Characterization of CD4+ and CD8+ T cell responses in HIV-1 C-Clade infection.

Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.HIV-1 specific CD4+ T cell activity in clade C infected subjects has not been studied. CD4+ T cells play a vital role in controlling infectious diseases and there is a need to augment our knowledge of HIV immunology to aid vaccine design. We therefore embarked on a study to characterize HIV-1 specific CD4+ T cell activity in both adults and infants; assess the relationship between CD4+ and CD8+ immune responses; and the relationship between CD4+ T cell activity and markers of disease progression (viral loads and CD4 counts). Our study revealed that the magnitude of CD8+ T cell responses correlated significantly with CD4+ T cell responses, but that the percentage of CD8+ T cells directed against HIV-1 was always greater than that of CD4+ T cells. Gag was the frequently targeted HIV-1 protein by CD4+ T cells and had the highest density of epitopes targeted by CD4+ T cells. Patients with either a dominant CD4 or CD8 T cell response against Gag had significantly lower viral loads than patients in whom non-Gag proteins were the main target (p< 0.0001 for CD4 activity and p= 0.007 for CD8 responses). Single IFN- producing CD4+ T cells were present in significantly higher numbers than cells producing both IFN- and IL-2 simultaneously (p=0.009). Gag also dominated the CD4+ T cell response in acutely infected infants with IFN- production detected more frequently than IL-2 or TNF- . Longitudinal analysis of infants receiving early ARV treatment and then ceasing after 12 months revealed that early treatment conferred no protection against increasing viremia and disease progression. CD4+ T cell responses were detected sporadically in untreated infants indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia. Taken together, the data reveal that a vaccine inducing Gag specific CD4+ T cell responses has the potential to confer some degree of protection, but other immunological parameters need to be investigated especially in infants

Human Immunodeficiency Virus-Specific CD8+ T-Cell Activity Is Detectable from Birth in the Majority of In Utero-Infected Infants▿

Human immunodeficiency virus (HIV)-infected infants in sub-Saharan Africa typically progress to AIDS or death by 2 years of life in the absence of antiretroviral therapy. This rapid progression to HIV disease has been related to immaturity of the adaptive immune response in infants. We screened 740 infants born to HIV-infected mothers and tracked development and specificity of HIV-specific CD8+ T-cell responses in 63 HIV-infected infants identified using gamma interferon enzyme-linked immunospot assays and intracellular cytokine staining. Forty-four in utero-infected and 19 intrapartum-infected infants were compared to 45 chronically infected children >2 years of age. Seventy percent (14 of 20) in utero-infected infants tested within the first week of life demonstrated HIV-specific CD8+ T-cell responses. Gag, Pol, and Nef were the principally targeted regions in chronic pediatric infection. However, Env dominated the overall response in one-third (12/36) of the acutely infected infants, compared to only 2/45 (4%) of chronically infected children (P = 0.00083). Gag-specific CD4+ T-cell responses were minimal to undetectable in the first 6 months of pediatric infection. These data indicate that failure to control HIV replication in in utero-infected infants is not due to an inability to induce responses but instead suggest secondary failure of adaptive immunity in containing this infection. Moreover, the detection of virus-specific CD8+ T-cell responses in the first days of life in most in utero-infected infants is encouraging for HIV vaccine interventions in infants