HIV-1 with multiple CCR5/CXCR4 chimeric receptor use is predictive of immunological failure in infected children

Background: HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5 viruses), was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT) of HIV-1 and pediatric disease progression. Methodology/Principal Findings: Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting) and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5 phenotype (n = 20), but R5 and R5X4 viruses were also found in seven and one case, respectively. The presence of R5 and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3) or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5 phenotype, however, the presence of the R5 virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5 viruses transmitted viruses with a similar chimeric coreceptor usage. Thus, the maternal R5 phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant. Conclusions/Significance: Our results show that R5 viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5 phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infection. © 2008 Cavarelli et al.