CTL-MEDIATED CONTROL--PEDIATRIC/ADULT C-CLADE INFECTION

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A rational approach to vaccine design would be, first, to understand what constitutes protective immunity in natural infection; then, to generate the same protective responses by means of vaccine. Determination of the correlates of protective immunity in HIV infection has proved elusive. However, data have accumulated over the past decade, which point to the importance of anti-HIV cellular immunity in this regard. More recently, very strong support for the critical role of T helper and, especially, cytotoxic T lymphocytes (CTL) has emerged from work both on HIV-infected humans and SIV-infected macaques. These recent data have leant heavily upon newly available peptide MHC tetrameric reagents to reveal the close interdependence of CTL numbers and control of viremia in HIV and SIV infection. Together with Elispot assays, the peptide-MHC tetramers have transformed the scope of work on CTL responses , increasing the sensitivity and the rapidity of the assays each approximately 50-fold. Most work, however, has neither focused upon the populations most affected by the global epidemic, nor upon C clade infection which predominates worldwide. Current estimates are that two-thirds of the global burden of HIV infection is borne in sub-Saharan Africa. This is where vaccine-directed research urgently needs to be applied. Understanding the CTL responses which can be expected to exert control of HIV infection, and which would be incorporated into candidate vaccine, requires study of the HLA class I molecules characteristic of these populations, and precise definition of the important C clade-specific CTL epitopes. The two demographic groups most critically affected by the global epidemic are infants and young adult females. This proposal therefore specifically concentrates upon establishing a cohort of C clade infected mothers from pregnancy with the aim of studying these mothers and their children from childbirth onwards. These study subjects will be recruited from an antenatal clinic in Durban, South Africa, where the HIV seroprevalence is presently 40-50 percent. The specific aims of the proposed study are a) to define the immunodominant C clade epitopes targeted by CTL, restricted by HLA class I molecules prevalent in this population; b) to compare CTL responses observed in infected mothers and children to defined epitopes, with the purpose of determining the circumstances in which CTL are effective in controlling viremia; and c) to address the relevance of epitope sequence variation to vaccine design.