Athena P. Kourtis

Breast milk and HIV-1: vector of transmission or vehicle of protection?

Transmission of HIV-1 to the infant through breastfeeding is a major cause of new paediatric HIV-1 infections worldwide. Although extended breastfeeding accounts for approximately 40% of infant HIV infections worldwide, most breastfed infants remain uninfected, despite prolonged and repeated exposure to HIV-1. Mechanisms associated with transmission of HIV-1 through breastfeeding and factors related to protection from such transmission remain poorly understood. Here we focus on the cellular origin of HIV in breast milk and on immune factors within the milk that may offer protection from transmission of HIV infection. The presence of innate immunity and induction of adaptive immunity against HIV is explored: in particular, specific antibodies, cellular responses, and their significance. The role of mucosal immune activation and epithelial integrity in HIV transmission is also addressed. We are of the opinion that advances in laboratory methods that study specific aspects of immunity will help open new areas of understanding of HIV transmission through breastfeeding and mechanisms of protection, and contribute to the development of novel prevention strategies.

The thymus during HIV disease: Role in pathogenesis and in immune recovery

The thymus is the primary lymphoid organ supplying new lymphocytes to the periphery. Clinical and morphologic studies of HIV-infected children and adults indicate that the thymus is affected by HIV. Thymic dysfunction and thymic involution occur during HIV disease and have been associated with rapid progression in infants infected perinatally with HIV. In vitro information of thymic organ culture, thymic epithelial cell culture, the SCID-hu mouse system and SHIV infection of primates have supported HIV-induced thymic damage. The mechanisms underlying this could be many, including direct thymocyte killing by the virus, apoptosis, or disruption of thymic stromal architecture. T cell receptor excision circles (TREC) have been developed as a marker of new thymic emigrants. Decreases in TREC concentrations have been found in both HIV-infected pediatric and adult patients. Mathematical models have suggested that thymic infection in children is more severe than in adults, particularly during infection with strains that use CXCR4 as coreceptor. Recent evidence suggests that thymic recovery may be achieved in some patients as a result of potent antiretroviral therapy. Extensive thymic damage may, however, hamper immune reconstitution, particularly in pediatric patients. This review attempts to summarize evidence for thymic involvement during HIV infection in children and in adults, the role of thymic infection in disease progression, and the contribution of the thymus to immune restoration following potent antiviral therapy. Immunologic interventions aiming at restoring thymic function in AIDS patients are also reviewed.

Prevention of Mother-to-Child Transmission of HIV-1 through Breast-Feeding: Past, Present, and Future

In this issue of The Journal of Infectious Diseases the Breastfeeding and HIV International Transmission Study (BHITS) group presents results from an individual patient data meta-analysis of 4085 HIV- 1–exposed breast-fed children from 9 clinical trials conducted in high-prevalence resource-limited settings. The risk of late postnatal transmission of HIV- 1 (after 4 weeks of age) was 8.9 transmissions/ 100 child-years of breast-feeding; late postnatal transmission was significantly associated with reduced maternal CD4 cell count and male sex of the child. The transmission rate was generally constant throughout the breast-feeding period between 1 and 18 months of age. A second article by Ferrantelli et al. in this same issue of the Journal demonstrates that a triple combination of monoclonal antibodies (MAbs) with potent anti-HIV neutralizing activity protected 4 of 4 neonatal macaques against infection after oral exposure to the virulent virus simian-human immunodeficiency virus (SHIV) 89.6P. This experiment in which antibodies were administered twice at 1 h and 8 days after virus exposure extends and confirms previous pre- and post-exposure passive immunization experiments conducted in newborn macaques. Taken together these interesting findings shed light on the risk of late postnatal transmission of HIV-1 in breast-fed children and point to novel biomedical interventions to potentially prevent such transmission in HIV-exposed children. (excerpt)

Prevention of perinatal HIV transmission: current status and future developments in anti-retroviral therapy.

Significant progress has been made in the battle against transmission of HIV-1 from mother to infant. Antiretroviral regimens covering the later part of gestation, labour and the first few weeks of neonatal life have shown great efficacy in reducing such transmission. With the advent of combination antiretroviral therapies, transmission rates lower than 2% have been achieved in clinical studies. Elective caesarean delivery has been shown to enhance the benefit of antiretroviral regimens; however, the risks associated with this approach in many resource-poor settings in developing countries limit its role worldwide. Abbreviated antiretroviral regimens covering labour and the first few days of neonatal life have shown considerable promise in the developing world, resulting in 50% reduction in transmission.Several questions and challenges remain, however. Amongst them, choice of the optimal antiretroviral agent(s), evaluation of purely post-exposure neonatal prophylaxis, availability of antiretroviral agents in developing countries, long-term safety of antiretroviral therapy during pregnancy and early neonatal life, and the problem of breastfeeding transmission in the developing world are some issues that need urgent attention.