Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
Natural killer (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cells recognize HIV-1 antigens are not fully understood. We investigated NK cell activation in response to HIV-1 peptides during early and chronic HIV-1 clade B infection using a whole-blood assay and multiparameter flow cytometry. Antibody-mediated NK cell activation in response to HIV-1 peptides was not detected in HIV-1-uninfected individuals. In contrast, 79% of individuals with chronic infection and 22% of individuals with early infection had detectable gamma interferon (IFN-γ) NK cell responses to HIV-1 antigens (P < 0.00001). IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing NK cells most frequently targeted Env gp120 (median of 4% and range of 0 to 31% of all NK cells). NK cells rarely targeted other HIV-1 proteins such as Gag, Pol, and Nef. Antibody-mediated NK cell responses to peptides mapped predominantly to Env protein, required the presence of plasma or plasma IgG, and resulted in lower CD16 expression on NK cells, suggesting an antibody-mediated activation of NK cells. Further studies are needed to assess the consequences of these antibody-mediated NK cell responses for HIV-1 disease progression and vaccine-induced protection from infection.
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.
Killer cell immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and subsets of T cells. The KIR genes are polymorphic and the KIR gene complex is polygenic with varying numbers of inhibitory and activating receptors. HLA class I molecules serve as ligands for the KIR. Interactions of the independently segregating KIR and HLA loci are important for recognition of targets by NK cells as well as NK cell ‘licensing’. Several disease association studies indicate a role for interactions between these loci in infectious diseases, autoimmune/inflammatory disorders, cancer and reproduction. Emerging functional data supports a mechanism based on a continuum of inhibition to activation through various compound KIR-HLA genotypes in diseases.
KIR; HLA; Natural killer cells; disease associations
Dendritic cells have critical roles for generating and fine-tuning adaptive immune responses and for regulating immune activity through cytokine secretion. In this study, we analyzed functional properties of dendritic cells in primary human immunodeficiency virus type 1 (HIV-1) infection. We found substantial disarray of the functional properties of myeloid and plasmacytoid dendritic cells in acute HIV-1 infection, which included defective antigen-presenting and cytokine secretion properties and was associated with a distinct surface expression profile of immunomodulatory dendritic cell receptors from the leukocyte immunoglobulin-like receptor family. These data indicate that key functional properties of dendritic cells are compromised during primary HIV-1 infection.
Purpose of review
The purpose of this review is to highlight recent advances in our understanding of host genetic determinants of HIV pathogenesis and to provide a theoretical framework for interpreting these studies in the context of our evolving understanding of HIV immunopathogenesis.
The first genome-wide association analysis of host determinants of HIV pathogenesis and other recent studies evaluating the interaction between killer cell immunoglobulin-like receptors and human leukocyte antigen alleles have implicated both adaptive and innate immune responses in the control of HIV replication. Furthermore, genetic variation associated with the expression of CCR5 and its ligand have been strongly associated with both decreased susceptibility to HIV infection and delayed clinical progression, independent of their effects on viral replication, suggesting a potential role for CCR5 inhibitors as immune-based therapies in HIV disease.
Host factors associated with the control of HIV replication may help identify important targets for vaccine design, while those associated with delayed clinical progression provide targets for future immune-based therapies against HIV infection.
CCR5; HIV pathogenesis; HLA; host genetic variation; KIR
Diversity across KIR haplotypes stems from differences in numbers of inhibitory and activating receptors, as well as allelic polymorphism of individual genes. The KIR locus has undergone large expansions and contractions over time and is believed to be coevolving with genes encoding its HLA class I ligands located within the MHC locus. KIR and HLA compound genotypes have been associated with susceptibility to or protection from infectious, autoimmune, reproductive, and malignant disorders. We describe here a simple and reliable multiplex PCR-SSP (sequence-specific priming) method for relatively rapid and inexpensive genotyping of 15 KIR genes using standard agarose gel electrophoresis.
KIR genotyping; NK cell; KIR haplotypes; multiplex PCR; PCR-SSP
Human leukocyte antigen (HLA) class I loci are essential to an effective immune response against a wide variety of pathogenic microorganisms, and they represent the prototypes for genetic polymorphism that are sustained through balancing selection. The functional significance of HLA class I variation is better exemplified by studies involving HIV type 1 (HIV-1) than any other infectious organism. HLA class I molecules are essential to the acquired immune response, but they are also important in innate immunity as ligands for the killer cell immunoglobulin-like receptors (KIR), which modulate natural killer cell activity. Here we concentrate on the interaction between the HLA-B and KIR3DL1/KIR3DS1 genes, describe the effects of these loci on HIV disease, and discuss questions that remain unresolved.
