scholarly journals Modeling the immunological pre-adaptation of HIV-1

2020 ◽  
Author(s):  
Christiaan H. van Dorp ◽  
Michiel van Boven ◽  
Rob J. de Boer
Keyword(s):  
Disease Progression ◽  
Immune Escape ◽  
Human Leukocyte ◽  
Population Level ◽  
Dependent Manner ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
Slow Progression ◽  
High Heritability ◽  
Hiv 1

AbstractIt is becoming increasingly evident that the evolution of HIV-1 is to a large extent determined by the immunological background of the host. On the population-level this results in associations between specific human leukocyte antigen (HLA) alleles and polymorphic loci of the virus. Furthermore, some HLA alleles that were previously associated with slow progression to AIDS have been shown to lose their protective effect, because HLA-specific immunological escape variants have spread through the population. This phenomenon is known as immunological pre-adaptation. Apart from adapting to human immune responses, the set-point virus load (SPVL) of HIV-1 is thought to have evolved to values that optimize the population-level fitness of the virus. This suggestion is supported by considerable heritability of the SPVL. Previous modeling studies show that whether or not SPVL optimization is expected to occur depends sensitively on the underlying assumptions with respect to the extent of within-versus between-host selection. Here we use a detailed and semi-realistic multi-level HIV-1 model in which immunological pre-adaptation and SPVL evolution can emerge from the underlying interactions of the virus with the immune system of the host. This enables us to study the effect of immunological escape on disease progression, and how disease progression may be molded by SPVL evolution. We find that the time to AIDS could decrease significantly (0.5-1.0 years) in a HLA-dependent manner by immunological pre-adaptation over the long-term course of the epidemic (> 100 years). We find that SPVL is not expected to evolve to optimize the population-level fitness of HIV-1, even though high heritability of the SPVL emerges from continual selection of immune-escape mutations.

scholarly journals Global Database-Driven Assessment of HIV-1 Adaptation to the Immune Repertoires of Human Populations

2015 ◽  
Vol 89 (20) ◽  
pp. 10693-10695 ◽  
Author(s):  
Aram Karakas ◽  
Zabrina L. Brumme ◽  
Art F. Y. Poon
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Human Populations ◽  
Hla Alleles ◽  
Global Database ◽  
Leukocyte Antigen ◽  
Ctl Escape ◽  
The Relationship ◽  
Hiv 1

Associations between HIV-1 cytotoxic T lymphocyte (CTL) escape mutations and their restricting human leukocyte antigen (HLA) alleles imply that HIV could adapt to divergent HLA repertoires of human populations globally. Using publicly available databases, we examine the relationship between the frequencies of 19 experimentally validated CTL escape mutations in HIV-1 reverse transcriptase and their restricting HLA alleles in 59 countries. From these extensive data, we find evidence of differential HIV adaptations to human populations at only a limited number of the studied epitope sites.

scholarly journals Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients

2008 ◽  
Vol 205 (5) ◽  
pp. 1009-1017 ◽  
Author(s):  
Paul A. Goepfert ◽  
Wendy Lumm ◽  
Paul Farmer ◽  
Philippa Matthews ◽  
Andrew Prendergast ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune Escape ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Viral Fitness ◽  
Leukocyte Antigen ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)–associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele–restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.

scholarly journals HAMdetector: A Bayesian regression model that integrates information to detect HLA-associated mutations

2021 ◽  
Author(s):  
Daniel Habermann ◽  
Hadi Karimzadeh ◽  
Andreas Walker ◽  
Yang Li ◽  
Rongge Yang ◽  
...  
Keyword(s):  
Regression Model ◽  
Immune Escape ◽  
Point Mutations ◽  
Human Leukocyte ◽  
Relevant Information ◽  
Quantitative Information ◽  
Host Population ◽  
Bayesian Regression ◽  
Mhc I ◽  
Hla Alleles

Motivation: A key process in anti-viral adaptive immunity is that the Human Leukocyte Antigen system (HLA) presents epitopes as Major Histocompatibility Complex I (MHC I) protein-peptide complexes on cell surfaces and in this way alerts CD8+ cytotoxic T-Lymphocytes (CTLs). This pathway exerts strong selection pressure on viruses, favoring viral mutants that escape recognition by the HLA/CTL system, e.g. by point mutations that decrease binding of viral peptides to MHC I. Naturally, such immune escape mutations often emerge in highly variable viruses, e.g. HIV or HBV, as HLA-associated mutations (HAMs), specific to the host HLA alleles and its MHC I proteins. The reliable identification of HAMs is not only important for understanding viral genomes and their evolution, but it also impacts the development of broadly effective anti-viral treatments and vaccines against variable viruses. By their very nature HAMs are amenable to detection by statistical methods in paired sequence / HLA data. However, HLA alleles are very polymorphic in the human host population which makes the available data relatively sparse and noisy. Under these circumstances, one way to optimize HAM detection is to integrate all relevant information in a coherent model. Bayesian inference offers a principled approach to achieve this. Results: We present a new regression model for the detection of HAMs. As we choose a Bayesian approach we can include the novel sparsity-inducing priors, and we obtain easily interpretable quantitative information on HAM candidates. The basic model can be extended to include prior information relevant to HAM detection, which we demonstrate by integrating predictions of epitope affinities to MHC I, predictions of epitope peptide processing, and computation of phylogenetic background. This integrative method improves performance in HAM detection considerably over state-of-the-art methods.

scholarly journals Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis

2008 ◽  
Vol 68 (1) ◽  
pp. 107-109 ◽  
Author(s):  
K A Guthrie ◽  
N R Tishkevich ◽  
J L Nelson
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte Antigen ◽  
Age Of Onset ◽  
Human Leukocyte ◽  
Paternal Allele ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
The North ◽  
Significant Difference ◽  
Hla Genotype

Objectives:Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.Methods:We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).Results:Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.Conclusions:Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

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