Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2020 Oct 11;31(2):e2160. doi: 10.1002/rmv.2160

Evidence for altered host genetic factors in KSHV infection and KSHV‐related disease development

Melissa J Blumenthal 1,2,3, Elena Maria Cornejo Castro 4, Denise Whitby 4, Arieh A Katz 2,3, Georgia Schäfer 1,2,3,✉
PMCID: PMC8047912  PMID: 33043529

Summary

Kaposi's sarcoma‐associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), the most common AIDS‐related malignancy. It also causes other rare, but certainly underreported, KSHV‐associated pathologies, namely primary effusion lymphoma, multicentric Castleman disease and KSHV inflammatory cytokine syndrome. Epidemiology and pathogenicity studies point to the potential for host genetic predisposition to KSHV infection and/or the subsequent development of KSHV‐associated pathologies partly explaining the peculiar geographic and population‐specific incidence of KSHV and associated pathologies and discrepancies in KSHV exposure and infection and KSHV infection and disease development. This review consolidates the current knowledge of host genetic factors involved in the KSHV‐driven pathogenesis. Studies reviewed here indicate a plausible connection between KSHV susceptibility and host genetic factors that affect either viral access to host cells via entry mechanisms or host innate immunity to viral infection. Subsequent to infection, KSHV‐associated pathogenesis, reviewed here primarily in the context of KS, is likely influenced by an orchestrated concert of innate immune system interactions, downstream inflammatory pathways and oncogenic mechanisms. The association studies reviewed here point to interesting candidate genes that may prove important in achieving a more nuanced understanding of the pathogenesis and therapeutic targeting of KSHV and associated diseases. Recent studies on host genetic factors suggest numerous candidate genes strongly associated with KSHV infection or subsequent disease development, particularly innate immune system mediators. Taken together, these contribute toward our understanding of the geographic prevalence and population susceptibility to KSHV and KSHV‐associated diseases.

Keywords: AIDS‐related malignancy, candidate gene association, genetic susceptibility, human herpesvirus 8, Kaposi's sarcoma, Kaposi's sarcoma‐associated herpesvirus

Abbreviations

ART

antiretroviral therapy

CCL2

C‐C chemokine ligand 2

CCND1

cyclin D1

CDKN1A

cyclin dependent kinase inhibitor 1A

CFLAR

CASP8 and FADD‐like apoptosis regulator

EPHA2

Eph receptor A2

FcγR

Fc gamma receptors

IL8RB

IL8 receptor, beta

KICS

KSHV inflammatory cytokine syndrome

KIR

killer cell immunoglobulin‐like receptors

KS

Kaposi's sarcoma

KSHV

Kaposi's sarcoma‐associated herpesvirus

MBL

mannose‐binding lectin

MCD

multicentric Castleman disease

MDM2

mouse double minute 2

NFκB

nuclear factor kappa B

NFκBIA

NFκB1 inhibitor alpha

NK

natural killer

PEL

primary effusion lymphoma

PTEN

phosphatase and tensin homologue

SNP

single nucleotide polymorphism

SSA

Sub‐Saharan Africa

TLR4

toll‐like receptor 4

TP53

tumour protein 53

VEGF

vascular endothelial growth factor

1. INTRODUCTION

Kaposi's sarcoma‐associated herpesvirus (KSHV, or human herpesvirus‐8) is a gammaherpesvirus with a particularly high seroprevalence in sub‐Saharan Africa (SSA, 30%‐50%) and the Mediterranean region (20%‐30%). 1 , 2 , 3 It is the etiological agent of the most common AIDS‐related malignancy, Kaposi's sarcoma (KS), 4 as well as the rare (although most certainly under‐reported 5 ) primary effusion lymphoma (PEL), multicentric Castleman disease (MCD) and KSHV inflammatory cytokine syndrome (KICS) which all primarily occur in HIV‐infected patients. 6 , 7 , 8 , 9 , 10 , 11 Exposure to and infection with KSHV is thought to occur early in life via saliva, 12 whereupon the virus establishes long‐term persistent infection which is usually clinically silent even during intermittent lytic reactivation, likely controlled by T cell responses. 10 , 13 , 14 However, with a decline in T cell immunity, most markedly in the context of HIV co‐infection but also in medically immunosuppressed and elderly people, KSHV‐infected patients become more likely to develop KSHV‐associated pathologies. 15 , 16 , 17 , 18

KSHV seroprevalence exhibits peculiar geographical epidemiology and incidence of KS and other KSHV‐associated diseases outside the setting of HIV are population‐specific. 3 , 19 , 20 Furthermore, there are discrepancies in KSHV exposure vs infection and KSHV/HIV co‐infection vs KS development in addition to evidence of familial aggregation of KSHV seroprevalence. 12 , 21 , 22 This growing body of evidence points to a potential underlying genetic risk of susceptibility to KSHV infection and associated disease development. In this review, we focus on studies reporting familial aggregation of susceptibility to KSHV infection and/or KSHV‐associated diseases and particular genetic polymorphisms in candidate susceptibility genes or haplotypes found to be statistically associated with aspects of KSHV pathogenesis. Further, we identify the limitations of gene association studies in isolation and suggest further research directions to elucidate the potential for targeted interventions in genetically susceptible populations.

2. EVIDENCE FOR THE EXISTENCE OF A GENETIC LINK

KSHV prevalence varies geographically and is particularly high in SSA (30%‐50%) and the Mediterranean region (20%‐30%). 1 , 2 , 3 Higher prevalence has been noted in people of specific ethnicities regardless of HIV infection where KSHV (and KS) was endemic even before the HIV/AIDS epidemic, such as in Uganda (14%‐95%), the Ivory Coast (43%‐100%), Cameroon (≥80%), the Amazonian basin in Brazil (53%), Peru (56%) and among people of Uygur and Han ethnicity in Xinjiang, China (40%‐60% and 21%‐31%, respectively). 3 , 20 , 23 , 24 , 25 , 26 , 27 , 28 In HIV‐infected people in the USA on antiretroviral therapy (ART), prevalence was 38%. 29 Furthermore, exposure to KSHV does not always result in KSHV infection; seroconversion even in areas of high exposure is 30% to 50%. 21 An epidemiological population‐based study on 1337 individuals of African origin in French Guinea where KSHV is endemic, showed strong correlation of KSHV seroprevalence between mother‐child and sibling‐sibling pairs, suggestive of familial aggregation. 12

KSHV infection is necessary for the development of KS, MCD, PEL and KICS but insufficient for tumorigenesis. Precipitating factors such as HIV infection or immune suppression are required for KSHV‐associated oncogenesis. Even so, HIV/KSHV co‐infection does not always result in cancer development. The most common of the KSHV‐associated pathologies, KS, is distinguished into four epidemiological forms. Classic KS primarily occurs in men from the Mediterranean and Eastern European region due to immune suppression related to old age, while endemic KS is found in Central Africa mostly in younger males. 17 , 30 Further, iatrogenic KS is associated with transplant‐related immunosuppression and therefore regresses with immune reconstitution. 31 , 32 With the onset of the AIDS epidemic, the incidence of an AIDS‐related or epidemic KS form, the most clinically aggressive, has burgeoned, driven by HIV/AIDS‐related immune suppression and HIV itself. 33 , 34 Within these epidemiological groupings, KS occurs with specific geographic distribution. 19 Risk of classic KS is threefold higher in men from the South of Italy than the North. 35 Transplant recipients of Mediterranean, Jewish and Middle Eastern ancestry (at risk for classic KS) are also overrepresented among iatrogenic KS patients regardless of their residence at the time of the transplant. 19 , 35 , 36 Among HIV‐positive patients, risk of developing AIDS‐KS is reported to be higher in South Africa than in Europe, North America and Latin America and the trend of decreased risk concomitant with increased CD4 count after initiation of ART evident in these regions was not observed in South Africa. 22 Geographic and population‐specific prevalence of KSHV and incidence of KS suggest a potential role for host genetic factors in susceptibility to KSHV infection and subsequent development of KS. Similarly, African ancestry has been shown to be a significant independent predictor of MCD incidence in HIV patients, suggesting a putative genetic susceptibility. 37

These observations point to genetic susceptibility to KSHV infection following exposure and/or progression to KS or other KSHV‐associated pathologies. 3 , 38 , 39 , 40

3. CANDIDATE SUSCEPTIBILITY GENES—CURRENT KNOWLEDGE

Thus far, immune‐modulatory genes have been the focus of investigations of candidate susceptibility genes. In particular, published studies have reported significant associations of KSHV infection or its associated pathologies with genetic polymorphism in genes encoding interleukins IL6, IL8 and IL13, 41 , 42 , 43 , 44 vascular endothelial growth factor (VEGF), 45 nuclear factor kappa B (NFκB), 46 mannose‐binding lectin (MBL)‐2, 47 Fc gamma receptors (FcγR), 48 HLA killer cell immunoglobulin‐like receptors (KIR) 49 , 50 and their HLA ligands and linked genes 50 , 51 , 52 , 53 , 54 , 55 , 56 and homologues of human genes pirated by KSHV, namely cyclin D1 (CCND1), IL6, C‐C chemokine ligand 2 (CCL2) and FADD‐like apoptosis regulator (CFLAR). 57 Additionally, we identified genetic variants in the KSHV entry receptor Eph receptor A2 (EPHA2) to be significantly associated with KSHV infection and KS development. 58 Conversely, tumour necrosis factors (TNF)‐α and ‐β, 41 , 44 IFNγ, 44 stromal‐derived factor 1 (SDF1), cyclin dependent kinase inhibitor 1A (CDKN1A), 59 C‐C chemokine receptor type 5 (CCR5) 41 and caspase 8 (CASP8) 57 have been investigated in relation to KS and KSHV but have not yielded statistically significant results. The above‐mentioned studies reporting statistically significant associations of host genetic polymorphisms or haplotypes with KSHV or KSHV‐associated pathologies are summarised in Table 1.

TABLE 1.

Summary of sequence variants and haplotypes associated with susceptibility to KSHV or KSHV‐associated pathologies

Gene HGVS a sequence variant (rsid)/ allele/ haplotype OR (95% CI) P value Associated with Description of study cohort Cases vs controls Reference
Susceptibility to KSHV infection
VEGF NG_008732.1:g.4822C>A (rs59260042) 4.8 (1.4‐17.1) .005 KSHV viral load Renal transplant recipients, KSHV+ or KSHV− after transplant 44 vs 128 Alkharsah et al 45
NM_001025366.3:c.‐94C>T (rs2010963) 3.98 (1.5‐11.1) .004 KSHV viral load Female only renal transplant recipients, KSHV+ or KSHV− after transplant 18 vs 50 Alkharsah et al 45
NFκB1 NG_050628.1:g.4670_4673ATTG[1] (rs28362491) 7.9 (3.3‐19.1) <.001 KSHV lytic antibody response HIV+/KSHV+ patients 63 vs 69 Gonçales et al 46
NFκBIA NM_020529.3:c.*126G>A (rs696)

Het: 12.3 (4.3‐34.9)

Hom: 9.4 (3.2‐27.9)

 <.001 KSHV lytic antibody response HIV+/KSHV+ patients 63 vs 69 Gonçales et al 46
MBL2 HYA/HXA, HYA/ HYO, HYA/LXA, HYA/LYO, LXA/LXA, LYA/LXA and LYA/LYO 3.1 (1.2‐7.6) .02 CD4 count response HIV+ patients who were KSHV+ or KSHV− 124 vs 213 De Morais et al 47
HLA and KIR HLA‐B Bw4‐80I+ and KIR3DS1 0.6 (0.4‐0.9) .01 KSHV seroprevalence HIV−/KSHV+ or KSHV− patients 277 vs 562 Goedert et al 50
HLA class I HLA‐C*01, *03, *07, *08 0.6 (0.4–0.9) .01 KSHV seroprevalence HIV−/KSHV+ or KSHV− patients 272 vs 549 Goedert et al 50
HLA‐A*6801 3.5 (1.4‐8.5) .0045 KSHV shedding in saliva HIV− mothers with or without detectable KSHV in saliva 84 vs 241 Alkharsah et al 60
HLA‐A*4301 5.3 (1.7‐17) .002 KSHV shedding in saliva HIV− mothers with or without detectable KSHV in saliva 84 vs 241 Alkharsah et al 60
HLA class II HLA‐DRB1*04 4.1 (1.4‐11.5) .0067 KSHV shedding in saliva Mothers with or without detectable KSHV in saliva 31 vs 332 Alkharsah et al 60
EPHA2 NM_004431.5:c.2572C>T 6.4 (1.4‐28.4) .03 KSHV serumpositivity HIV+/KSHV+ or HIV+/KSHV− patients 100 vs 50 Blumenthal et al 58
Susceptibility to KSHV‐associated pathologies
IL6 XM_011515390.2:c.‐84‐153C>G (rs1800795) 2.11 (1.2‐3.7) .0046 AIDS‐related KS HIV+ male patients with or without KS 115 vs 126 Foster et al 41
5.3 (1.5‐18.9) .008 Iatrogenic KS Renal transplant recipients with or without KS 15 vs 40 Gazouli et al 42
ns ns Classic KS HIV−/KSHV+ patients with or without KS 132 vs 169 Brown et al 44
IL8 NM_000584.4:c.65‐204C>T (rs2227306) 0.62 (0.38‐1.00) .16 Classic KS HIV−/KSHV+ patients with or without KS 132 vs 167 Brown et al 44
NG_029889.1:g.4802A>T (rs4073) ns ns Classic KS HIV−/KSHV+ patients with or without KS 132 vs 164 Brown et al 44
0.49 (0.25‐0.97) .039 AIDS‐related KS HIV+/KSHV+ male patients with or without KS 84 vs 154 van der Kuyl et al 43
IL8RB NM_001557.4:c.*127T>C (rs1126579)

Het: 0.51 (0.31‐0.84)

Hom: 0.45 (0.21‐0.96)

 .01 Classic KS HIV−/KSHV+ patients with or without KS 133 vs 167 Brown et al 44
NM_001557.4:c.*359G>A (rs1126580) 0.48 (0.24‐0.94) .07 Classic KS HIV−/KSHV+ patients with or without KS 129 vs 160 Brown et al 44
IL13 NM_002188.3:c.431A>G (rs20541) 1.82 (1.12‐2.97) .04 Classic KS HIV−/KSHV+ patients with or without KS 133 vs 168 Brown et al 44
FcγRIIIA NM_000569.8:c.526T>C (rs396991) 2.47 (1.46‐4.16) .0063 AIDS‐related KS HIV‐infected males with or without KS 112 vs 128 Lehrnbecher et al 48
HLA and KIR HLA‐B Bw4‐80I+ and KIR3DS1 2.1 (1.3‐3.4) .002 Classic KS HIV−/KSHV+ patients with or without KS 248 vs 277 Goedert et al 50
2.06 (0.4‐12.3) ns Classic KS Patients with or without KS (those without KS were KSHV+ or KSHV−) 11 vs 19 Guerini et al 49
ns ns AIDS‐related KS HIV‐infected patients with or without KS 81 vs 88 Qi et al 61
HLA‐B Bw4‐80I‐ and KIR3DS1 6.00 (1.5‐24.6) .006 Classic KS Patients with or without KS (those without KS were KSHV+ or KSHV−) 21 vs 32 Guerini et al 49
KIR KIR2DS1 3.82 (1.4‐10.9) .008 Classic KS Patients with or without KS (those without KS were KSHV+ or KSHV−) 32 vs 51 Guerini et al 49
KIR3DS1 4.0 (1.4‐11.4) .006 Classic KS Patients with or without KS (those without KS were KSHV+ or KSHV−) 32 vs 51 Guerini et al 49
HLA class I HLA‐A*11:01 0.4 (0.2‐0.7) .002 Classic KS HIV− patients with or without KS 248 vs 855 Goedert et al 50
HLA‐C*01, *03, *07, *08 1.8 (1.2‐2.7) .005 Classic KS HIV− patients with or without KS 247 vs 272 Goedert et al 50
HLA‐C*07:01 1.6 (1.2‐2.1) .002 Classic KS HIV− patients with or without KS 250 vs 846 Goedert et al 50
HLA‐B*14:01 4.2 (1.1‐15.5) .03 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
4.27 (1.67‐10.91) .033 AIDS‐related KS HIV+ patients with or without KS 157 vs 523 Cornejo Castro et al 52
HLA‐B*14 0.14 (0.02‐0.7) .0135 AIDS‐related KS HIV+ patients with or without KS 116 vs 59 Marmor et al 62
HLA‐B*2702/5 0.37 (0.15‐0.94) .04 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
0.39 (0.16‐0.94) .04 AIDS‐related KS HIV+ CD4 decline matched patients with or without KS 96 vs 96 Dorak et al 53
HLA‐CW4 4.96 (2.9‐8.12) .03 Iatrogenic KS HIV− renal transplant recipients with or without KS 44 vs 15 Azmandian et al 54
HLA‐A30 0.48 (0.25‐0.90) .48 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐CW5 0..32 (0.16‐0.65) .0006 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐CW7 2.48 (1.27‐4.72) .01 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐B58 0.035 (0.002‐0.58) .00001 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA class II HLA‐DRB1*1302‐DQB1*0604 6.12 (1.29‐28.9) .02 AIDS‐related KS HIV+, CD4 decline matched patients with or without KS 96 vs 96 Dorak et al 53
HLA‐DRB1*F13 2.24 (1.19‐4.20) .016 AIDS‐related KS AIDS patients with or without KS 122 vs 94 Gaya et al 56
HLA‐DRB1*1104 2.12 (1.05‐4.25) .047 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DRB1*1302 5.83 (1.73‐19.83) .004 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DRB1*1601 0.50 (0.26‐1.0) .043 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DQA1*0302 11.97 (1.27‐103.36) .019 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DQB1*0502 0.52 (0.27‐0.97) .047 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DQB1*0604 7.75 (2.02‐29.70) .0017 Classic KS HIV− patients with or without KS 62 vs 220 Masala et al 55
HLA‐DMB NM_002118.4:c.55+649T>C (rs6902982) 4.09 (1.90‐8.80) .0003 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
TAP1 NM_000593.5:c.2090A>G (rs1135216) 1.54 (1.09‐2.18) .014 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
NM_000593.5:c.1177A>G (rs1057141) 1.45 (1.05‐1.99) .024 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
TAP1/TAPSAR1 NG_011759.1:g.13891T>C (rs2071541) 1.6 (1.11‐2.32) .012 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
GPANK1 NM_001199237.1:c.*90T>C (rs7029) 1.55 (1.17‐2.05) .002 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
TRIM31 NM_007028.3:c.1261G>A (rs1116221) 0.74 (0.56‐0.96) .033 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
LTA NM_000595.4:c.‐10+90A>G (rs909253) 0.75 (0.58‐0.96) .022 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
LY6G6C NM_025261.3:c.243C>T (rs1065356) 1.60 (1.18‐2.16) .002 AIDS‐related KS HIV+/KSHV+ patients with and without KS 348 vs 318 Aissani et al 51
EPHA2

