title: Combination of immune and viral factors distinguishes low-risk versus high-risk HIV-1 disease progression in HLA-B*5701 subjects.
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.
authors: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
authors: Melissa M
authors: MM
authors: Norström
authors: Marcus
authors: M
authors: Buggert
authors: Johanna
authors: J
authors: Tauriainen
authors: Wendy
authors: W
authors: Hartogensis
authors: Mattia C
authors: MC
authors: Prosperi
authors: Mark A
authors: MA
authors: Wallet
authors: Frederick M
authors: FM
authors: Hecht
authors: Marco
authors: M
authors: Salemi
authors: Annika C
authors: AC
authors: Karlsson
mesh_terms: D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018450:Disease Progression; D019143:Evolution, Molecular; D016655:HIV Core Protein p24 / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016013:Likelihood Functions; D008137:Longitudinal Studies; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D012307:Risk Factors
chemical_list: D016655:HIV Core Protein p24; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen