Immunodominance of HIV-1 specific CD8+ T-cell responses is related to disease progression rate in vertically infected adolescents

• Published in: PloS one 2011-07, Vol.6 (7), p.e21135-e21135
• Main Authors: Sharp, Elizabeth R, Willberg, Christian B, Kuebler, Peter J, Abadi, Jacob, Fennelly, Glenn J, Dobroszycki, Joanna, Wiznia, Andrew A, Rosenberg, Michael G, Nixon, Douglas F
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adolescent; Adolescents; AIDS; Alleles; Amino Acid Sequence; Antiretroviral agents; Biology; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - physiology; Cell Degranulation; Cell Differentiation - immunology; Children; Cohort Studies; Cytokines - metabolism; Development and progression; Disease control; Disease Progression; Drugs; Female; gag Gene Products, Human Immunodeficiency Virus - immunology; Highly active antiretroviral therapy; Histocompatibility antigen HLA; HIV; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; HLA antigens; HLA Antigens - immunology; Human immunodeficiency virus; Humans; Immunodominance; Immunodominant Epitopes - immunology; Immunosuppressive agents; Infectious Disease Transmission, Vertical; Lymphocytes; Lymphocytes T; Male; Medicine; Molecular Sequence Data; Pediatric diseases; Peptides; Peptides - chemistry; Peptides - immunology; Species Specificity; Statistical analysis; T cell receptors; T cells; Teenagers; Vaccines; Youth
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021135

HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.