NM_004431.5:c.2099T>C

NM_004431.5:c.2835G>T

1.2 (1.1‐1.3)

1.2 (1.1‐1.4)

.04

.02

 AIDS‐related KS HIV+/KSHV+ patients with or without KS 50 vs 50 Blumenthal et al 58
TLR4 NM_138554.5:c.896A>G (rs4986790) 4.34 (1.3‐14.4) .021 MCD HIV+ patients with or without MCD 20 vs 89 Lagos et al 63
Open in a new tab
a

Variants are named according to Human Genome Variation Society (HGVS)‐nomenclature 64 with reference to their reference SNP identification (rsid) number, corresponding to the SNP database, where applicable. Alternatively, the haplotype is given where appropriate. HLA haplotypes are named according to the naming convention determined by the WHO Nomenclature Committee for Factors of the HLA System. Odds ratio (OR), confidence interval (CI) and P values are extracted from papers referenced in the table or calculated from the published data as required. An OR >1 is indicative of increased risk; OR <1 indicates decreased risk; ns indicates an OR with a confidence interval crossing 0 and a P value >.05.

3.1. Susceptibility to KSHV infection

A foundational study conducted by Plancoulaine et al 65 identified, by segregation analysis of KSHV seroprevalence among a French Guinean population, the presence of an unidentified recessive major gene that affects, in combination with age, KSHV seroconversion in children under 10 years of age. This was mapped to chromosome region 3p22 which encodes the following genes: programmed cell death 6 interacting protein (PDCD6IP), ubiquitin‐specific protease (UBP), F‐box and leucine‐rich repeat protein (FBXL2), cyclic AMP‐regulated phosphoprotein 21 (ARPP‐21), leucine‐rich repeat flightless‐interacting protein 2 (LRRFIP2) and C‐C motif chemokine receptor 4 (CCR4). 66 Several studies assessing genetic factors underlying susceptibility to KSHV infection have since been conducted.

Two triplet infants have been reported with familial hemophagocytic lymphohistiocytosis related to compound heterozygous perforin mutations and KSHV infection; in these cases, a defective perforin‐granzyme pathway is suggested to have led to reduced viral clearance ability and therefore to the onset of symptoms related to lytic KSHV infection. 67 Other studies have similarly focused on viral immune response genes. MBL2 haplotypes (based on combinations of two promoter region genotypes (−550 H/L and −221 Y/X) and a structural region genotype (exon 1 A/O)) associated with intermediate expression of MBL, an innate immune system protein, were found to be associated with lower CD4 count in HIV and KSHV co‐infected patients compared to patients with only HIV infection. 47 Additionally, polymorphisms in the NFκB1 promoter (NG_050628.1:g.4670_4673ATTG[1], reference SNP (rs)28 362 491) and the 3′ UTR region of the NFκB1 inhibitor alpha (NM_020529.3:NFκBIA c.*126G>A, rs696) were found to be associated with the presence of antibodies to KSHV lytic antigens. 46 Natural killer (NK) cell activation is important in the immune response to viruses and proposed to be protective against KSHV infection. 50 , 68 NK cells are regulated by killer Ig‐like receptors (KIR) which are activated by interaction with HLA molecules. The combination of KIR3DS1 (an activating haplotype of KIR) and HLA‐B Bw4‐80I (the Bw4 haplotype with an isoleucine at position 80) as well as HLA‐C group 1 (HLA‐C*01, *03, *07, *08) homozygosity was indeed found to be protective against KSHV infection. 50 Conversely, HLA‐A*6801, HLA‐A*4301 and HLA‐DRB1*04 were associated with KSHV shedding in saliva in mothers in rural South Africa, 60 while HLA‐DRB1 alleles investigated in relation to KSHV susceptibility in a Sardinian population were not shown to be statistically associated although HLA‐DR2 antigens were slightly overrepresented in KSHV‐positive patients (but did not withstand statistical correction for multiple testing). 69

Key molecules involved in the initial stages of KSHV entry are interesting candidate genes for KSHV association studies. We investigated sequence variants in a major KSHV entry receptor in endothelial cells, EPHA2, in relation to KSHV infection. Mutation analysis revealed a novel heterozygous transition (NM_004431.5:c.2572C>T) associated with KSHV infection in a cohort of HIV‐infected South African patients stratified by KSHV status. 58 The angiogenesis‐related VEGF, shown to augment entry of KSHV into target cells, 70 harboured a promoter region SNP (NG_008732.1:g.4822C>A, rs59260042) associated with KSHV viremia in kidney transplant recipients, and a SNP in the 5′ untranslated region (UTR, NM_001025366.3:c.‐94C>T, rs2010963) was likewise associated with KSHV viremia but in females only. 45

As the necessary etiological agent for the development of KS, MCD, PEL and KICS, enhanced susceptibility to KSHV infection subsequently increases the risk for KSHV‐associated pathologies. However, KSHV‐associated tumorigenesis may be caused by additional underlying genetic factors as described below.

3.2. Susceptibility to KSHV‐associated pathologies

As the most prevalent of the KSHV‐associated pathologies, KS, also the most common AIDS‐related malignancy worldwide, has been the focus of most studies concerning genetic susceptibility to KSHV‐associated pathology. Other KSHV‐associated pathologies, namely MCD, PEL and KICS, are considered rare although are almost certainly underreported due to difficult diagnoses, particularly in resource‐limited regions where HIV burden is high. Consequently, there is a lack of research into the rarer KSHV‐associated pathologies and particularly on potential host genetic contributors; therefore, only few reports were identified for inclusion in this review.

3.2.1. Kaposi's sarcoma

There is evidence from several case reports to suggest that genetic primary immunodeficiency predisposes to KS. 71 , 72 , 73 , 74 , 75 Three unrelated Turkish children, aged 2, 9 and 9, born to consanguineous parents were reported to develop classic KS in early childhood, an extremely rare occurrence in the Mediterranean basin, strongly suggesting autosomal recessive predisposition. 73 One of these children, who died from severe disseminated KS at the age of two, harboured a homozygous splice‐site stromal interaction molecule 1 (STIM1) mutation resulting in T cell immunodeficiency. 74 A further case report describes a Turkish boy with inherited IFNγR1 deficiency due to homozygous INFGR1 mutation (NP_000407.1:p.Cys77Tyr, rs104893974) who developed and died from classic KS. 71 A cryptic splicing mediated CTLA4 haploinsufficiency, associated with defective NK cell function, has recently been shown to have facilitated classic KS development in the case of a 52‐year‐old HIV‐negative male of Italian ancestry. 75 A Tunisian boy with Wiskott‐Aldrich syndrome caused by a WAS deletion (NP_000368.1:p.Asp130_Glu131del) provides further evidence of a possible predisposition to classic KS. 72

Several notable associations have been identified in genes encoding proteins that are known to be pro‐inflammatory. A SNP in the IL6 promoter (XM_011515390.2:c.‐84‐153C>G, rs1800795) which is associated with increased levels of IL6 was noted in a familial clustering of classic KS and was further associated with KS in HIV‐infected men and renal transplant recipients. 39 , 41 , 42 IL6 potently promotes the growth of KS spindle cells in an autocrine and paracrine manner. 76 Additionally, a SNP in the IL13 promoter region (NM_002188.3:c.431A>G, rs20541) was associated with classic KS in patients latently infected with KSHV. 44 Similarly, an IL8 promoter SNP (NG_029889.1:g.4802A>T, rs4073), linked to below normal IL8 expression, was identified in a cohort of patients with classic KS 44 ; however, it was conversely found to decrease the risk of AIDS‐KS in HIV‐positive patients. 43 An IL8 SNP (NM_000584.4:c.65‐204C>T, rs2227306) was reported to decrease risk of classic KS 44 and the combination of two SNPs (NM_001557.4:c.*127T>C, rs1126579 and NM_001557.4:c.*359G>A, rs1126580) in the human homologue to the KSHV‐encoded viral G‐protein coupled receptor (vGPCR), IL8 receptor beta (IL8RB), were similarly found to be protective against the development of classic KS. 44

Immunoregulatory genes have also been implicated in KS development in addition to KSHV susceptibility. A polymorphic form (NM_000569.8:c.526T>C, rs396991) of the IgG binding receptor, FcγRIIIA, was associated with AIDS‐KS in a cohort of HIV‐positive men and was found to enhance IgG affinity in vitro and promote NK cell activation. 48 , 77 Inflammation mediated by NK cell activation is postulated to promote KS oncogenesis. 50 , 68 Goedert et al 50 reported that the combination of KIR3DS1 (an activating haplotype of KIR) and HLA‐B Bw4‐80I (the Bw4 haplotype with an isoleucine at position 80) was protective against KSHV seroprevalence (see Section 3.1) but increased the risk of classic KS among KSHV‐positive patients in a cohort of HIV‐negative patients without KS, however, this association was not corroborated in a HIV‐infected cohort investigated for KS development 61 nor a smaller cohort of Italian classic KS patients, in which the KIR3DS1+/Bw4*80I‐genotype was statistically more frequent among classic KS cases than control. 49 Additionally, activating KIR haplotypes, KIR3DS1 and KIR2DS1, were associated with classic KS. 49 Similarly, Goedert et al 50 found HLA‐C group 1 (HLA‐C*01, *03, *07, *08) homozygosity to be protective against KSHV infection (see Section 3.1), but once infected to confer increased risk of KS development through a proposed mechanism of NK cell activation and induced inflammation.

Additionally, several HLA class I and II haplotypes have been thoroughly investigated. KS development post kidney transplant was associated with HLA‐CW4 in a small study. 54 In a familial clustering of classic KS, the homozygous HLA‐A*24/B*18/Cw*12/DRB1*11/DQB1*03 haplotype was present in family members with KS and not in those without KS, with the DRB1*11 subtype present in most family members. 39 In a study of classic KS in a Sardinian population (high risk for classic KS), a number of class I and class II HLA haplotypes were associated with an increased (class I: HLA‐CW7; Class II: HLA‐DRB1*1104, HLA‐DRB1*1302, HLA‐DQA1*0302, HLA‐DQB1*0604) or decreased (class I: HLA‐A30, HLA‐CW5, HLA‐B58; class II: HLA‐DRB1*1601, HLA‐DQB1*0502) risk of classic KS. 55 HLA‐C*07:01 has also been associated with classic KS, while HLA‐A*11:01 was found to decrease risk 50 and HLA‐B*2705 was similarly reported to be protective. 51 , 53 HLA‐B14 has been reported to be underrepresented among AIDS‐KS cases, 62 but the specific allele, HLA‐B*14:01, was found to be a risk allele for AIDS‐related KS. 51 , 52 HLA‐DRB1*1302 in linkage disequilibrium with DQB1*0604 was identified as a risk haplotype for AIDS‐related KS 53 as were HLA‐DRB1 alleles with a phenylalanine residue at position 13. 56 HLA‐DR5 has been noted to be present at an increased frequency among (presumed) AIDS‐related KS, 78 classic KS patients 78 , 79 as well as among iatrogenic KS patients 80 , 81 , 82 while other studies have not found this to be the case. 62

Several variants identified in a SNP screening of the HLA‐DMB gene region were found to increase AIDS‐KS risk. Most significantly, a SNP in the HLA‐DMB intronic region (NM_002118.4:c.55+649T>C, rs6902982) was associated with a four‐times higher risk of AIDS‐KS in HIV‐KSHV co‐infected men. 51 Non‐synonymous SNPs in tripartite motif‐containing protein 31 (TRIM31, NM_007028.3:c.1261G>A, rs1116221) and lymphotoxin alpha (LTA, NM_000595.4:c.‐10+90A>G, rs909253) were observed to be protective whereas SNPs within HLA‐DMB linked genes, transporter associated with antigen processing 1 (TAP1, NM_000593.5:c.2090A>G, rs1135216; c.1177A>G, rs1057141), TAPSAR1 microRNA (NG_011759.1:g.13891T>C, rs2071541), G‐patch domain and ankyrin repeats 1 (GPANK, NM_001199237.1:c.*90T>C, rs7029) and lymphocyte antigen 6 family member G6C (LY6G6C, NM_025261.3:c.243C>T, rs1065356), were associated with increased risk of AIDS‐KS. 51

Recently, human genes that are cellular homologues of KSHV‐expressed genes have been investigated hypothesising that virally expressed homologues, which promote immune‐silent proliferation, may be advantaged by genetic SNPs in their cellular counterparts. 57 A SNP screening in AIDS‐KS patients including several cellular homologues identified SNPs in CCND1, IL6, CCL2 and CFLAR (homologues of KSHV‐encoded vCyclin, vIL6, viral FLICE‐inhibitory protein (vFLIP) and viral CC chemokine ligand (vCCL), respectively). Various combinations of these SNPs (but not a single SNP alone) were associated with AIDS‐KS. 57

EPHA2, in addition to being a key entry receptor for KSHV into endothelial cells, has been implicated in oncogenesis via alteration of its canonical signalling pathway and noncanonical signalling pathway mediated by phosphorylation of key tyrosine and serine residues. 83 , 84 Indeed, mutation analysis revealed two novel, non‐synonymous heterozygous variants (NM_004431.5:c.2099T>C and NM_004431.5:c.2835G>T) in the EPHA2 tyrosine kinase domain to be significantly associated with KS in a cohort of HIV‐infected South African patients stratified by KS status. 58

3.2.2. Other KSHV‐associated pathologies

In addition to KS, rare (although likely underreported) KSHV‐associated pathologies MCD, PEL and KICS may develop in KSHV‐infected patients, particularly in the context of KSHV/HIV co‐infection.

Childhood MCD, like classic KS, may be favoured by rare inborn errors of immunity against KSHV infection as suggested by Leroy et al 85 in their report of a Comorian child born to consanguineous parents who presented with MCD at the age of 7. However, a study from Japan including 342 MCD patients found no evidence of family history. 86 A toll‐like receptor 4 (TLR4) SNP (NM_138554.5:c.896A>G, rs4986790) which results in decreased surface expression of TLR4, an important pattern recognition receptor in activation of the innate immune system, was associated with increased incidence of MCD in KSHV+ HIV‐1+ patients compared to non‐KSHV cancer controls and patients with KS 63 ; this SNP was further linked to patients with African ancestry. 87

KICS and PEL, under‐researched in themselves, are yet to be investigated in relation to genetic associations.

