HLA and predisposition to infectious diseases

A) viruses

EBV : individuals carrying the HLA-A*02 allele have a reduced risk of developing EBV+ HL, while individuals carrying the HLA-A*01 allele have an increased risk. It is known that HLA-A*02 can present EBV-derived peptides and can evoke an effective immune response, which may explain the protective phenotypE (ref)

HIV-1 :

• HLA-B*57 (Migueles et al., 2000; Altfeld et al., 2003; Miura et al., 2009) and HLA-B*27 (Goulder et al., 1997; Feeney et al., 2004; Altfeld et al., 2006; Schneidewind et al., 2007): lower viral loads in the chronic phase and slow disease progression
• HLA-B*35-Px alleles including HLA-B*35:02, B*35:03, and B*35:04 associate with rapid disease progression, whereas the latter HLA-B35-Py alleles including HLA-B*35:01 and HLA-B*35:08 associate with relatively slower progression (Gao et al., 2001). Such differences in disease progression among HLA-B subtypes are also known in HLA-B*58 (Leslie et al., 2010).
• the HLA-B*57, -B*14, -C*8 alleles, and mainly -B*27, were found to be negatively associated with progression of the disease, and they are possible protective factors
• HLA-B*18 allele was associated with a significantly lower risk of early HIV-1 vertical transmission. An increase in the early acquisition of HIV-1 was also observed in children who had the HLA-A*29 allele. Transmission is increased if the fetus or the newborn has the HLA-DRB1*03:011 allele, while the HLA-DR13 antigen and the HLA-DRB1*1501 allele would appear to protect against infection
• HLA-A*3601 allele was associated with greater risk of developing tuberculosis in HIV-positive patients
• HLA-A*6802 appears to facilitate rapid progression to pleural disease and to allow mycobacterial replication that is difficult to control
• HLA-A1, -B8, -DR3 antigens are protective factors against infection by cytomegalovirus and by the Mycobacterium avium Complex (MAC) in HIV patients with severe immunodeficiency and that have not yet been submitted to highly effective antiretroviral therapy

HIV-2 :

• HLA-B*53 allele and HLA-B*35-Cw*4 and -A*23-Cw*7 haplotypes were associated with a greater risk of progression to AIDS [92].

Dengue virus :

• in Thail patients who acquired the disease after a second infection, the HLA-A*02:03 allele was associated with dengue fever, irrespective of the viral serotype; -A*02:07 with severe hemorrhagic dengue by serotypes 1 and 2; -B*51 with hemorrhagic dengue on second exposure to the virus; -B*52 with dengue fever in patients with secondary infection by serotypes 1 and 2, and the antigens HLA-B*44, -B*62, -B*76 and -B*77 were negatively associated with the development of the disease after secondary infection.
• in Mexico, individuals who had the HLA-DR4 antigen had 3.6 times less chance of developing hemorrhagic dengue after primary infection, when compared with individuals who did not have this antigen
• in Brazil with patients who had contracted dengue fever after the first infection with serotype 1, the HLA-DQ1 antigen was associated with this disease, while no significant association was found with the HLA-DR1 antigen

HTLV-1 :

• HLA-DR15 and -DQ1 antigens were found with greater frequency in patients with the virus when compared with healthy controls, while the HLA-DRB1*1501, -DRB1*1101 and -DQB1*0602 alleles were observed with greater frequency in patients with leukemia/lymphoma of adult T cells than in those with tropical spastic paraparesis
• HLA-DRB1*1101-DQB1*0301 and -DRB1*1501-DQB1*0602 haplotypes were more frequent in patients with neoplasia than in those with myelopathy
• patients with a HLA-A*02 allele had a 50% lower risk of developing myelopathy, while the presence of -DRB1*0101 conferred a risk two times greater, in the absence of the protective HLA-A*02
• HLA-Cw*08 allele with protection against the disease and low viral load in asymptomatic patients
• HLA-A*02 and -Cw*08 alleles prevented 36% of the potential cases of myelopathy and that HLA-B*54:01 was associated with a greater risk of developing myelopathy

Hepatitis B virus (HBV)

• HLA-DPB1*05:01 homozygotes have significantly lower post-booster anti-HBs titers (ref)
• HLA-DRB1*1302 [100,102] and -A*0301[100] alleles were found to be associated with greater elimination of the viral infection.
• persistence of infection was associated with HLA-B*08 and with the haplotypes HLA-A*01-B*08-DRB1*03, -B*44-Cw*1601 and -B*44-Cw*0501
• HLA-DRB1*0301, -DQA1*0501 and -DQB1*0301 alleles are associated with susceptibility to chronic liver disease by the B virus
• HLA-DRB1*1101, -DRB1*1104 and -DQA1*0301 are associated with less evolution to chronicity
• HLA-A24 and -Cw1 antigens were found to be associated with a lower risk of developing chronic hepatic disease, as were HLA-B13, -B8, -DR7, -DR13 and -DQ3
• HLA-DR6 antigen, more specifically -DR13, appears to be associated with self-limiting hepatitis B