NK cell activity is regulated by the integration of positive and negative signals. One important source of these signals for human NK cells is the KIR family which includes both members that transduce positive and those that generate negative signals. KIR3DL1 inhibits NK cell activity upon engagement by its ligand HLA-Bw4. The highly homologous KIR3DS1 is an activating receptor, which has implicated in the outcome of a variety of pathological situations. However, unlike KIR3DL1, direct binding of KIR3DS1+ cells to HLA has not been demonstrated. We analyzed four key amino acid differences between KIR3DL1*01502 and KIR3DS1*013 to determine their role in KIR binding to HLA. Single substitutions of these residues dramatically reduced binding by KIR3DL1. In the reciprocal experiment, we found that the rare KIR3DS1 allotype KIR3DS1*014 binds HLA-Bw4 even though it differs from KIR3DS1*013 at only one of these positions (138). This reactivity was unexpectedly dependent on residues at other variable positions, as HLA-Bw4 binding was lost in receptors with KIR3DL1-like residues at both positions 199 and 138. These data provide the first evidence for the direct binding of a KIR3DS1+ cells to HLA-Bw4, and highlights the key role for position 138 in determining ligand specificity of KIR3DS1. They also reveal that KIR3DS1 reactivity and specificity is dictated by complex interactions between the residues in this region, suggesting a unique functional evolution of KIR3DS1 within the activating KIR family.
We examined associations between maternal HLA and vertical HIV-1 transmission in a perinatal cohort of 277 HIV-infected women in Nairobi. HLA class I genes were amplified using sequence-specific oligonucleotide probes and analyses were performed using logistic regression. Maternal A*2301 was associated with increased transmission risk before and after adjusting for maternal viral load (odds ratio [OR]=3.21; 95% CI: 1.42, 7.27, p=0.005, pcorr=0.04; adjusted OR=3.07; 95% CI: 1.26, 7.51, p=0.01, pcorr=NS). That maternal HLA-A*2301 was associated with transmission independent of plasma HIV-1 RNA levels, suggests that HLA may alter infectivity through mechanisms other than influencing HIV-1 viral load.
Human immunodeficiency virus; vertical HIV-1 transmission; human leukocyte antigen
Accumulating evidence suggests an important role for Natural Killer (NK) cells in the control of HIV-1 infection. Recently, it was shown that NK cell-mediated immune pressure can result in the selection of HIV-1 escape mutations. A potential mechanism for this NK cell escape is the selection of HLA class I-presented HIV-1 epitopes that allow for the engagement of inhibitory killer cell immunoglobulin-like receptors (KIRs), notably KIR2DL2. We therefore investigated the consequences of sequence variations within HLA-Cw*0102-restricted epitopes on the interaction of HLA-Cw*0102 with KIR2DL2 using a large panel of overlapping HIV-1 p24 Gag peptides. 217 decameric peptides spanning the HIV-1 p24 Gag consensus sequence were screened for HLA-Cw*0102 stabilization by co-incubation with Cw*0102(+)/TAP-deficient T2 cells using a flow cytometry-based assay. KIR2DL2 binding was assessed using a KIR2DL2-IgG fusion construct. Function of KIR2DL2(+) NK cells was flow cytometrically analyzed by measuring degranulation of primary NK cells after co-incubation with peptide-pulsed T2 cells. We identified 11 peptides stabilizing HLA-Cw*0102 on the surface of T2 cells. However, only one peptide (p24 Gag209–218 AAEWDRLHPV) allowed for binding of KIR2DL2. Notably, functional analysis showed a significant inhibition of KIR2DL2(+) NK cells in the presence of p24 Gag209–218-pulsed T2 cells, while degranulation of KIR2DL2(−) NK cells was not affected. Moreover, we demonstrated that sequence variations in position 7 of this epitope observed frequently in naturally occurring HIV-1 sequences can modulate binding to KIR2DL2. Our results show that the majority of HIV-1 p24 Gag peptides stabilizing HLA-Cw*0102 do not allow for binding of KIR2DL2, but identified one HLA-Cw*0102-presented peptide (p24 Gag209–218) that was recognized by the inhibitory NK cell receptor KIR2DL2 leading to functional inhibition of KIR2DL2-expressing NK cells. Engagement of KIR2DL2 might protect virus-infected cells from NK cell-mediated lysis and selections of sequence polymorphisms that increase avidity to KIR2DL2 might provide a mechanism for HIV-1 to escape NK cell-mediated immune pressure.
