Title: Pathogen Genomics Phenotype and Immunity / Research aimed at designing an effective HIV vaccine
Funder: Medical Research Council

Abstract: Overall aim: To contribute to better understanding of HIV protective immunity and vaccine design. Specific objectives are a) to study immunological correlates of protection in exposed sero negative individuals (ESN), ii) to characterize immune responses among individuals with different viral set points in early/acute HIV infection, iii) to investigate correlates of protection from HIV disease progression, iv) to study the correlation between HIV diversity and cross clade immune responses in individuals with chronic HIV infection, v) to investigate whether being treated at primary HIV infection (PHI) for a limited duration may delay damage to the immune system and prolong time to initiation of long-term anti-HIV therapy, vi) to study immune responses to vaccine candidates, vii) to study the prevalence of pre-existing adeno virus-specific T cells and their effect on Chimp Ad vector induced immune responses. One of the major challenges of developing an HIV vaccine is the poor understanding of protective immune responses. This broad research programme contributes to solving this problem. We are using different cohorts, especially serodiscordant couples, where in the ESN we follow HIV negative individuals at regular intervals while providing HIV prevention counselling. Immune responses to HIV are investigated in both ESN and in newly infected individuals. For the adeno virus project we identified individuals in Entebbe who have been screened for pre-existing Ad-specific T cells and humoral responses. We are defining the phenotype, function and potential cross-reactivity of T cell responses generated against adenovirus serotypes AdHu5, AdC6, and AdC7 in the Ugandan population. Another study, conducted in our Rural Clinical Cohort, looks at broadly neutralizing antibodies and their association with disease progression. To look at the potential protective effects of early short-term treatment of new HIV infection with anti-retroviral drugs, we contribute to the international SPARTAC trial. Furthermore, we participate in studies to evaluate immune responses to HIV vaccines, including a phase I study to evaluate the safety and immunogenicity of ALVAC-HIV vCP 1521 in infants born to HIV-1 infected women, in whom we investigate neutralizing and binding antibodies Immunological methods used include ELISpot and flowcytometery. We have introduced the cultured IFN-gamma ELISPOT assay in which PBMC are stimulated with HIV peptides in the presence of anti-apoptotic factor (IL-7) and T cell growth factor IL-2. After 10-11 days the cells are rested for 29-34 hours in the absence of peptide stimuli or cytokines and then tested for secretion of IFN-g upon re-exposure to HIV peptides as in the ex-vivo assay. For flowcytometry, the Unit has acquired an LSR II with 4 lasers which can measure up to 18 fluorescence parameters. For the neutralizing antibodies, we use the pseudovirion neutralization assay. This programme of work is funded from different complementary sources including the MRC/UVRI Uganda Unit core budget, EDCTP, the Wellcome Trust and others.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION