The Role Of Human Immunodeficiency Virus Envelope During Mother-to-infant Transmission

Mother-to-child transmission(MTCT) of the humanimmunodeficiency virus type1(HIV-1) remains a significant problem inthe resource-constrained settings. This is especially worse in sub-SaharanAfrica where more than90%of the infected children under the age of15are living and the majority (95%) of new pediatric infections occurred,and where therapeutic intervention is still not widely available. Moreover,the HIV-1subtype C is the most prevalent and account for more than60%of infections in that epidemic region. Given the absence of aprophylactic vaccine or universal access to preventive treatment in thesedeveloping countries, a clear understanding of the characteristics ofpreferentially transmitted viruses is critical to the development ofeffective measures to reduce rates of MTCT.Our previous study demonstrated that the newly transmitted viruses (in infant) of chronically infected mother-infant pairs (MIPs) were morefit in growth, as imparted by their envelope glycoproteins V1-V5regions,than those in their corresponding chronically infected mothers. In orderto investigate whether the higher fitness of transmitted viruses wasconferred by their higher entry efficiency directed by the V1-V5regionsduring perinatal transmission, we analyzed the fusogenicity of Envcontaining V1-V5regions derived from transmitted andnon-tranmsmitted viruses of five chronically infected MIPs and twoacutely infected MIPs via two different cell-to-cell fusion assays. Theresults showed that higher fusion efficiency induced by infant EnvV1-V5than their corresponding mothers was observed in one chronicallyinfected MIP. Moreover, the V4V5regions play an important role todiscriminate the transmitted and non-transmitted viruses in this pair.However, neither consistent pattern nor significant differences offusogenicity mediated by V1-V5regions between maternal and infant variants was observed in other MIPs. Our study suggests that there is noconsistent and significant correlation between viral fitness selection andentry efficiency directed by V1-V5regions during perinatal transmission.Other factors such as the route and timing of transmission may also beinvolved.Antiretroviral drugs (ARVs) for HIV-1-infected pregnant women andtheirinfants are highly effective in reducing MTCT of HIV-1, whereasconcerns have been raised about the public health implications of theemergence of resistance to antiretroviral drugs. Small molecular CCR5inhibitors represent a new class of drugs for treating HIV-1infection.Maraviroc was the only CCR5antagonist approved by the FDA to beutilized as a salvage therapy for multi-drug resistant patients with R5tropic virus but has been recently approved for first-line treatmentregimens. No studies have evaluated the prevalence and transmission ofnaturally occurring mutations associated with maraviroc during peranatal transmission since they may have a profound impact on the clinicalmanagement of maraviroc in MTCT in future.To evaluate the prevalence and transmission of natural resistancemutations to maraviroc during peranatal transmission and analyze thesensitivity of mother-infant pairs to maraviroc, six chronically infectedMIPs and three acutely infected MIPs were recruited to analyze theprevalence and transmission of natural resistance mutations to maravirocand another small molecular CCR5antagonist-vicriviroc. And fourrepresentative chronically infected MIPs and two acutely infected MIPswere employed to construct provirus clones and to analyze the sensitivityto maraviroc. Mutations A316T, conferring partial resistance tomaraviroc, and T307I and R315Q, both conferring partial resistance tovicriviroc are prevalent in mother and infant cohorts of either acutelyinfected MIPs or chronically infected MIPs, indicating the transmissionof natural resistance mutations during peranatal transmission. The mutations present at viral quasispecies of acutely infected mothers seemto directly transmit to their corresponding infants, while some mutationsespecially at low frequency of chronically infected mothers would be lostduring transmission except the very high frequency. Moreover, thesensitivities to maraviroc of maternal and infant viruses of acutelyinfected MIPs are less susceptive than chronically infected MIPsrespectively.Our study suggests that the transmission mode of natural resistancemutations and the sensitivity to maraviroc are dependent on infectionstate of MIPs either acutely infected or chronically infected. These resultsmay indicate that higher dose of maraviroc is indispensable for treatmentof acutely infected MIPs compared to chronically infected MIPs.