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

Journal of Biology

Viral Load, Amino Acid Sequence, Base Sequence, CD4 Lymphocyte Count, DNA Primers, Disease Progression, Enzyme-Linked Immunosorbent Assay, HIV Infections, immunology, virology, HIV-1, HLA-B Antigens, genetics, Humans, Molecular Epidemiology, Molecular Sequence Data, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, T-Lymphocytes, Cytotoxic

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      Abstract

      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.

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      Journal
      10.1128/JVI.02543-10
      3126593
      21613398

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