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: Melissa M Norström, Marcus Buggert, Johanna Tauriainen, Wendy Hartogensis, Mattia C Prosperi, Mark A Wallet, Frederick M Hecht, Marco Salemi, Annika C Karlsson
• Journal: Journal of virology (J Virol) Vol. 86 Issue 18 Pg. 9802-16 (Sep 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22761389 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HIV Core Protein p24
• HLA-B Antigens
• HLA-B*57:01 antigen

Topics

• CD4 Lymphocyte Count
• CD8-Positive T-Lymphocytes (immunology, virology)
• Disease Progression
• Evolution, Molecular
• HIV Core Protein p24 (genetics)
• HIV Infections (genetics, immunology, virology)
• HIV-1 (genetics, immunology)
• HLA-B Antigens (genetics)
• Host-Pathogen Interactions (genetics, immunology)
• Humans
• Likelihood Functions
• Longitudinal Studies
• Male
• Molecular Sequence Data
• Phylogeny
• Risk Factors