4. LIMITATIONS OF CURRENT REPORTS AND GENETIC ASSOCIATION STUDIES

The major limitation of genetic association studies, including those reported in this review, is lack of consistent replication due to the small number of studies conducted and difficulties related to case‐control association studies. Indeed, few associations reported here have been satisfactorily replicated yet, with the exception of the reported association of an IL6 promoter polymorphism (XM_011515390.2:c.‐84‐153C>G) with increased risk of AIDS‐related KS and iatrogenic KS, 41 , 42 the HLA‐B*1401 allele with increased risk of AIDS‐KS 51 , 52 and the HLA‐B*2702/5 haplotype with decreased risk of AIDS‐related KS. 51 , 53

Observed associations may well be ethnicity‐ and geography‐specific, especially with regards to HLA haplotypes, as allele frequencies vary and as such may not be able to be replicated in studies conducted in different populations. Even so, replicability is hindered by heterogeneous study populations, with proposed associated genetic polymorphisms potentially being artefacts of population stratification or other confounding factors between cases and controls. 88 Some populations included in studies reviewed here are ethnically diverse, particularly recently admixed populations, such as those from Brazil, 46 , 47 South Africa 58 and the United States. 51 Family studies, such as the report by Guttman‐Yassky et al 39 of the IL6 promoter GC genotype and the HLA‐DRB1*11 allele in a familial clustering of classic KS, are thought to bypass this limitation although these are limited in population applicability and statistical power and also require validation.

A narrowly defined phenotype to test in candidate association studies is important for consistent results. Lagging diagnostics, particularly of KSHV‐associated pathologies other than KS, are an issue. Even diagnosis of KSHV infection (by antibody response using various serological assays 23 , 46 , 58 or viral load in peripheral blood leukocytes 45 ) or KS (by clinical examination with or without indicated biopsy and histological confirmation, 50 , 52 , 58 with or without investigations for visceral KS and with or without tumour staging) is heterogeneously performed or not reported at all. For example, KSHV seropositivity may not be a consistently defined phenotype between studies, as Newton et al 23 noted disparity in KSHV seroprevalence estimates between their study and those previously reported due to the sensitivity of different serological assays (peptide based EIAs, protein ELISA and immunofluorescent assays). This highlights an underlying disjunction between the clinical and laboratory aspects of research. Clear and consistent diagnostic frameworks and phenotype standardization implemented in the clinical research setting is needed to overcome this in future studies. Further variability is introduced through differing laboratory techniques used to identify genetic polymorphism (eg, SNP screening using a commercial BeadArray genotyping platform of selected SNPs from candidate genes 51 vs Sanger sequencing of the entire coding region of candidate genes with a discovery approach 58 ), and future research would benefit from established guidelines to promote consistency. For instance, the numerous studies investigating HLA haplotypes reported here are certainly indicative of an association with KS, particularly in class I and II HLA types. However, the heterogeneity of studied populations and different HLA genotyping techniques (eg, targeted next generation sequencing method 52 vs PCR‐sequence based typing 50 ) used has led to inconsistent reports that require validation. 52 Careful attention should be paid to the design of future studies to ensure validity and reproducibility.

5. POTENTIAL TARGETS FOR FUTURE INVESTIGATION

While a significant amount of research has been conducted into genetic polymorphisms associated with KS development, it would be beneficial for future research to address the possibility of a host genetic contribution to a broader range of KSHV‐associated pathologies. As the prerequisite for all KSHV‐related disease developments, emphasis should be placed on understanding susceptibility to KSHV infection. KSHV entry (most recently reviewed by Kumar and Chandran 89 and Dollery 90 ) is therefore an interesting target for study, and recent advances in understanding these mechanisms offer many new candidate susceptibility genes for investigation. Further insights into KSHV infection mechanisms provide new potential candidate genes such as the androgen receptor, recently described by Wang et al, 91 to promote KSHV endocytosis and trafficking via EPHA2 serine phosphorylation.

While classic p53 mutations have not been implicated in KSHV‐associated pathologies, p53‐linked genes are under‐researched. A plausible candidate SNP for future studies is a homozygous variant (309 G/G) of the p53‐modulator, MDM2, which has been suggested as a potential risk factor for development of visceral KS, PEL or MCD after the heterozygous form was found to be associated with cutaneous classic KS in Caucasians and the homozygous form identified in a number of PEL cell lines. 59 , 92

Improved understanding of specific genes involved in KSHV infection and KSHV‐related disease causation may have implications in the development of new therapeutic targets, and candidate gene association studies are therefore a relevant avenue of research. Although many different genetic variants predisposing individuals to either KSHV infection and/or KSHV‐associated diseases appear to exist which makes designing a therapy against all of them rather difficult, there are a few promising candidate genes: familiar KS has been linked to inborn defects in T cell immunity, in particular T cell effector functions and possibly interferon signalling, 71 , 74 while genetic polymorphism associated with differing sensitivities to cytotoxic drugs have been reported, such as the EPHA2 substitution, NP_004422.2:p.Gly391Arg, which showed increased sensitivity to rapamycin 93 , 94 and low dose resistance to cisplatin 94 in human lung epithelial cells. Selected validated genetic variants conferring KSHV and KS susceptibility should therefore be assessed for drug sensitives.

6. CONCLUSIONS

The rationale for an underlying genetic risk of KSHV infection and subsequent KSHV‐associated disease development is well established in the literature through epidemiological observation. The numerous association studies reviewed here point to interesting candidate genes that may prove important in achieving a more nuanced understanding of the pathogenesis and therapeutic targeting of KSHV. Taken together (Figure 1), the studies reviewed here indicate a plausible connection between KSHV susceptibility and host genetic factors that may affect either host immunity to viral infection (perforin‐granzyme pathway, MBL, NK cell activation) or viral access to host cells via entry mechanisms (EPHA2 entry receptor). KSHV‐associated pathogenesis subsequent to infection is likely influenced by an orchestrated concert of innate immune system interactions (NK‐KIR‐HLA), downstream inflammatory pathways (interleukins, NK cell activation) and oncogenic mechanisms (EPHA2 oncogenic pathways). Infectious diseases and related pathologies are likely to become an increasing global public health burden, particular in parallel with the HIV epidemic and in the era of HAART. 95 Identifying genetically susceptible populations and affected genes in the pathogenesis of KSHV therefore remains an important scientific goal.

FIGURE 1.

FIGURE 1

Open in a new tab

Summary figure depicting the reviewed genetic factors associated with KSHV infection and KS development. KSHV infects endothelial cells and following lytic infection, establishes latency from which reactivation events can occur; KS develops from latently infected endothelial cells (grey box). Gene names in green text indicate an association with decreased risk; red text an association with increased risk. Details of the single nucleotide polymorphism or haplotype involved in these associations are found in Table 1 or in text. *Various HLA haplotypes are either protective or increase risk of KS development as detailed in Table 1. Figure created with BioRender.com

CONFLICT OF INTEREST

The authors have no competing interest.

AUTHOR CONTRIBUTIONS

Melissa J. Blumenthal and Georgia Schäfer conceptualised the review. Melissa J. Blumenthal performed the literature search and wrote the manuscript. Georgia Schäfer, Arieh A. Katz, Elena Maria Cornejo Castro and Denise Whitby contributed to the interpretation and critically revised the manuscript. All authors read and approved the final manuscript.

ACKNOWLEDGEMENTS

Not applicable.

Blumenthal MJ, Cornejo Castro EM, Whitby D, Katz AA, Schäfer G. Evidence for altered host genetic factors in KSHV infection and KSHV‐related disease development. Rev Med Virol. 2021;31:e2160. 10.1002/rmv.2160

Funding information Cancer Association of South Africa; Ernest Oppenheimer Memorial Trust; European and Developing Countries Clinical Trials Partnership, Grant/Award Number: TMA2018SF‐2446; Frederick National Laboratory for Cancer Research, Grant/Award Number: HHSN261200800001E; Harry Crossley Foundation; National Cancer Institute, Grant/Award Number: 75N91019D00024

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are openly available at PubMed (https://pubmed.ncbi.nlm.nih.gov/).

