Mother-to-child transmission of HIV-1: advances and controversies of the twentieth centuries.

Mother-to-child transmission (MTCT) is the overwhelming source of HIV-1 infection in young children. According to the World Health Organization (WHO), during the year 2003, despite effective antiretroviral (ARV) therapy, there were approximately 700,000 new infections in children worldwide, the majority of whom were from resource-limited countries. Alternative protocols to the long-course and complex regimens of ARV drugs, which in high-income countries have almost eradicated HIV MTCT, have been shown to reduce early transmission rates by 38-50%. However, the accumulation of drug resistance and the long-term toxicities of ARVs mean that alternative approaches need to be developed. Furthermore, transmission via breastfeeding, which accounts for one third of all transmission events, can reduce the benefits of short-course therapies given to women for the prevention of MTCT. The complex mechanisms and determinants of HIV-1 MTCT and its prevention in the different routes of transmission are still not completely understood. Despite the large contribution that many international agencies have made during the past 10-15 years in support of observational and intervention trials, as well as basic scientific research, HIV-1 MTCT intervention trials and basic research often are not integrated, leading to the generation of a fragmented picture. Maternal RNA levels, CD4+ T-cell counts, mode of delivery and gestational age were shown to be independent factors associated with transmission. However, these markers are only partial surrogates and cannot be used as absolute predictors of MTCT of HIV-1. Studies on the role of viral characteristics, immune response and host genomic polymorphisms did not always achieve conclusive results. Although CCR5-using viruses are preferentially carried by HIV-1 infected women as well as transmitted to their infants, the 32-basepair deletion of the CCR5 gene was not shown to influence perinatal MTCT. X4 viruses are apparently hampered in MTCT, although transmission of syncytium-inducing (SI) viruses, which use CXCR4, can occur when the mother carries such virus. Recently, there has been evidence of multiple virus variant transmission during peripartum MTCT. If viral escape from cytotoxic T-lymphocyte (CTL) recognition was repeatedly detected in transmitting mothers, no conclusive results were obtained on the role of the humoral immune response. The hypothesis on the mechanisms of selection during MTCT are still an open question, and include possibly that the transmitted variant is derived from a variant in the mother that escaped immune response, or that transmission is a stochastic event with the random transmission of a limited number of viral variants, or otherwise that selection occurs in the infant through a replication advantage of some transmitted viral variants. Although global access to ARV therapy certainly remains the primary goal to achieve the immediate reduction of MTCT of HIV-1, it is also evident that new and additional innovative strategies are needed.