51. Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects
- Author
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Norström, Melissa M, Buggert, Marcus, Tauriainen, Johanna, Hartogensis, Wendy, Prosperi, Mattia C, Wallet, Mark A, Hecht, Frederick M, Salemi, Marco, and Karlsson, Annika C
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Immunization ,Clinical Research ,Vaccine Related ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,CD4 Lymphocyte Count ,CD8-Positive T-Lymphocytes ,Disease Progression ,Evolution ,Molecular ,HIV Core Protein p24 ,HIV Infections ,HIV-1 ,HLA-B Antigens ,Host-Pathogen Interactions ,Humans ,Likelihood Functions ,Longitudinal Studies ,Male ,Molecular Sequence Data ,Phylogeny ,Risk Factors ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8(+) T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4(+) T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8(+) T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8(+) T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.
- Published
- 2012