REFERENCES

  • 1. Martin JN. The epidemiology of KSHV and its association with malignant disease. In: Arvin A, Campadelli‐Fiume G, Mocarski E, et al., eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007:960‐985. [Google Scholar]
  • 2. de Sanjose S, Mbisa G, Perez‐Alvarez S, et al. Geographic variation in the prevalence of Kaposi sarcoma–associated Herpesvirus and risk factors for transmission. J Infect Dis. 2009;199(10):1449‐1456. 10.1086/598523. [DOI] [PubMed] [Google Scholar]
  • 3. Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10(10):707‐719. 10.1038/nrc2888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Thakker S, Verma SC. Co‐infections and pathogenesis of KSHV‐associated malignancies. Front Microbiol. 2016;7:1‐14. 10.3389/fmicb.2016.00151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Goncalves PH, Uldrick TS, Yarchoan Y. HIV‐associated Kaposi sarcoma and related diseases. Aids. 2017;31(14):1903‐1916. 10.1016/j.physbeh.2017.03.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Chang Y, Cesarman E, Pessin MS, et al. Identification of Herpesvirus‐like DNA sequences in AIDS‐associated Kaposi's sarcoma. Science. 1994;266:1865‐1869. [DOI] [PubMed] [Google Scholar]
  • 7. Cesarman E, Chang Y, Moore P, Said J, Knowles DM. Kaposi's sarcoma‐associated herpesvirus‐like DNA sequences in aids‐related body‐cavity‐based lymphomas. N Engl J Med. 1995;332:1186‐1191. [DOI] [PubMed] [Google Scholar]
  • 8. Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin‐6, interleukin‐10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV‐infected patients. Blood. 2000;96(6):2069‐2073. [PubMed] [Google Scholar]
  • 9. Polizzotto MN, Uldrick TS, Wyvill KM, et al. Clinical features and outcomes of patients with symptomatic Kaposi sarcoma Herpesvirus (KSHV)‐associated inflammation: prospective characterization of KSHV inflammatory cytokine syndrome (KICS). Clin Infect Dis. 2015;62(6):730‐738. 10.1093/cid/civ996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV‐MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol. 2012;3:1‐9. 10.3389/fmicb.2012.00073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Uldrick TS, Wang V, O'Mahony D, et al. An Interleukin‐6‐related systemic inflammatory syndrome in patients co‐infected with Kaposi sarcoma‐associated herpesvirus and HIV but without multicentric Castleman disease. Clin Infect Dis. 2010;51(3):350‐358. 10.1086/654798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Plancoulaine S, Abel L, Van Beveren M, et al. Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population. Lancet. 2000;356:1062‐1065. [DOI] [PubMed] [Google Scholar]
  • 13. Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll‐like receptor signaling controls reactivation of KSHV from latency. Proc Natl Acad Sci U S A. 2009;106(28):11725‐11730. 10.1073/pnas.0905316106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Wang QJ, Jenkins FJ, Jacobsen LP, et al. Primary human herpesvirus 8 infection generates a broadly specific CD8+ T‐cell response to viral lytic cycle proteins. Blood. 2001;97(8):2366‐2373. 10.1182/blood.V97.8.2366. [DOI] [PubMed] [Google Scholar]
  • 15. Mularoni A, Gallo A, Riva G, et al. Successful treatment of Kaposi sarcoma–associated Herpesvirus inflammatory cytokine syndrome after kidney–liver transplant: correlations with the human Herpesvirus 8 miRNome and specific T cell response. Am J Transplant. 2017;17(11):2963‐2969. 10.1111/ajt.14346. [DOI] [PubMed] [Google Scholar]
  • 16. Teruya‐Feldstein J, Zauber P, Setsuda JE, et al. Expression of human herpesvirus‐8 oncogene and cytokine homologues in an HIV‐seronegative patient with multicentric Castleman's disease and primary effusion lymphoma. Lab Invest. 1998;78(12):1637‐1642. [PubMed] [Google Scholar]
  • 17. Cook‐Mozaffari P, Newton R, Beral V, Burkitt DP. The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic. Br J Cancer. 1998;78(11):1521‐1528. 10.1038/bjc.1998.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Schäfer G, Blumenthal MJ, Katz AA. Interaction of human tumor viruses with host cell surface receptors and cell entry. Viruses. 2015;7:2592‐2617. 10.3390/v7052592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Boshoff C, Weiss RA. Epidemiology and pathogenesis of Kaposi's sarcoma‐associated herpesvirus. Philos Trans R Soc B Biol Sci. 2001;356(1408):517‐534. 10.1098/rstb.2000.0778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Dedicoat M, Newton R. Review of the distribution of Kaposi's sarcoma‐associated herpesvirus (KSHV) in Africa in relation to the incidence of Kaposi's sarcoma. Br J Cancer. 2003;88(1):1‐3. 10.1038/sj.bjc.6600745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Bourboulia D, Whitby D, Boshoff C, et al. Serologic evidence for mother‐to‐child transmission of Kaposi sarcoma‐associated Herpesvirus infection. JAMA. 1998;280(1):31‐32. 10.1001/jama.280.1.28. [DOI] [PubMed] [Google Scholar]
  • 22. Rohner E, Bütikofer L, Schmidlin K, et al. Comparison of Kaposi sarcoma risk in human immunodeficiency virus‐positive adults across 5 continents: a multiregional multicohort study. Clin Infect Dis. 2017;65(8):1316‐1326. 10.1093/cid/cix480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Newton R, Labo N, Wakeham K, et al. Kaposi sarcoma‐associated Herpesvirus in a rural Ugandan cohort, 1992‐2008. J Infect Dis. 2018;217(2):263‐269. 10.1093/infdis/jix569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Stolka K, Ndom P, Hemingway‐Foday J, et al. Risk factors for Kaposi's sarcoma among HIV‐positive individuals in a case control study in Cameroon. Cancer Epidemiol. 2014;38(2):137‐143. 10.1016/j.canep.2014.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Nalwoga A, Cose S, Nash S, et al. Relationship between anemia, malaria coinfection, and Kaposi sarcoma‐associated herpesvirus seropositivity in a population‐based study in rural Uganda. J Infect Dis. 2018;218(7):1061‐1065. 10.1093/infdis/jiy274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Biggar RJ, Whitby D, Marshall V, Linhares AC, Black F. Human herpesvirus 8 in Brazilian Amerindians: a hyperendemic population with a new subtype. J Infect Dis. 2000;181(5):1562‐1568. 10.1086/315456. [DOI] [PubMed] [Google Scholar]
  • 27. Mohanna S, Portillo JA, Carriquiry G, et al. Human herpesvirus‐8 in peruvian blood donors: a population with hyperendemic disease? Clin Infect Dis. 2007;44(4):558‐561. 10.1086/511044. [DOI] [PubMed] [Google Scholar]
  • 28. Zheng J, Yang Y, Cui M, et al. Prevalence of Kaposi's sarcoma‐associated herpesvirus in Uygur and Han populations from the Urumqi and Kashgar regions of Xinjiang, China. Virol Sin. 2017;32(5):396‐403. 10.1007/s12250-017-4049-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Labo N, Miley W, Benson CA, Campbell TB, Whitby D. Epidemiology of Kaposi's sarcoma‐associated herpesvirus in HIV‐1‐infected US persons in the era of combination antiretroviral therapy. AIDS. 2015;29(10):1217‐1225. 10.1097/QAD.0000000000000682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Iscovich J, Boffetta P, Franceschi S, Azizi E, Sarid R. Classic Kaposi sarcoma epidemiology and risk factors. Cancer. 2000;88(3):500‐517. [PubMed] [Google Scholar]
  • 31. Harwood AR, Osoba D, Hofstader SL, et al. Kaposi's sarcoma in recipients of renal transplants. Am J Med. 1979;67(5):759‐765. [DOI] [PubMed] [Google Scholar]
  • 32. Andreoni M, Goletti D, Pezzotti P, et al. Prevalence, incidence and correlates of HHV‐8/KSHV infection and Kaposi's sarcoma in renal and liver transplant recipients. J Infect. 2001;43(3):195‐199. 10.1053/jinf.2001.0899. [DOI] [PubMed] [Google Scholar]