Hepatitis C virus (HCV) :

• HLA-A*03, -B*27, -DRB1*0101, -DRB1*0401 and -DRB1*15 alleles are associated with eliminating the virus in the acute stage of the disease.
• HLA-A*2301 and -Cw*04, on the contrary, are associated with the persistence of HCV in the hepatic cells. The HLA-DRB1*13 allele is associated with progression to chronic liver disease [108], whereas the absence of hepatic disease or the light form of the disease is associated with HLA-DRB1*11.
• HLA-DQB1*0301 allele was associated with more effective viral elimination in Blacks
• in Whites, viral suppression was associated with the HLA-DRB1*0101 allele and with the HLA-DRB1*0101-DQB1*0501 haplotype, while the permanence of the virus was associated with the HLA-DRB1*0301 allele and with the HLA-DRB1*0301-DQB1*0201haplotype
• HLA-DR13 antigen is negatively associated with the risk for vertical transmission
• HLA-DQB1*0301 and -DRB1*11 alleles with a self-limiting infection
• supertype DRB3 (prevalence ratio (PR)=0.4; P=0.004) was associated with HCV persistence, whereas DR8 (PR=1.8; P=0.01) was associated with HCV clearance. HLA-B*57:03 (PR=1.9; P=0.008) and DRB1*07:01 (PR=1.7; P=0.005)ref

HHV-6 encephalopathy after allo-HSCT : HLA-B*40:06 (P=0.027), in linkage with HLA-A*26:01 and HLA-C*08:01  (P<0.001)ref

JCV : alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite associationref.

BKV : HLA C7 negative donors and recipientsref, and  HLA-A28 and A68 positive recipientsref have sustained viremia, while recipient HLA-A2 and donor HLA-A9 increased the risk of BKPyVANref. HLA-B51-positivity reduced the risk of viremia approximately five-fold (HR 0.18) (Wunderink et al. 2018)

VZV : HLA-A*33 and HLA-B*44 are significantly enriched in PHN patients, while HLA-A*02 and HLA-B*40ref.

B) bacteria

Mycobacterium tuberculosis :

• HLA-DRB2*1501 and -DRB1*1502 is associated with the development of severe and multibacillary forms of tuberculosis, as well as with the greater prevalence of forms resistant to drug therapy. The HLA-DRB1*07 and -DQA1*0101 alleles are associated with greater susceptibility to the development of pulmonary tuberculosis and the HLA-DQA1*0301 and -DQA1*0501 alleles are associated with protection against this infection
• HLA-DPB1*04 allele with protection against tuberculosis, while -DRB1*1501 and -DQB1*0601 are associated with susceptibility. Mehra et al. (1995) reported association of the HLA-DRB1*1501 allele with susceptibility to tuberculosis, emphasizing the importance of the HLA-DRB1*1501-DRB5*0101-DQA1*0103-DQB1*0601 haplotype. The diversity of the HLA antigens in populations from different ethnic-racial origins can be demonstrated by means of a few examples. In Poles, it was suggested that the HLA-DR16 antigen increases the risk of developing tuberculosis, while the antigen HLA-DR13 protects against the disease. In India, the results are controversial. One study showed that the HLA-A10, -B8 and -DR2 antigens presented with greater frequency in persons with tuberculosis than in healthy controls, while another did not find any association between HLA class II antigens and pulmonary tuberculosis.

Mycobacterium leprae (Hansen's disease, leprosy) :

• Some studies suggest associations of the HLA-DR2 and -DR3 antigens with the tuberculoid form and the HLA-DQ1 antigens with the virchowian form of Hansen's disease.
• contaminated individuals had a greater frequency of the alleles HLA-A*0203, -A*0206, -A*1102, -B*1801, -B*4016, -B*5110, -Cw*0407 and -Cw*0703 and a lower frequency of HLA-A*0101, -A*0211, -B*4006, -Cw*03031, -Cw*04011 and -Cw*0602 [22].
• HLA-DRB1*1502 allele is positively associated with the development of Hansen's disease, and that the HLA-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0502 haplotype is associated with protection
• HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype was associated with susceptibility to leprosy
• high frequency of the HLA-DRB1*1501 and -DRB1*1502 alleles in patients with the multibacillary and tuberculoid form and of -DQA1*0103 in those who had the virchowian form. The HLA-DQA1*0102 allele was more frequent in patients with the light form of the disease. On the other hand, the HLA-DRB1*0701, -DQB1*0201 and -DQB1*0503 alleles were less frequent in patients with the multibacillary form, when compared with patients with the tuberculoid form; in this latter group there was a low frequency of the HLA-DQB1*0503 allele. Thus, patients that presented with HLA-DR2 and -DQ1 antigens, especially the HLA-DRB1*1501, -DQB1*0601 and -DQA1*0103 alleles, are considered to be more susceptible to developing severe forms of this disease, multibacillary lepromatous leprosy. The HLA-DRB1*0701, -DQB1*0201 and -DQA1*0201 alleles would appear to protect against the severe forms of the disease and -DQB1*0503 against the lighter forms.
• the HLA-A*1102-B*4006-Cw*1502, HLA-A*0203-B*4016-Cw*0703 and HLA-A*11-B*40 haplotypes were associated with protection against the multibacillary form
• in Brazil, Marcos et al. (2000) found no association of the ulcerated type 1 hansen reaction (manifestation of hypersensitivity due to bacillary multiplication) with HLA class II antigens [10]. However, Miller et al. (2004) suggested an association of molecules coded by genes from the HLA-DQA region with the occurrence of this disease. Another study, also conducted on Brazilians, found a positive association between the HLA-DR2 antigen and the tuberculoid form of Hansen's disease.

