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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283497155
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Host genetic polymorphisms associated with innate immune factors and HIV-1

Sobieszczyk, Magdalena E.a; Lingappa, Jairam R.b,d; McElrath, M. Julianab,c

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Author Information

aDepartment of Medicine, Columbia University College of Physicians and Surgeons, New York, New York

bDepartments of Global Health and Medicine, University of Washington

cVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center

dDepartment of Pediatrics, University of Washington, Seattle, Washington, USA

Correspondence to M. Juliana McElrath, MD, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N D3-100, PO Box 19024, Seattle, WA 98109-1024, USA Tel: +1 206 667 6704; e-mail:

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Purpose of review: Our understanding of the early events in HIV-1 infection continues to grow, along with the heightened recognition of the important contribution that innate immunity plays in response to HIV-1. Here, we review the epidemiological and functional studies of genetic polymorphisms associated with innate immune factors that are believed to modulate host responses, focusing specifically on recent findings related to Toll-like receptor, cytokine, host restriction and KIR genes and their activities.

Recent findings: A growing number of genomic studies have described polymorphisms in innate immune genes that are associated with early postseroconversion events, including TLR4, TLR9, IRF-3, TRIM5α and the ABOBEC3 gene family. Genetic and functional data confirm the importance of KIR–HLA interactions and provide new understanding of the role of innate restriction factors in resistance to HIV-1 and disease progression.

Summary: Single-gene, genome-wide association and expression studies have permitted the identification of innate immune genes and their variants that contribute to protection from disease progression. Characterization of the pathogen–innate immune system interactions and discovery of new and rare host genetic variants that account for a portion of the observed variance in the HIV-1 phenotype is critical to gain new insights into promising treatment and prevention strategies.

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Considerable variability exists among individuals in their susceptibility to HIV-1 infection and subsequent disease progression. Candidate genome studies and more recent genome-wide association studies (GWAS) have identified a number of common host genetic polymorphisms involved in HIV-1 immunopathogenesis. Much of the data derive from genetic analyses of populations classified with extreme phenotypes in their response to HIV-1 infection and disease, including highly exposed seronegatives, rapid progressors, long-term nonprogressors and elite controllers. Genetic variants located near the HLA-B and HLA-C loci and in CC chemokine receptor 5 (CCR5) are the strongest determinants of viral control reported thus far [1••], yet they account for only 15–20% of the known heterogeneity in the course of infection. Thus, the large portion of variability in the natural history of HIV-1 remains unexplained and may be attributable to the pathogenic properties of the virus itself, environmental factors, rare genetic variants and other immune factors (e.g., innate immune factors).

Polymorphisms in genes controlling innate immunity have been associated with early postexposure events and are linked to the rate of disease progression. Candidate genome studies recently revealed a role for natural killer (NK) cells in HIV-1 control and point to possible involvement of innate restriction factors. Many studies still require independent validation in adequately powered, relevant clinical cohorts with well defined outcomes. Inclusion of populations from different geographic regions and different ancestries will also be important to understand how these factors influence HIV disease in regions where the epidemic is most profound. In the meantime, a more comprehensive picture is emerging of the genetic variations in innate immune factors that shape responses to HIV-1.

This review focuses on the major findings and recent advances in the area of host genetic polymorphisms associated with innate immune factors in HIV-1. These factors are described in the sequence in which the cascade of responses may be invoked in response to HIV exposure and infection. Polymorphisms associated with innate immune responses to the virus, including defensins, mannose-binding lectin and DC-SIGN receptors, are summarized in Table 1[2–21].

Table 1
Table 1
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Polymorphisms in toll-like receptors

Toll-like receptors (TLRs), transmembrane proteins expressed on most immune cells, are activated by specific molecular patterns of pathogens, including HIV-1-derived products, which stimulate the production of innate immune effectors such as inflammatory and chemotactic cytokines. The single-stranded HIV-1 RNA can activate TLR7/8, and HIV-1 gp120 envelope protein can inhibit TLR9-triggered plasmacytoid dendritic cell activation and interferon alpha (IFN-α) protection, thereby modifying the levels of immune activation and activation of T cells [22–24]. Furthermore, in-vitro stimulation of TLR7/8 leads to enhanced activation and upregulation of IL-6, IL-8, IL-12 and TNF-α in exposed seronegative individuals [25], suggesting a protective early effect following HIV-1 exposure. Polymorphisms in TLR7 and TLR8 have also been reported in association with CD4+ T-cell decline in a cohort of recently infected, antiretroviral naive Europeans [26], but these findings are yet to be replicated in other studies. TLR9 1635A/G has also been associated with lower viral load set-point and slower disease progression prior to antiretroviral initiation among white North Americans [2], with a similar protective effect noted in a Spanish cohort [4]. However, another study in Europeans found more rapid progression for this and another TLR9 variant [3]. Differences in study populations, duration of infection or definitions of disease progression may account for some of these discrepancies. Furthermore, the impact of reduced B-cell expression of TLR9 in viremic individuals is not fully elucidated [27].

Recently, two TLR4 SNPs in strong linkage disequilibrium (1063A/G [D299G] and 1363C/T [T399I]) were found in significantly greater frequency among patients with higher compared to lower peak viremia [2]. Previous studies have shown that carriers of these alleles have greater susceptibility to other infections, including RSV and severe malaria [28]. Again, the mechanism underlying altered protection against HIV-1 related to these TLR4 variants is not known.

Of note, TLR variants have not been identified in GWAS for either common [21,29,30] or low-frequency (<5%) SNP variants affecting HIV-1 viral set-point or other measures of disease progression [31•]. Given the unique role of TLR signaling during acute HIV-1 infection and their potential role in chronic inflammation, it will be important to elucidate whether other TLR polymorphisms, as yet unidentified, contribute to HIV-1 pathogenesis and variability in disease progression.

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Polymorphisms in cytokine and cytokine receptor pathways

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One of the earliest responses to HIV-1 is the upregulation of type-I interferon (IFN) synthesis, leading to a signaling cascade and expression of over 100 IFN-stimulated genes (ISG), including proinflammatory cytokines induced mainly through the TLR7/8 pathways. Polymorphisms in genes encoding several cytokines and cytokine receptors are associated with resistance to HIV-1 infection and other outcomes (Table 1). However, many of these associations have not been validated in larger studies. Furthermore, these variants have not been identified in recent GWAS [29,32], which could also be attributed to low population frequency or small effect size [33].

A recent report indicates that HIV-1 suppression of interferon regulatory factor 3 (IRF-3) disrupts IRF-3-dependent TLR and RIG-1-like receptor innate pathways, which permits CD4+ T cells to become more permissive to secondary infections [34]. This effect was observed preferentially in CD4+ T cells from acutely infected patients rather than in long-term nonprogressors. Moreover, correlation between viral load and expression of IFN signaling and ISG has also been reported [35••]. Although expression of one ISG (OAS1) was found to be strongly associated with a SNP variant, no association of this SNP with viral load set-point was identified. This study highlights the challenges of relating subtle changes of expression and low-frequency genetic variants to differences in viral load in early infection, but underscores the importance of continuing efforts to integrate these data [35••].

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Polymorphisms in intrinsic immunity factors: APOBEC and TRIM5α

A number of intrinsic retroviral restriction factors, such as APOBEC3 family of cytidine deaminases and TRIM5α, have been shown to act as potent inhibitors of retroviral replication (Table 1). Their expression is robustly upregulated in response to type-I IFN in the setting of viral infection (reviewed in [36]).

The seven identified APOBEC3 proteins in humans typically act on the dinucleotide motifs CC or TC in single-stranded HIV-1 DNA and cause G-to-A hypermutation. Innate immune signaling may induce varying expression of APOBEC3 deaminase activities, and these in turn may also vary depending on host cell type and defense against HIV-1 [37]. This deaminase activity is counteracted by the HIV-1 accessory protein Vif, although the level of resistance to Vif-mediated degradation differs among the seven APOBEC proteins [38].

Polymorphisms in APOBEC genes have been investigated in diverse populations, with some evidence pointing to population-specific impacts on HIV-1 acquisition and progression. The H186R variant in APOBEC3G, for example, is strongly associated with CD4+ T-cell decline and accelerated disease progression in Black Americans [39], but not in white Americans or Europeans [40]. More recently, APOBEC3G polymorphisms were studied in early and acute subtype C infection in a high-risk female cohort [41•]. The authors confirmed the previous association of H186R with high viral loads and decreased CD4+ T-cell counts; importantly, they reported higher APOBEC3G expression levels in HIV-seronegative compared with HIV-seropositive individuals, although no association was found between APOBEC3G mRNA levels and viremia or CD4+ T-cell count in infected individuals. These findings raise key questions about whether increased expression of APOBEC3 genes can prevent acquisition or limit viral replication. Previous studies suggested a correlation between higher expression and hypermutation of APOBEC3G and resistance to infection [42,43], especially in the early phase following exposure [44], and an inverse correlation with HIV-1 viral load [45]. The relationship between gene polymorphisms, mRNA and protein expression levels and HIV-1 acquisition or viral control need further study.

Recent reports have also shed light on the role of APOBEC3H in HIV-1 pathogenesis. In-vitro experiments have identified variants of APOBEC3CH which are associated with improved resistance to Vif (K121D) and enhanced antiviral activity (G150R) [46,47•]. The implications of these variants for susceptibility to HIV-1 infection or disease progression will require additional study, but better characterization of polymorphisms affecting Vif–APOBEC3 interactions or APOBEC3 expression could lead to therapies that increase APOBEC3-mediated restriction by increased protein expression, incorporation into HIV-1 virions, or by protecting APOBEC3 from Vif-mediated degradation [48,49].