Distinguishing between “self” and “non-self” is one of the fundamental principles of immune responses against viral infections. Upon viral infection the peptide repertoire presented by HLA class I molecules changes, potentially providing signals that result in recognition and elimination of the infected cell by the host immune system. Viruses, in particular HIV-1, developed multiple strategies to escape T cell and Natural Killer (NK) cell-mediated immune pressure, including sequence variations that lead to the engagement of inhibitory receptors expressed on T cells and NK cells. The systematic approach used in this study led to the identification of an HLA-presented HIV-1 peptide that allows engagement of the inhibitory NK cell receptor KIR2DL2 and inhibition of NK function. Our findings help to elucidate the complex interaction between KIR molecules, such as KIR2DL2, and HLA/peptide complexes and provide a foundation for further studies investigating the role of sequence variations within HIV-1 epitopes on HLA/KIR interactions, and the ability of viruses to evade NK cell-mediated recognition.
Mounting evidence suggests a role for innate immunity in the early control of HIV infection, before the induction of adaptive immune responses. Among the early innate immune effector cells, dendritic cells (DCs) respond rapidly following infection aimed at arming the immune system, through the recognition of viral products via pattern recognition receptors. This early response results in the potent induction of a cascade of inflammatory cytokines, intimately involved in directly setting up an antiviral state, and indirectly activating other antiviral cells of the innate immune system. However, epidemiologic data strongly support a role for natural killer (NK) cells as critical innate mediators of antiviral control, through the recognition of virally infected cells through a network of receptors called the killer immunoglobulin-like receptors (KIRs). In this review, the early events in innate immune recognition of HIV, focused on defining the biology underlying KIR-mediated NK-cell control of HIV viral replication, are discussed.
Early events during HIV infection, likely mediated by the innate arm of the immune system, strongly influence disease progression. Natural killer cells, in particular, may contribute to antiviral containment.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10−9)—rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10−7 and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.
Background. Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression.
Methods. Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL).
Results. Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P = .01) or placebo participants with neutral HLA alleles (P = .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm.
Conclusions. Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors.
Clinical Trials Registration. NCT00080106.
While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (β = −0.7; 95% confidence interval [CI] = −0.9 to −0.5; P = 5 × 10−11) and Bw4 (β = −0.2; 95% CI = −0.4 to −0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients.
In the placebo-controlled trial ACTG A5197, a trend favoring viral suppression was seen in the HIV-1-infected subjects who received a recombinant Ad5 HIV-1 gag vaccine.
To identify individuals with initial viral suppression (plasma HIV-1 RNA set point <3.0 log10 copies/ml) during the analytic treatment interruption (ATI) and evaluate the durability and correlates of virologic control and characteristics of HIV sequence evolution.
HIV-1 gag and pol RNA were amplified and sequenced from plasma obtained during the ATI. Immune responses were measured by flow cytometric analysis and intracellular cytokine expression assays. Characteristics of those with and without initial viral suppression were compared using the Wilcoxon rank sum and Fisher's exact tests.
Eleven out of 104 participants (10.6%) were classified as initial virologic suppressors, nine of whom had received the vaccine. Initial virologic suppressors had significantly less CD4+ cell decline by ATI week 16 as compared to non-suppressors (median 7 CD4+ cell gain vs. 247 CD4+ cell loss, P = 0.04). However, of the ten initial virologic suppressors with a pVL at ATI week 49, only three maintained pVL <3.0 log10 copies/ml. HIV-1 Gag-specific CD4+ interferon-γ responses were not associated with initial virologic suppression and no evidence of vaccine-driven HIV sequence evolution was detected. Participants with initial virologic suppression were found to have a lower percentage of CD4+ CTLA-4+ cells prior to treatment interruption, but a greater proportion of HIV-1 Gag-reactive CD4+ TNF-α+ cells expressing either CTLA-4 or PD-1.
Among individuals participating in a rAd5 therapeutic HIV-1 gag vaccine trial, initial viral suppression was found in a subset of patients, but this response was not sustained. The association between CTLA-4 and PD-1 expression on CD4+ T cells and virologic outcome warrants further study in trials of other therapeutic vaccines in development.
Background.The HLA class II molecules play a central role in the generation of human immunodeficiency virus (HIV)–specific CD4+ T-helper cells, which are critical for the induction of cytotoxic CD8+ T cell responses. However, little is known about the impact of HLA class II alleles on HIV disease progression.
Methods.In this study we investigated the effect of HLA class II alleles on HIV disease outcome and HIV-specific T cell responses in a cohort of 426 antiretroviral therapy–naive, HIV-1 clade C–infected, predominantly female black South Africans.
Results.The HLA class II allele DRB1*1303 was independently associated with lower plasma viral loads in this population (P = .02), an association that was confirmed in a second cohort of 1436 untreated, HIV-1 clade B–infected, male European Americans, suggesting that DRB1*1303-mediated protection is independent of ethnicity, sex, and viral clade. Interestingly, DRB1*1303 carriage was not associated with an increased frequency of interferon (IFN) γ–positive HIV-specific CD4+ T cell responses.