  • 33. Grulich AE, Van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta‐analysis. Lancet. 2007;370:59‐67. [DOI] [PubMed] [Google Scholar]
  • 34. Ramos da Silva S, Elgui de Oliveira D. HIV, EBV and KSHV: viral cooperation in the pathogenesis of human malignancies. Cancer Lett. 2011;305(2):175‐185. 10.1016/j.canlet.2011.02.007. [DOI] [PubMed] [Google Scholar]
  • 35. Franceschi S, Geddes M. Epidemiology of classic Kaposi's sarcoma, with special reference to mediterranean population. Tumori. 1995;81(5):308‐314. 10.1177/030089169508100502. [DOI] [PubMed] [Google Scholar]
  • 36. Varmazyar S, Marashi SM, Shoja Z, et al. MDM2 gene polymorphisms and risk of classic Kaposi's sarcoma among Iranian patients. Med Microbiol Immunol. 2017;206(2):157‐163. 10.1007/s00430-016-0491-9. [DOI] [PubMed] [Google Scholar]
  • 37. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV‐8 in the increasing incidence of HIV‐associated multicentric Castleman's disease. Ann Oncol. 2009;20(4):775‐779. 10.1093/annonc/mdn697. [DOI] [PubMed] [Google Scholar]
  • 38. Cavallin LE, Goldschmidt‐Clermont P, Mesri EA. Molecular and cellular mechanisms of KSHV Oncogenesis of Kaposi's sarcoma associated with HIV/AIDS. PLoS Pathog. 2014;10(7):5‐8. 10.1371/journal.ppat.1004154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Guttman‐Yassky E, Cohen A, Kra‐Oz Z, et al. Familial clustering of classic Kaposi sarcoma. J Infect Dis. 2004;189(11):2023‐2026. 10.1086/386308. [DOI] [PubMed] [Google Scholar]
  • 40. Hengge UR, Ruzicka T, Tyring SK, et al. Review update on Kaposi's sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis. 2002;2:281‐292. [DOI] [PubMed] [Google Scholar]
  • 41. Foster CB, Lehrnbecher T, Samuels S, et al. An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus. Blood. 2000;96(7):2562‐2567. [PubMed] [Google Scholar]
  • 42. Gazouli M, Zavos G, Papaconstantinou I, et al. The Interleukin‐6‐174 promoter polymorphism is associated with a risk of development of Kaposi's sarcoma in renal transplant recipients. Anticancer Res. 2004;24(2 C):1311‐1314. [PubMed] [Google Scholar]
  • 43. van der Kuyl AC, Polstra AM, Jan Weverling G, Zorgdrager F, van der Burg R, Cornelissen M. An IL‐8 gene promoter polymorphism is associated with the risk of the development of AIDS‐related Kaposi's sarcoma: a case–control study. Aids. 2004;18:1203‐1216. [DOI] [PubMed] [Google Scholar]
  • 44. Brown EE, Fallin D, Ruczinski I, et al. Associations of classic Kaposi sarcoma with common variants in genes that modulate host immunity. Cancer Epidemiol Biomarkers Prev. 2006;15(5):926‐934. 10.1158/1055-9965.EPI-05-0791. [DOI] [PubMed] [Google Scholar]
  • 45. Alkharsah KR, Alzahrani AJ, Obeid OE. Vascular endothelial growth factor A polymorphism and risk of Kaposi's sarcoma herpesvirus viremia in kidney allograft recipients. Transpl Infect Dis. 2014;16:783‐789. 10.1111/tid.12277. [DOI] [PubMed] [Google Scholar]
  • 46. Gonçales JP, Silva Júnior JVJ, Lopes TRR, et al. Association of polymorphisms in NFκB1 promoter and NFκBIA gene with the development of antibodies against HHV‐8 in HIV‐infected individuals. Virology. 2019;535(July):255‐260. 10.1016/j.virol.2019.07.011. [DOI] [PubMed] [Google Scholar]
  • 47. De Morais VMS, De Lima ELS, Cahú GGDOM, et al. MBL2 gene polymorphisms in HHV‐8 infection in people living with HIV/AIDS. Retrovirology. 2018;15(1):1‐9. 10.1186/s12977-018-0456-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Lehrnbecher TL, Foster CB, Zhu S, et al. Variant genotypes of FcγRIIIA influence the development of Kaposi's sarcoma in HIV‐infected men. Blood. 2000;95(7):2386‐2390. [PubMed] [Google Scholar]
  • 49. Guerini FR, Mancuso R, Agostini S, et al. Activating KIR/HLA complexes in classic Kaposi's sarcoma. Infect Agent Cancer. 2012;7:1‐5. 10.1186/1750-9378-7-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Goedert JJ, Martin MP, Vitale F, et al. Risk of classic kaposi sarcoma with combinations of killer immunoglobulin‐like receptor and human leukocyte antigen loci: a population‐based case‐control study. J Infect Dis. 2016;213(3):432‐438. 10.1093/infdis/jiv413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Aissani B, Boehme AK, Wiener HW, Shrestha S, Jacobson LP, Kaslow R a. SNP screening of central MHC‐identified HLA‐DMB as a candidate susceptibility gene for HIV‐related Kaposi's sarcoma. Genes Immun. 2014;15(6):424‐429. 10.1038/gene.2014.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Cornejo Castro EM, Morrison BJ, Marshall VA, et al. Relationship between human leukocyte antigen alleles and risk of Kaposi's sarcoma in Cameroon. Genes Immun. 2019;20(8):684‐689. 10.1038/s41435-019-0077-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Dorak MT, Yee LJ, Tang J, et al. HLA‐B, ‐DRB1/3/4/5, and ‐DQB1 gene polymorphisms in human immunodeficiency virus‐related Kaposi's sarcoma. J Med Virol. 2005;76(3):302‐310. 10.1002/jmv.20361. [DOI] [PubMed] [Google Scholar]
  • 54. Azmandian J, Lessan‐Pezeshki M, Alipour Abedi B, Mahdavi‐Mazdeh M, Nafar M, Farhangi S. Posttransplant malignancies and their relationship with human leukocyte antigens in kidney allograft recipients. Iran J Kidney Dis. 2007;1(2):98‐101. [PubMed] [Google Scholar]
  • 55. Masala MV, Carcassi C, Cottoni F, Mulargia M, Contu L, Cerimele D. Classic Kaposi's sarcoma in Sardinia: HLA positive and negative associations. Int J Dermatol. 2005;44(9):743‐745. 10.1111/j.1365-4632.2004.02206.x. [DOI] [PubMed] [Google Scholar]
  • 56. Gaya A, Esteve A, Casabona J, et al. Amino acid residue at position 13 in HLA‐DR beta chain plays a critical role in the development of Kaposi's sarcoma in AIDS patients. Aids. 2004;18(2):199‐204. 10.1097/01.aids.0000096931.51231.14. [DOI] [PubMed] [Google Scholar]
  • 57. Aissani B, Wiener HW, Zhang K, et al. A candidate gene approach for virally induced cancer with application to HIV‐related Kaposi's sarcoma. Int J Cancer. 2014;134(2):397‐404. 10.1002/ijc.28351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Blumenthal MJ, Schutz C, Meintjes G, et al. EPHA2 sequence variants are associated with susceptibility to Kaposi's sarcoma‐associated herpesvirus infection and Kaposi's sarcoma prevalence in HIV‐infected patients. Cancer Epidemiol. 2018;56:133‐139. 10.1016/j.canep.2018.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Tornesello ML, Buonaguro L, Cristillo M, et al. MDM2 and CDKN1A gene polymorphisms and risk of Kaposi's sarcoma in African and Caucasian patients. Biomarkers. 2011;16(1):42‐50. 10.3109/1354750X.2010.525664. [DOI] [PubMed] [Google Scholar]
  • 60. Alkharsah KR, Dedicoat M, Blasczyk R, Newton R, Schulz TF. Influence of HLA alleles on shedding of Kaposi sarcoma–associated Herpesvirus in saliva in an African population. J Infect Dis. 2007;195(6):809‐816. 10.1086/511827. [DOI] [PubMed] [Google Scholar]
  • 61. Qi Y, Martin MP, Gao X, et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog. 2006;2(8):741‐745. 10.1371/journal.ppat.0020079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Marmor M, Winchester R, Zeleniuch‐Jacquotte A, et al. Evidence for an effect of human leukocyte antigens on susceptibility to Kaposi's sarcoma related to charge and peptide‐binding properties of class I molecules [2]. AIDS. 1995;9(10):1194‐1195. 10.1097/00002030-199510000-00013. [DOI] [PubMed] [Google Scholar]
  • 63. Lagos D, Vart RJ, Gratrix F, et al. Toll‐like receptor 4 mediates innate immunity to Kaposi sarcoma Herpesvirus. Cell Host Microbe. 2008;4:470‐483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37(6):564‐569. 10.1002/humu.22981. [DOI] [PubMed] [Google Scholar]
