Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals

• Published in: Journal of virology Vol. 85; no. 14; pp. 7070 - 7080
• Main Authors: Chopera, D R, Mlotshwa, M, Woodman, Z, Mlisana, K, de Assis Rosa, D, Martin, D P, Abdool Karim, S, Gray, C M, Williamson, C
• Format: Journal Article
• Language: English
• Published: United States 01.07.2011
• Subjects: Amino Acid Sequence; Base Sequence; CD4 Lymphocyte Count; Disease Progression; DNA Primers; Enzyme-Linked Immunosorbent Assay; HIV Infections - immunology; HIV Infections - virology; HIV-1; HLA-B Antigens - genetics; HLA-B Antigens - immunology; Humans; Molecular Epidemiology; Molecular Sequence Data; Mutation; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Amino Acid; T-Lymphocytes, Cytotoxic - immunology; Viral Load
• ISSN: 1098-5514
• DOI: 10.1128/JVI.02543-10

Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.