TRIM5α, another well described restriction factor, interferes with uncoating of viral particles after entry into the host cell prior to integration, thereby protecting the cell from productive infection [50]. Several TRIM5α polymorphisms correlate with differences in HIV-1 restriction [12,13]. A recent report from an acute subtype C infection cohort reported higher TRIM5α expression levels in peripheral blood mononuclear cell of exposed uninfected women compared with seroconverters [51], suggesting that TRIM5α protein levels may affect acquisition. However, studies evaluating the association of these polymorphisms with HIV-1 acquisition or progression have been inconsistent (Table 1) and suggest only a modest effect on HIV-1 disease outcome. Most of the data comes from populations of European descent; it will be important to follow-up these studies in diverse cohorts with differing exposures and genetic backgrounds.

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Killer cell immunoglobulin-like receptor polymorphisms

NKs cells are an essential component of the innate immune response against viruses via production of cytokines, chemokines and direct cytotoxicity [52]. Their function is predominantly modulated by a large repertoire of activating and inhibitory killer-immunoglobulin-like receptors (KIR) [53–55], a set of highly polymorphic monomeric cell-surface glycoproteins with short (S) activating or long (L) inhibitory cytoplasmic tails. Integration of activating and inhibitory signals modulates NK-cell activity and may account for the variability in early NK-cell responses to HIV-1 [53].

Although there is a great deal of variation in KIR genes, most individuals carry loci encoding KIR2DL1, KIR2DL2/2DL3 and KIR3DL1/3DS1. These genes can mediate NK-cell recognition of target cells by interacting with HLA-B (KIR3DL1) and HLA-C molecules (KIR2DL1, KIR2DL2 and KIR2DL3) [56••]. KIR3DL1 (and most likely KIR3DS1) binds to the peptide–HLA-B complex near key amino acid positions [1••], suggesting that part of the effect of HLA class I on HIV-1 infection is because of the interactions with KIR proteins.

To date, 14 KIR genes and two pseudogenes have been described (; several of them – KIR3DS1, 3DL1, 2DS2, 2DL2 and 2DS4, alone or in combination with their HLA ligands – have been the focus of increasing number of epidemiologic and functional studies that provide strong evidence implicating KIR polymorphisms in the natural history of HIV-1 (Table 2) [57–66] (see also recent reviews [56••,67]). Some of these epidemiologic associations await confirmation in larger, racially and ethnically diverse cohorts.

Table 2
Table 2
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Martin et al.[61] provided the first evidence that coexpression of activating KIR3DS1 and HLA-B alleles of the Bw4-80I group resulted in delayed disease progression in white and black Americans. They found a synergistic relationship between KIR3DS1 and HLA-Bw4-80I, as the KIR–HLA combination genotype was more predictive of disease progression than each locus alone; in fact, in the absence of HLA-Bw4-80I, KIR3DS1 homozygosity was associated with rapid progression to AIDS [61]. The beneficial effect of KIR3DS1 and HLA-Bw4-80I on early postinfection viral load and CD4+ T-cell count was also reported in other cohorts, but in those the effect was additive rather than synergistic [63]; other studies have also shown that coexpression of KIR3DS1/3DL1 with HLA-Bw4-80I results in protection from opportunistic infections [68]. The inhibitory KIR3DL1 gene, which segregates with KIR3DS1 as an allele of same locus, is the most polymorphic of the KIR genes, with more than 50 alleles with variable expression and inhibitory capacity [56••]. Interestingly, combinations of high-expression KIR3DL1 alleles and HLA-Bw4 ligand molecules are associated with slower disease progression, better control of HIV-1 viral load [64] and protection from acquisition [65]. This suggests that engagement of both activating and inhibitory KIR is important and beneficial in the early response to HIV-1. The proposed model explaining this invokes the concept of ‘licensing’ whereby during NK maturation the interaction between inhibitory receptors and MHC class I molecules results in generation of a more functionally competent NK cell [69,70]. As a result, under normal conditions responses against ‘self’ are inhibited by inhibitory KIR binding HLA-B. After HIV-1 infection and Nef-mediated MHC downregulation this inhibition is released, leading to stronger NK-cell activation and better disease outcome [71,72].

