflict of interest

The author has no conflict of interest.

Acknowledgements

This work was supported by grants from the NIH (AI40378, AI40378-06, and TW01345) and Arizona Biomedical Research Commission (9601, 7002, and 8001). The author thanks Drs. Colombe Chappey, Raymond C. Baker, Ziad M. Shehab, Erik Matala, Venkat Yedavalli, Tobias Hahn, Mohammad Husain, Rajesh Ramakrishnan, Vasudha Sundaravaradan, Shailendra Saxena, Roshni Mehta and Brian Wellensiek for their contribution.

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