HLA Class I and KIR Genes Do Not Protect Against HIV Type 1 Infection in Highly Exposed Uninfected Individuals With Hemophilia A

A recent genome-wide association study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with human immunodeficiency virus type 1 (HIV-1) did not reveal genetic variants associated with resistance to HIV-1 infection, beyond homozygosity for CCR5-Δ32. Since variation in HLA class I and KIR genes is not well interrogated by standard GWAS techniques, we tested whether these 2 loci were involved in protection from HIV-1 infection in the same hemophilia cohort, using controls from the general population. Our data indicate that HLA class I alleles, presence or absence of KIR genes, and functionally relevant combinations of the HLA/KIR genotypes are not involved in resistance to parenterally transmitted HIV-1 infectio

A Dendritic Cell–Specific Intercellular Adhesion Molecule 3–Grabbing Nonintegrin (Dc-Sign)–Related Protein Is Highly Expressed on Human Liver Sinusoidal Endothelial Cells and Promotes HIV-1 Infection

The discovery of dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3–grabbing nonintegrin (DC-SIGN) as a DC-specific ICAM-3 binding receptor that enhances HIV-1 infection of T cells in trans has indicated a potentially important role for adhesion molecules in AIDS pathogenesis. A related molecule called DC-SIGNR exhibits 77% amino acid sequence identity with DC-SIGN. The DC-SIGN and DC-SIGNR genes map within a 30-kb region on chromosome 19p13.2-3. Their strong homology and close physical location indicate a recent duplication of the original gene. Messenger RNA and protein expression patterns demonstrate that the DC-SIGN–related molecule is highly expressed on liver sinusoidal cells and in the lymph node but not on DCs, in contrast to DC-SIGN. Therefore, we suggest that a more appropriate name for the DC-SIGN–related molecule is L-SIGN, liver/lymph node–specific ICAM-3–grabbing nonintegrin. We show that in the liver, L-SIGN is expressed by sinusoidal endothelial cells. Functional studies indicate that L-SIGN behaves similarly to DC-SIGN in that it has a high affinity for ICAM-3, captures HIV-1 through gp120 binding, and enhances HIV-1 infection of T cells in trans. We propose that L-SIGN may play an important role in the interaction between liver sinusoidal endothelium and trafficking lymphocytes, as well as function in the pathogenesis of HIV-1

Variants in interferon-alpha pathway genes and response to pegylated interferon-Alpha2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial

Combination treatment with pegylated-interferon-alpha (PEG IFN-Α) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-Α2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9+14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2 -2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2 -2256 carried the A variant compared with 68 of 120 (57%) nonresponders ( P = 0.006). Conclusion: Genetic polymorphisms in the interferon-Α pathway may affect responses to antiviral therapy of chronic hepatitis C. (H EPATOLOGY 2009.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63061/1/22877_ftp.pd

LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (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 human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (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 used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show 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 associates 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. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement

On stand by: host genetics of HIV control

The impact of host genetic variation on determining the differential outcomes after HIV infection has been studied by two approaches: targeting of candidate genes and genome-wide association studies (GWASs). The overlap in genetic variants that has been identified by these two means has essentially been restricted to variants near to the human leukocyte antigen (HLA) class I genes, although variation in the CCR5 locus, which was first shown to have an effect on HIV outcomes using the candidate gene approach, does reach significance genome-wide when very large samples sizes (i.e. thousands) are used in GWAS. Overall, many of the variants identified by the candidate gene approach are likely to be spurious, as no additional variants apart from a novel variant near the HLA-C gene have been consistently identified by GWAS. Variants with low frequency and/or low impact on HIV outcomes are likely to exist in the genome and there could be many of them, but these are not identifiable, given current GWAS sample sizes. Several loci centrally involved in the immune response, including the immunoglobulin genes, T-cell receptor loci, or leukocyte receptor complex, are either poorly covered on the GWAS chips or difficult to interpret due to their repetitive nature and/or the presence of insertion/deletion polymorphisms in the region. These loci warrant further interrogation, but genetic characterization of these regions across a range of individuals will first be required. Finally, synergistic interactions between loci may affect outcome after infection, as suggested by associations of specific, functionally relevant HLA and killer cell immunoglobulin-like receptor variants with HIV disease outcomes, and these require further consideration as well

HLA/KIR Restraint of HIV: Surviving the Fittest

Multiple epidemiological studies have demonstrated associations between the human leukocyte antigen (HLA) loci and human immunodeficiency virus (HIV) disease, and more recently the killer cell immunoglobulin-like (KIR) locus has been implicated in differential responses to the virus. Genome-wide association studies have convincingly shown that the HLA class I locus is the most significant host genetic contributor to the variation in HIV control, underscoring a central role for CD8 T cells in resistance to the virus. However, both genetic and functional data indicate that part of the HLA effect on HIV is due to interactions between KIR and HLA genes, also implicating natural killer cells in defense against viral infection and viral expansion prior to initiation of an adaptive response. We review the HLA and KIR associations with HIV disease and the progress that has been made in understanding the mechanisms that explain these associations

Novel Member of the CD209 (DC-SIGN) Gene Family in Primates

Two CD209 family genes identified in humans, CD209 (DC-SIGN) and CD209L (DC-SIGNR/L-SIGN), encode C-type lectins that serve as adhesion receptors for ICAM-2 and ICAM-3 and participate in the transmission of human and simian immunodeficiency viruses (HIV and SIV, respectively) to target cells in vitro. Here we characterize the CD209 gene family in nonhuman primates and show that recent evolutionary alterations have occurred in this family across primate species. All of the primate species tested, specifically, Old World monkeys (OWM) and apes, have orthologues of human CD209. In contrast, CD209L is missing in OWM but present in apes. A third family member, that we have named CD209L2, was cloned from rhesus monkey cDNA and subsequently identified in OWM and apes but not in humans. Rhesus CD209L2 mRNA was prominently expressed in the liver and axillary lymph nodes, although preliminary data suggest that levels of expression may vary among individuals. Despite a high level of sequence similarity to both human and rhesus CD209, rhesus CD209L2 was substantially less effective at binding ICAM-3 and poorly transmitted HIV type 1 and SIV to target cells relative to CD209. Our data suggest that the CD209 gene family has undergone recent evolutionary processes involving duplications and deletions, the latter of which may be tolerated because of potentially redundant functional activities of the molecules encoded by these genes