  • 65. Plancoulaine S, Gessain A, Van Beveren M, Tortevoye P, Abel L. Evidence for a recessive major gene predisposing to human Herpesvirus 8 (HHV‐8) infection in a population in which HHV‐8 is endemic. J Infect Dis. 2003;8:1944‐1950. [DOI] [PubMed] [Google Scholar]
  • 66. Pedergnana V, Gessain A, Tortevoye P, et al. A major locus on chromosome 3p22 conferring predisposition to human herpesvirus 8 infection. Eur J Hum Genet. 2012;20:690‐695. 10.1038/ejhg.2011.260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Grossman WJ, Radhi M, Schauer D, Gerday E, Grose C, Goldman FD. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV‐8. Blood. 2005;106(4):1203‐1206. 10.1182/blood-2005-03-0950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Matthews NC, Goodier MR, Robey RC, Bower M, Gotch FM. Killing of Kaposi's sarcoma‐associated herpesvirus‐infected fibroblasts during latent infection by activated natural killer cells. Eur J Immunol. 2011;41(7):1958‐1968. 10.1002/eji.201040661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Cottoni F, Masala MV, Santarelli R, et al. Susceptibility to human herpesvirus‐8 infection in a healthy population from Sardinia is not directly correlated with the expression of HLA‐DR alleles [12]. Br J Dermatol. 2004;151(1):247‐249. 10.1111/j.1365-2133.2004.06060.x. [DOI] [PubMed] [Google Scholar]
  • 70. Ford PW, Hamden KE, Whitman AG, McCubrey JA, Akula SM. Vascular endothelial growth factor augments human herpesvirus‐8 (HHV‐8/KSHV) infection. Cancer Biol Ther. 2004;3(9):876‐881. 10.4161/cbt.3.9.1054. [DOI] [PubMed] [Google Scholar]
  • 71. Camcioglu Y, Picard C, Lacoste V, et al. HHV‐8‐associated Kaposi sarcoma in a child with IFNγR1 deficiency. J Pediatr. 2004;144(4):519‐523. 10.1016/j.jpeds.2003.11.012. [DOI] [PubMed] [Google Scholar]
  • 72. Picard C, Mellouli F, Duprez R, et al. Kaposi's sarcoma in a child with Wiskott‐Aldrich syndrome. Eur J Pediatr. 2006;165(7):453‐457. 10.1007/s00431-006-0107-2. [DOI] [PubMed] [Google Scholar]
  • 73. Sahin G, Palanduz A, Aydogan G, et al. Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds. Pediatrics. 2010;125(3):e704‐e708. 10.1542/peds.2009-2224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Byun M, Abhyankar A, Lelarge V, et al. Whole‐exome sequencing‐based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J Exp Med. 2010;207(11):2307‐2312. 10.1084/jem.20101597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Yap JY, Gloss B, Batten M, et al. Everolimus‐induced remission of classic Kaposi's sarcoma secondary to cryptic splicing mediated CTLA4 Haploinsufficiency. J Clin Immunol. 2020;40:774‐779. 10.1007/s10875-020-00804-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76. Miles SA, Rezai AR, Salazar‐González JF, et al. AIDS Kaposi sarcoma‐derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990;87(11):4068‐4072. 10.1073/pnas.87.11.4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AEGK, de Haas M. FcgRIIIa‐158V/F polymorphism influences the binding of IgG by natural killer cell FcgRIIIa, independently of the FcgRIIIa‐48L/R/H phenotype. Blood. 1997;90(3):1109‐1114. [PubMed] [Google Scholar]
  • 78. Pollack MS, Safai B, Myskowski PL, Gold JWM, Pandey J, Dupont B. Frequencies of HLA and Gm immunogenetic markers in Kaposi's sarcoma. Tissue Antigens. 1983;21(1):1‐8. 10.1111/j.1399-0039.1983.tb00364.x. [DOI] [PubMed] [Google Scholar]
  • 79. Kaloterakis A, Papasteriades C, Filiotou A, Economidou J, Hadjiyannis S, Stratigos J. HLA in familial and nonfamilial Mediterranean Kaposi's sarcoma in Greece. Tissue Antigens. 1995;45(2):117‐119. 10.1111/j.1399-0039.1995.tb02427.x. [DOI] [PubMed] [Google Scholar]
  • 80. Berber I, Altaca G, Aydin C, et al. Kaposi's sarcoma in renal transplant patients: predisposing factors and prognosis. Transplant Proc. 2005;37(2):967‐968. 10.1016/j.transproceed.2004.12.034. [DOI] [PubMed] [Google Scholar]
  • 81. Bubic‐Filipi L, Basić‐Jukić N, Pasini J, Kastelan Z, Kes P. Clinical features of Kaposi's sarcoma in Croatian renal transplant recipients. Prilozi. 2009;30(2):175‐184. [PubMed] [Google Scholar]
  • 82. El‐Agroudy AE, El‐Baz MA, Ismail AM, Ali‐El‐Dein B, El‐Dein ABS, Ghoneim MA. Clinical features and course of Kaposi's sarcoma in Egyptian kidney transplant recipients. Am J Transplant. 2003;3(12):1595‐1599. 10.1046/j.1600-6135.2003.00276.x. [DOI] [PubMed] [Google Scholar]
  • 83. Zhou Y, Sakurai H. Emerging and diverse functions of the EphA2 noncanonical pathway in cancer progression. Biol Pharm Bull. 2017;40(10):1616‐1624. 10.1248/bpb.b17-00446. [DOI] [PubMed] [Google Scholar]
  • 84. Hahn AS, Kaufmann JK, Wies E, et al. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus. Nat Med. 2012;18(6):961‐966. 10.1038/nm.2805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85. Leroy S, Moshous D, Cassar O, et al. Multicentric Castleman disease in an HHV‐8‐infected child born to consanguineous parents. Pediatrics. 2012;129(1):199‐203. 10.1542/peds.2010-2739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Murakami M, Johkoh T, Hayashi S, et al. Clinicopathologic characteristics of 342 patients with multicentric Castleman disease in Japan. Mod Rheumatol. 2020;30:1‐9. 10.1080/14397595.2019.1704983. [DOI] [PubMed] [Google Scholar]
  • 87. Westrop SJ, Lagos D, Boshoff C, Bower M, Imami N. African ancestry and innate immunity contribute to the incidence of multicentric Castleman's disease in HIV‐1/Kaposi's sarcoma herpesvirus‐ coinfected individuals. Future Virol. 2012;7(7):729‐734. 10.2217/fvl.12.54. [DOI] [Google Scholar]
  • 88. Daly AK, Day CP. Candidate gene case‐control association studies: advantages and potential pitfalls. Br J Clin Pharmacol. 2001;52(5):489‐499. 10.1046/j.0306-5251.2001.01510.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Kumar B, Chandran B. KSHV entry and trafficking in target cells—hijacking of cell signal pathways, Actin and membrane dynamics. Viruses. 2016;8(305):1‐23. 10.3390/v8110305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Dollery SJ. Towards understanding KSHV fusion and entry. Viruses. 2019;11(1073):1‐17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91. Wang X, Zou Z, Deng Z, et al. Male hormones activate EphA2 to facilitate Kaposi's sarcoma‐associated herpesvirus infection: implications for gender disparity in Kaposi's sarcoma. PLoS Pathog. 2017;13(9):1‐23. 10.1371/journal.ppat.1006580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Boulanger E, Marchio A, Hong SS, Pineau P. Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/β‐catenin genes in human herpesvirus 8‐associated primary effusion lymphoma. Haematologica. 2009;94(8):1170‐1174. 10.3324/haematol.2009.007260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Faoro L, Singleton PA, Cervantes GM, et al. EphA2 mutation in lung squamous cell carcinoma promotes increased cell survival, cell invasion, focal adhesions, and mammalian target of rapamycin activation. J Biol Chem. 2010;285(24):18575‐18585. 10.1074/jbc.M109.075085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Tan YHC, Srivastava S, Won BM, et al. EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma. Oncogenesis. 2019;8(9):49. 10.1038/s41389-019-0159-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95. Blumenthal MJ, Ujma S, Katz AA, Schäfer G. The role of type 2 diabetes for the development of pathogen‐associated cancers in the face of the HIV/AIDS epidemic. Front Microbiol. 2017;8:1‐10. 10.3389/fmicb.2017.02368. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are openly available at PubMed (https://pubmed.ncbi.nlm.nih.gov/).

Articles from Reviews in Medical Virology are provided here courtesy of Wiley

RESOURCES