A number of functional studies provide support for these epidemiologic and genetic associations. It was shown previously that KIR3DS1+ NK cells degranulate and suppress viral replication more potently in the presence of HLA-Bw4-80I+ CD4+ T cells [73,74] and that KIR3DL1+ NK cells in the presence of HLA-B ligands demonstrate enhanced functional potential leading to improved outcomes [66]. Importantly, recent findings confirmed that KIR3DS1+ and KIR3DL1+ NK cells expand preferentially during acute and early HIV-1 infection and persist at increased levels, but only in the presence of HLA-Bw4-80I [62]. Data from functional studies also indicate that elevated NK-cell activity and KIR3DS1 expression may help mediate resistance to infection in exposed seronegative cohorts [75,76].

Additional KIR and HLA-C combinations have been investigated in African and White populations [58,60,77] and in the context of mother-to-child transmission [57]. In the latter study, an association was noted between KIR2DL2/KIR2DL3 heterozygosity or KIR2DL3 homozygosity (regardless of the presence of HLA-C ligand) and protection from transmission after adjusting for other factors such as viral load and maternal nevirapine use. These results need to be confirmed in larger studies and the mechanisms behind these protective interactions still require elucidation. Interestingly, recent GWAS analyses confirmed that a SNP located 35 kb upstream from HLA-C gene is associated with increased expression of HLA-C and lower viral load set-point [1••,78,79]; it is possible that in individuals with this polymorphism increased HLA-C expression may lead to more functionally competent KIR2DL2+ NK cells capable of a more rapid and potent response [67].

Overall, these studies emphasize the complexity of interactions of KIR polymorphisms with their HLA ligands and their effect on NK-cell function, especially in the critical early response to HIV-1 virus.

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Host innate immune responses and HIV-2

Although confined to regions of West Africa, HIV-2 provides an important contrast to HIV-1 insofar as most HIV-2-infected individuals remain relatively healthy and maintain high CD4+ T-cell counts for a long duration. Although few studies have evaluated specific interactions of host innate immune molecules with HIV-2, differences in these interactions compared to HIV-1 may be instructive.

HIV-2 may be more susceptible to TRIM5α restriction, thereby explaining variability in disease progression. In a cohort of HIV-2-infected individuals in Guinea-Bissau, lower viral loads were associated with variation in the p26 capsid protein of HIV-2 and altered susceptibility to TRIM5α [80•]. Furthermore, in a study comparing HIV-1-infected and HIV-2-infected individuals in Guinea-Bissau, TLR7/8 responsiveness was lower in HIV-2-infected individuals [81]. Finally, HLA alleles associated with differences in HIV-1 disease progression were not similarly associated with HIV-2 disease progression in a West African cohort; however, HLA-B*0801 may be associated with increased susceptibility to infection and HLA-B*1503 with lower CD4+ T-cell counts and higher HIV-2 viral loads [82•]. Although frequencies of activating KIR (e.g., KIR3DS1) were higher in this cohort compared with other African cohorts, no significant effect of individual KIR genes or KIR–HLA combination genotypes on HIV-2 disease progression or acquisition was noted [82•].

Clearly, further studies are needed to better understand the innate immune responses to HIV-2 and the extent to which those responses may underlie slower HIV-2 disease progression.

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The sequence of events immediately following HIV-1 exposure are of critical importance in contributing to the variability in HIV-1 disease course and in initiating the cascade of interactions ultimately leading to immune activation during chronic infection. Although an increasing number of gene association and functional studies have added to our understanding of the interactions between the virus and the innate immune system, many questions remain. With the recent data from candidate gene association studies, advances in GWAS, and gene-expression analyses, opportunities exist for applying a multiscale approach to identify rare variants contributing to immunopathogenesis and interperson variability in the natural history of HIV-1. Eventually these new insights may aid in the development of novel drug and vaccine targets.

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We thank Stephen P. Voght for technical assistance and critical reading of the manuscript.

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Conflicts of interest

There are no conflicts of interest.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* • of special interest

* •• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 448).

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80•. Onyango CO, Leligdowicz A, Yokoyama M, et al. HIV-2 capsids distinguish high and low virus load patients in a West African community cohort. Vaccine 2010; S2:B60–B67.

This study describes the association between HIV-2 capsid p26 sequence variation, susceptibility to TRIM5α restriction and HIV-2 viral load in a cohort from Guinea-Bissau.

81. Nowroozalizadeh S, Månsson F, da Silva Z, et al. Studies on toll-like receptor stimuli responsiveness in HIV-1 and HIV-2 infection. Cytokine 2009; 46:325–331.

82•. Yindom L-M, Leligdowicz A, Martin MP, et al. Influence of HLA class I and HLA–KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako Community in West Africa. J Virol 2010; 84:8202–8208.

This study describes the lack of association between previously described HLA class I and KIR genotypes on HIV-2 susceptibility or disease progression, suggesting, however, a link between HLA-B*1503 and more rapid HIV-2 disease progression in a long-standing cohort from Guinea-Bissau.


disease pathogenesis; innate immunity; polymorphism

© 2011 Lippincott Williams & Wilkins, Inc.


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