Analysis of T cell responses to HIV-1 infection in Kenyan infant cohorts. (360G-Wellcome-089567_Z_09_Z)

General aim: to determine immunological correlates that contribute to lack of viral suppression during vertical transmission of HIV-1 in two Kenyan infant cohorts. Specific aims 1) To determine the varying capacity of infant cytotoxic T lymphocytes (CTL) to suppress HIV-1 replication 2) To investigate the mechanism by which CD4+ T cell and dendritic cell (DC) responses contribute to the lack of viral control during primary HIV-1 infection in infants The dynamics of primary Human Immunodeficiency Virus-1 (HIV-1) infection differs markedly between adults and infants. During acute infection in adults, an initial rise in viraemia that peaks 3-4 weeks after infection is brought under control1,2. By contrast, vertically infected infants experience a greater rise in peak viraemia coupled with a reduced capacity to contain viral replication3. As a result, disease progression proceeds rapidly with mortality rates in Kenyan infant cohorts of up to 52% within 2 years of life in the absence of ART4. Several lines of evidence indicate that HIV-specific T cell responses play critical roles in the control of viral replication in adults during acute and chronic stages of infection. For instance, CD8+ T cell numbers correlate inversely with viral load during acute infection1,5 , broad HIV-specific CD4+ and CD8+ T cell responses are associated with long term control of chronic infection6,7 and specific escape mutations emerge in the viral genome as a response to the selective pressure exerted by cytotoxic T cells (CTLs)8. The role of T cell responses during infant HIV infection is less clear. CD8 T+ cell cytokine production and proliferation are reported to be compromised in infants compared to adults9,10. By contrast, congenital cytomegalovirus infection leads to virus-specific CD8+ T cell responses with the same functional phenotype as those in adults11. Such disparate outcomes suggest a fundamental flaw in the machinery used to prime and maintain effective CD8+ T cell responses during primary HIV infection in infants. The focus of the present project is to investigate the mechanisms by which the immune axis involved in priming and maintaining CD8+ T cell activity contributes to the lack of viral control during infant HIV-I infection.