Understanding the impact of antiretroviral therapy (ART) on pathogen-specific immune reconstitution to endemic infections in children initiating ART in sub-Saharan Africa is critical to the optimal care of HIV-1 - infected children and the effective use of scarce resources. The first long-term objective of this proposal is to characterize the degree of pathogen-specific immune reconstitution in children initiating ART in sub-Saharan Africa, using immune responses to measles virus as a model. The second long-term objective is to apply recent advances in the understanding of immunologic memory to probe the impact of ART in children on memory T- and B-lymphocyte immune responses to measles virus. The third long-term objective is to assess the impact of ART on population immunity to measles virus as a basis for policy decisions regarding measles revaccination of HIV-1-infected children receiving ART in sub-Saharan Africa. Building upon our studies of measles and measles vaccination in HIV-1-infected children in Lusaka, Zambia, we will conduct a prospective, observational cohort study of HIV-1-infected children initiating ART at public clinics in Lusaka, Zambia to address the following specific aims: 1) characterize the magnitude and quality of mmune reconstitution in HIV-1 infected Zambian children initiating ART and determine pathogen-specific immune reconstitution by measuring memory immune responses to measles virus;2) measure humoral and cellular immune responses to measles virus before and after revaccination of HIV-1-infected Zambian children receiving ART who lack protective antibody titers;3) use mathematical models to evaluate the importance for measles elimination of a policy to revaccinate HIV-1-infected children receiving ART in regions of high HIV-1 prevalence. Estimates of the proportion of HIV-1-infected children receiving ART who are protected against measles virus both before and after revaccination will be used in a mathematical model to assess the impact of ART on population immunity to measles virus, with and without a policy of revaccination. The public health relevance of this research, linking epidemiologic and immunologic studies, is to guide ART treatment recommendations for children in sub-Saharan Africa by evaluating the impact of ART on immune reconstitution and immunity to vaccine-preventable diseases, and to enhance strategies for measles elimination by evaluating a policy to revaccinate children receiving ART against measles virus.
