Related Experiment Videos
Maternal-fetal interactions affect growth of human immunodeficiency virus type 1 transgenic mice
R R Franks1, P E Ray, C C Babbott
1Laboratory of Oral Medicine, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
Insights
Human immunodeficiency virus type 1 (HIV-1) transgene expression causes severe postnatal growth failure in mice. Maternal HIV-1 transgene expression reduces pregnancy rates, but in-utero fetal growth is protected.
Area of Science:
- Virology
- Immunology
- Developmental Biology
Background:
- Infants with vertically transmitted human immunodeficiency virus type 1 (HIV-1) often exhibit severe growth deficiencies.
- The precise pathological mechanisms underlying pediatric HIV-1-associated growth failure remain unclear.
Purpose of the Study:
- To investigate the impact of HIV-1 transgene expression on fetal growth and maternal-fetal interactions using a transgenic mouse model.
- To elucidate the role of maternal factors and gene expression levels in mediating growth outcomes.
Main Methods:
- Generation of transgenic mice homozygous for a gag/pol deletion mutant of HIV-1 provirus pNL4-3.
- Examination of intrauterine growth, birth weights, and postnatal development in transgenic and nontransgenic mice.
- Embryo transfer experiments into normal and heterozygous transgenic mothers.
- Northern blot analysis to determine transgene expression levels in fetal, placental, and maternal tissues.
Main Results:
- Homozygous HIV-1 transgenic mice showed normal intrauterine and birth weights but severe postnatal growth retardation.
- Transgene expression was detected in fetuses, placentas, and maternal uteri, with higher levels in homozygous versus heterozygous animals, particularly postnatally.
- Maternal HIV-1 transgene expression significantly reduced postfertilization pregnancy rates, though in-utero fetal growth was not affected by embryo transfer.
Conclusions:
- HIV-1 transgene expression impacts both maternal reproductive capacity and neonatal growth.
- Maternal factors or inhibitory mechanisms may protect the fetus in utero from the detrimental effects of HIV-1 transgene expression.
- Postnatal growth failure in HIV-1 transgenic neonates is strongly associated with increased transgene expression.
Abstract:
Infants vertically infected with human immunodeficiency virus type 1 (HIV-1) often manifest profoundly deficient growth with failure to thrive. The pathologic mechanisms that produce growth failure associated with pediatric HIV infection are not clear. Transgenic mice homozygous for a gag/pol deletion mutant of the infectious provirus pNL4-3 have been found to manifest a similar growth failure pattern. To explore the influence of HIV-1 on fetal growth and maternal-fetal interactions, we examined intrauterine growth of transgenic and nontransgenic mice and evaluated the consequence of embryo transfer into normal and heterozygous transgenic mothers. Mice homozygous for the HIV transgene had normal intrauterine and birth weights but uniformly displayed severe growth retardation postnatally. Transgene expression was prominent in transgenic fetuses and their placentas and in uteri of transgenic mothers, as determined by Northern analysis. Although embryo transfer did not affect intrauterine growth, the pregnancy rate in transgenic mothers was markedly lower than in nontransgenic controls. In both fetal and neonatal tissues, transgene expression was significantly greater in homozygous animals when compared with heterozygotes, but the difference was magnified postnatally. These results suggest that HIV gene expression affected both mother and neonate. In the mother, expression of the HIV-1 transgene reduced postfertilization pregnancy rate. Once the animal was pregnant, however, the effects of transgene expression on the homozygous fetus were overcome in utero, possibly by the contribution of maternal factors or by inhibition of HIV-1 gene expression by a fetal or maternal factor(s). In the neonate, HIV-1 transgene expression increased dramatically in homozygotes and was associated with profound growth failure.(ABSTRACT TRUNCATED AT 250 WORDS)