HIV-1 populations in blood and breast milk are similar

Department of Medicine, University of North Carolina at Chapel Hill, North Carolina, United States
Virology (Impact Factor: 3.32). 01/2005; 330(1):295-303. DOI: 10.1016/j.virol.2004.09.004
Source: PubMed


Mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) through breast milk is a significant mechanism of infection in many regions of the world. We compared the HIV-1 populations in paired blood and breast milk samples using a heteroduplex tracking assay (HTA) for the V1/V2 regions of env (V1/V2-HTA). V1/V2-HTA patterns were similar in the eight pairs of samples for which adequate template sampling could be demonstrated. No unique variants existed in either compartment, and differences detected in the relative abundance of variants between compartments were small, occurred among low abundance variants, and were not statistically significant. We also documented the impact of template sampling as a limiting feature in comparing two viral populations. The absence of unique variants and the lack of significant differences in the relative abundance of variants between these compartments support the conclusion that viruses in the blood plasma and breast milk are well equilibrated.

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Available from: Francis E Martinson
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    • "One study of the genetic diversity of milk virus suggested a difference in the dominant virus species in milk and peripheral blood [4]. A second study subsequently reported that the predominant virus in blood and milk were genetically similar, suggesting an equilibrium of virus between these compartments [12]. Thus, the production site of the virus transmitted via breastfeeding and the selection pressures that shape its genetic composition are not well understood. "
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    • "These results are in agreement with compartmentalization of HIV-1 previously described in semen and cervicovaginal secretions (Delwart et al., 1998; Ellerbrock et al., 2001; Overbaugh et al., 1996; Zhu et al., 1996). However, a recent study comparing HIV-1 RNA populations by a V1/V2 heteroduplex tracking assay concluded that HIV-1 V1/V2 variants in blood plasma and breast milk are similar (Henderson et al., 2004). "
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    ABSTRACT: The genotypic and phenotypic characteristics of HIV-1 CRF02_AG strains from infected patients in Burkina Faso were determined in order to understand about resistance development and susceptibility to antiretroviral drugs of HIV-1 non-subtype B. Drug resistance studies among Nevirapine (NVP) naïve and exposed women from Nouna, and HAART-exposed HIV patients attending the University Hospital in Ouagadougou, Burkina Faso were performed. The diversity and evolution of HIV-1 reverse transcriptase (RT) quasispecies in paired plasma, breast milk whey and/or breast milk cells from seventeen HIV-infected NVP-naïve and exposed women were determined by direct sequencing and clonal analysis. NVP resistance mutations were detected in 8% of infected mothers by direct sequencing. By using clonal analysis, the detection rate increased to 46% which indicates the high sensitivity of clonal analysis in detecting low proportion of drug resistance variants. To analyze compartmentalization of virus population in different anatomic compartments, phylogenetic analysis comparing virus populations of plasma, breast milk and/or breast milk cells from individual patients at both single and multiple time points was performed and the circulation of both compartmentalized (50%) and non-compartmentalized (45.5%) variants were found. These results suggest that in some individuals, viruses in breast milk whey may be evolving separately from plasma viruses. In most cases, breast milk whey variants were completely different from those of breast milk cells suggesting that free HIV virions in breast milk do not originate from infected breast milk cells. Different resistance mutation patterns were observed between viruses in plasma, breast milk and breast milk cells which suggest that transmission of HIV-1 from mother-to-child via breastfeeding may involve variants harbouring resistance mutations which cannot be predicted from variants present in plasma. To determine possible influences of genetic background