The HLA class I genes are the most polymorphic loci in the human genome, resulting in the ability of the system to bind and present a great variety of antigenic peptides to cytotoxic T lymphocytes. HLA-C molecules are expressed at a low level on the cell surface compared with HLA-A and -B. Unlike HLA-A and -B, HLA-C surface expression is not down-regulated by Nef upon HIV infection. We previously demonstrated that HLA-C allotypes are expressed at variable levels on the cell surface in a manner that is allotype-specific, and higher surface expression mediates greater selection pressure on HIV-1 and better viral control overall. We further showed that polymorphism in the miR-148a binding site in the HLA-C 3prime untranslated region (3 prime UTR) region partially explains differential expression of the various HLA-C allotypes, where miR-148a inhibits expression of HLA-C alleles that have an intact binding site but does not affect expression of escape HLA-C alleles that contain a disrupted binding site, which is not recognized by miR-148a. In general, the escape alleles are expressed at a higher level than the inhibited alleles (although there are exceptions). We have now demonstrated that the expression levels of miR-148a, as marked by MIR148A gene variation, correlate positively with HIV viral load among those individuals who carry at least one inhibited HLA-C allele. There is no correlation between the level of miR-148a and HIV control among those individuals who carry two copies of HLA-C escape alleles. Alternatively, the genotype marking higher miR-148a expression levels (which lead to lower HLA-C expression) results in protection against Crohn's disease (CD) among those who carry at least one inhibited HLA-C allele. These data underscore the importance of immune gene interactions in human disease and the independent role of HLA-C expression levels in HIV viral control and risk of CD. Natural progression of HIV-1 infection depends on genetic variation in the human MHC class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against HIV-1 by changing interactions of HLA class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Analyses in persons of European descent, the largest ethnic group examined, showed that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10-2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associated with viral replication in the absence of therapy in patients of both European (p = 10-11-10-9) and African (p = 10-5-10-3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. In vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs, suggesting an impact of LILRB2 on HIV-1 immune control through altered regulation of DCs by LILRB2-HLA engagement. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In collaboration with Dr. Malini Raghavan at the University of Michigan, we showed that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death. Consistent with these findings, allotypes such as HLA-B*57:01 and HLA-B*27:05 that are associated with slow progression to AIDS display low or intermediate tapasin independence. Some studies also suggest protective effects of HLA-Bw4 homozygosity in HIV infections, and low tapasin independence is strongly prevalent within the HLA-Bw4 serotype. Conversely, some allotypes such as HLA-B*35:03 and HLA-B*35:01 that are associated with more rapid AIDS progression are highly tapasin independent for their assembly. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes. Further studies are needed to better understand the influences of HLA-B assembly/stability characteristics upon disease outcomes in other disease contexts and upon global CD8+ T cell responses during infections. A recent genome-wide association study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with HIV-1 did not reveal genetic variants associated with resistance to HIV-1 infection, beyond homozygosity for CCR5-delta32. Variation at the HLA and KIR loci is usually not extensively tested by standard GWAS, because most HLA alleles are not efficiently tagged by any single-nucleotide polymorphism (SNP) present on the genotyping arrays and because of the extreme insertion/deletion polymorphism within the KIR locus. Given the importance of HLA and KIR for both innate and acquired immunity, we tested the same hemophilia cohort on which GWAS was performed, to determine whether variation within these loci may influence HIV acquisition as they do for post-infection events. Controls were randomly drawn from the general population in order to avoid the frailty bias that is inherent to virtually all HIV+ cohorts (ie, the enrichment of alleles associated with better HIV control in cohorts of chronic patients, due to longer survival which confounds association results). Use of a random control population is essential when probing for an effect of HLA on HIV infection, since HLA class I is the only locus genome-wide to consistently show an effect on control of HIV after infection. Analysis of the data indicates that HLA class I and KIR genes do not appear to impact HIV acquisition among hemophiliac patients exposed to contaminated blood products. Host genetic factors could still be involved in the resistance phenotype observed in highly exposed seronegative (HESN) individuals (eg, low-frequency variants poorly tagged by genotyping arrays or structural variants, such as insertion and deletion polymorphisms), and this should be investigated further.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010791-08
Application #
8937845
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Wang, Sophia S; Carrington, Mary; Berndt, Sonja I et al. (2018) HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes. Cancer Res 78:4086-4096
Adland, Emily; Hill, Matilda; Lavandier, Nora et al. (2018) Differential Immunodominance Hierarchy of CD8+ T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection. J Virol 92:
Manolio, Teri A; Hutter, Carolyn M; Avigan, Mark et al. (2018) Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis. Clin Pharmacol Ther 103:390-394
Pavlos, Rebecca; McKinnon, Elizabeth J; Ostrov, David A et al. (2017) Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles. Sci Rep 7:8653
Naranbhai, Vivek; Carrington, Mary (2017) Host genetic variation and HIV disease: from mapping to mechanism. Immunogenetics 69:489-498
Walker-Sperling, Victoria E; Pohlmeyer, Christopher W; Veenhuis, Rebecca T et al. (2017) Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller. EBioMedicine 16:141-149
Strickland, Natalie; Müller, Tracey L; Berkowitz, Natacha et al. (2017) Characterization of Mycobacterium tuberculosis-Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease. J Immunol :
Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos et al. (2017) HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+ Gag-Specific CD4+ T Cells in Chronic Clade C HIV-1 Infection. J Virol 91:
Park, You Jeong; Etemad, Behzad; Ahmed, Hayat et al. (2017) Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption. Pathog Immun 2:431-445
Körner, Christian; Simoneau, Camille R; Schommers, Philipp et al. (2017) HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells. Cell Host Microbe 22:111-119.e4

Showing the most recent 10 out of 120 publications