Conclusions.These data demonstrate the independent effect of an HLA class II allele, DRB1*1303, on HIV disease progression, in the absence of increased IFN-γ–positive HIV-specific CD4+ T cell frequencies, suggesting that the protective activity of DRB1*1303 may be mediated via an alternative mechanism.
An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis.
Individuals with autoimmune disease generally demonstrate excessive immune system activation, leading to inflammation and damage of specific target organs. However, in some cases the detrimental effects of an overactive immune system might be counterbalanced by a beneficial effect in protecting against certain infections. In this study, we investigated whether patients with psoriasis, a common autoimmune disease of the skin, harbor genetic variants that are associated with an enhanced ability to limit replication of the HIV-1 virus. We profiled the HLA (human leukocyte antigen) immune genes located on chromosome 6 in 1,727 Caucasian psoriasis cases and 3,581 healthy controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. We found that this enrichment for HIV-1 protective variants was unique to psoriasis and largely absent in patients with other autoimmune or inflammatory diseases such as rheumatoid arthritis, Crohn's disease, type 1 diabetes, type 2 diabetes, and coronary artery disease. Our results suggest the possibility that the excessive skin inflammation in psoriasis may be associated with activation of anti-viral immune pathways that were important to human ancestors who encountered viruses similar to HIV-1.
Natural Killer (NK) cells play an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors1–3. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory Killer Immunoglobulin-like receptors (KIRs)4–7. However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino acid polymorphisms in the HIV-1 sequence of chronically infected individuals on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4+ T cells, leading to reduced antiviral activity of KIR+ NK cells. These data demonstrate that KIR+ NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK cell mediated immune pressure by selecting for sequence polymorphisms, as previously described for virus-specific T cells and neutralizing antibodies8. NK cells might therefore play a previously underappreciated role in contributing to viral evolution.
Background and Aims
HLA Class I alleles are linked to spontaneous control of HCV and HIV-1, but for HCV the roles of particular alleles and corresponding CD8+ T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcome of HCV and determine associated key T cell responses.
In a cohort of HCV individuals we determined HLA Class I alleles, HCV outcome, T-cell responses, and examined sequence data for mutational changes within key epitopes.
Carriage of HLA-B*57 was associated with a higher rate of viral clearance [RR=2.0, 95% C.I. 1.2–3.4] while HLA-B*08 was associated with a lower rate [RR=0.34, 95% C.I. 0.1–0.9]. Two HLA-B*57 restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B*57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B*57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution towards less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B*57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B*57-mediated immune pressure.
Our data indicate a role of HLA-B*57-restricted CD8+ T cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B*57. The finding that HLA-B*57-mediated antiviral immunity is associated with control of both HIV-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.
CD8 T cell; HLA-B57; spontaneous clearance; viral escape
HIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined. Soluble HLA class I molecules can have important inhibitory effects on T cells and NK cells, but may also contribute to reduced functional properties of professional antigen-presenting cells. Here, we investigated the expression of soluble HLA class I isoforms during HIV-1 infection and assessed their functional impact on antigen-presenting characteristics of dendritic cells.
Soluble HLA class I molecules were highly upregulated in progressive HIV-1 infection as determined by quantitative Western blots. This was associated with strong increases of intracellular expression of HLA class I isoforms in dendritic cells and monocytes. Using mixed lymphocyte reactions, we found that soluble HLA class I molecules effectively inhibited the antigen-presenting properties of dendritic cells, however, there was no significant influence of HLA class I molecules on the cytokine-secretion properties of these cells. The immunomodulatory effects of soluble HLA class I molecules were mediated by interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family.
During progressive HIV-1 infection, soluble HLA class I molecules can contribute to systemic immune dysfunction by inhibiting the antigen-presenting properties of myeloid dendritic cells through interactions with inhibitory myelomonocytic HLA class I receptors.
HIV-1; dendritic cells; HLA; immunoregulation; Leukocyte Immunoglobulin Like Receptor (LILR)
Increased NK activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected subjects. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1high) has also been observed in a subset of HIV-1 exposed, uninfected subjects. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intra-venous drug users (EU-IDU) remains to be elucidated.
We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU subjects and 15 control, uninfected donors from Philadelphia.
We assessed the activation status of NK cells and Dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU subjects.
As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU subjects compared to control uninfected donors (p=0.0056, n=13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU subjects. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared to control uninfected donors (p=0.0011, n=12). When stimulated in vitro, both PDCs and NK cells from EU-IDU subjects maintained strong effector cell function and did not exhibit signs of exhaustion.
Increased maturation of PDCs is associated with heightened NK activation in EU-IDU subjects suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.
Plasmacytoid DC; NK Cells; HIV/AIDS; Exposed/Uninfected; IDU