on drug susceptibility of virus, a new CRF02_AG proviral plasmid (pBD6TB9RI) and the derivative CRF02_AG/subtype B chimera containing PR-RT fragment of pNL4-3 were generated. By testing drug susceptibility against 5 protease inhibitors (PIs), 6 nucleoside reverse transcriptase inhibitors (NRTIs), and 3 non-nucleoside reverse transcriptase inhibitors (NNRTIs), the CRF02_AG virus showed similar phenotypic results like the CRF02_AG/subtype B chimera. To further evaluate the CRF02_AG plasmid backbone, PR-RT amplified fragments derived from HAART-experienced HIV patients were cloned into the pBD6TB9RI plasmid and transfection derived viruses were tested against the panel of antiretroviral drugs. The phenotypic results for both NRTIs and NNRTIs strongly correlated with the predicted genotypic resistance patterns. However, there were minor discordances with some PIs. This suggests that the novel recombinant viral assay should be useful in assessing the drug susceptibility of CRF02_AG and other non-B strains which are widely distributed in West and Central Africa. Die genotypische und phänotypische Eigenschaften von HIV-1 CRF02_AG Subtyp von infizierten Patienten aus Burkina Faso wurden bestimmen um die Entwicklung der Resistenz und die Suszeptibilität für antivirale Medikamenten dieses HIV-1 Subtypes zu verstehen. In dieser Arbeit wurde die Resistenz von HIV gegen antivirale Medikamenten in Nevirapin (NVP)-naiven bzw. –therapierten Patientinnen aus Nouna und HIV-Patienten unter hochaktiver antiretroviraler Therapie (HAART) am Universitätsklinikum in Ouagadougou, Burkina Faso untersucht. Die Diversität und die Evolution der HIV-1 Reverse Transkriptase (RT) Quasispezies im Blutplasma Muttermilch und/oder Muttermilchzellen von siebzehn HIV-infizierten, NVP-naiven bzw. -therapierten Patientinnen wurde durch direkte Sequenzierung und Klonalanalyse ermittelt. Die Ergebnisse zeigen, dass die klonale Analyse eine höhere Sensititvität bei dem Nachweis von Resistenzvarianten aufweist, die in der Viruspopulation nur in einem kleinen Anteil vorliegen. Während die direkte Sequnzierung nur bei 8% der HIV-infizierten Mütter NVP-Resistenzmutationen nachwies, wurden durch Klonalanalyse bei 46% dieser Frauen Mutationen detektiert. Die Kompartimentierung von Viruspopulationen in Blutplasma gegenüber Muttermilch und/oder Zellen aus Muttermilch wurde mittels phylogenetischer Methoden analysiert. In 50% der Fälle zeigte sich eine Kompartimentalisierung der Viruspopulationen. Dies weist darauf hin, dass zumindest in einem Teil der Patientinnen eine unabhängige Entwicklung der Viren in Muttermilch stattfindet. Da sich die Viren in Muttermilch in den meisten Fällen von den Viren in Muttermilchzellen unterschieden, kann man annehmen, dass die freie HIV-Virionen in Muttermilch nicht von der Mehrzahl der infizierten Muttermilchzellen stammten. Aufgrund des Unterschieds von HIV-Varianten in Blutplasma, Muttermilch und Muttermilchzellen ist anzunehmen, dass Resistenzmutationen enthaltende Viren außerhalb von Blutplasma bei der Mutter-Kind Übertragung durch das Stillen eine wichtige Rolle spielen. Dies muss berücksichtigt werden, weil die meisten HIV-infizierten Mütter in Afrika ihre Kinder noch stillen. Um mögliche Einflüsse des viralen Genotyps auf die Suszeptibilität von HIV gegnüber antiretroviralen Medikamenten zu untersuchen, wurde ein prototypisches provirales Plasmid des in Westafrika verbreiteten AG rekombinanen Subtyps (pBD6TB9RI) hergestellt, und die Sensitivität dieses Virus gegenüber 5 Protease-Inhibitoren (PI), 6 nukleosidischen Reverse-Transkriptase-Inhibitoren (NRTI) und 3 nichtnukleosidischen Reverse-Transkriptase-Inhibitoren (NNRTI) bestimmt. Ein Austausch der PR-RT kodierenden Region mit entsprechenden Sequenzen aus dem Subtyp B Isolat NL4-3 bewirkte keine Veränderung des Sensitivitätsprofils. Anschließend wurde die PR-RT Region aus Viren aus dem Plasma von Patienten unter HAART in pBD6TB9RI überführt und die Suszeptibilität der rekombinanten Viren gegen die verschiedenen Inhibitoren getestet. Überwiegend ergab sich eine Übereinstimmung mit der genotypischen Vorhersage. Im Fall der PI ergaben sich zum Teil jedoch Abweichungen zwischen den Ergebnissen der genotypischen und der phnotypischen Bestimmung. Dies zeigt den Nutzen des hier etablierten phänotypischen Resistenztests für Viren des AG rekombinanten Subtyps.
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