C) Parasites

Plasmodium spp. (malaria) :

• increased frequency of the HLA-B46 and -B56 antigens and of the HLA-DRB1*1001 allele were found among groups of patients with severe non-cerebral and cerebral malaria [40]. An association with the HLA-B53 antigen and protection against severe forms of the disease is well established, reducing the risk of death by up to 40%. The HLA-DRB1*1302-DQB1*0501 haplotype appears to protect against severe forms. As this association is related to parasitic antigens present in the hepatic stage of the illness, it may influence the development of vaccines that use this antigen as one of their components. In India, increased frequency of the HLA-A3, -B27 and -B49 antigens and of the HLA-DRB1*04 and -DRB1*0809 alleles were found. In the same population the HLA-A19, -A34, -B18, and -B37 antigens and the HLA-DQB1*0203 allele were associated with protection. Johnson et al. (2000) suggested that immunity against Plasmodium falciparum varies in accordance with the individual's age. They indicated that the HLA-DQB1*0301 and -DQB1*03:03:2 alleles only showed age-dependent association with the levels of antibody against rRAP1 proteins of the plasmodium in children from 5 to 15 years old. After this age, immunity against malaria becomes independent of these two alleles. The HLA-DRB1*03:011 allele is associated with higher levels of antibody against the parasite's rRAP2 protein in adults over 30 years of age. These data suggest that the effect of HLA on the evolution of infection by malaria differs in accordance with age, that it is stimulated by different antigens of the plasmodium, and that HLA is able to influence the quantity of antibodies to be produced against the parasite.

Leishmania donovani (cutaneous and visceral leishmaniasis)

• HLA-Cw7 antigen as a marker of susceptibility to cutaneous leishmaniasis
• HLA-A11, -B5, -B7, -Bw2 and -DQw3 antigens were found to be associated with an increased susceptibility to cutaneous leishmaniasis
• HLA-DR2, with greater protection
• HLA-A26 antigen is associated with the occurrence of kala-azar

Schistosomiasis.

• hepatosplenomegaly and its severity to the occurrence of the HLA-A1 (HLA-A*01) and -B5 (HLA-B*5106) antigens 
• greater degree of hepatic fibrosis with the HLA-A2 (HLA-A*02) and -B12 (-B*4409) antigens
• lower degree of hepatic fibrosis with the HLA-DR2 (HLA-DRB1*1603 or -DRB1*1605) antigen 
• HLA-B5 (-B*85106) and -DR3 (-DRB1*0306) antigens with schistosomiasis mansoni [61].
• HLA-DRB1*12:02 and -DQA1*06:01 alleles are considered to be protectors against the advance of hepatic fibrosis, since these two alleles frequently co-occur, although their individual protective effects have not yet been explained. In patients with an advanced degree of hepatic fibrosis, the presence of the HLA-DQB1*05:031 allele is common, while the HLA-DQA1*06:01 allele is considered to be protective. The HLA-DRB1*15:01-DRB5*01:01 haplotype is associated with an advanced degree of hepatic fibrosis, and the HLA-DRB1*11:01-DQA1*05:01-DQB1*03:01, -DQA1*01:03-DPB1*02:01 haplotypes are associated with protection against fibrosis. Recently McManaus et al. (2001) associated the HLA-DRB1*0901, -DRB1*13:02, -DQB1*03:03 and -DQB1*06:09 alleles with greater susceptibility to advanced hepatic fibrosis. The HLA-DRB1*15:01 and -DQB1*06:01 alleles appear to be protective. Although many factors are involved in the inflammatory process of hepatic fibrosis, the HLA genes, mainly the HLA-DRB5*01:01 allele, seem to be among the main factors that affect its prognosis. The heterogeneity of the studies available till now on hepatic fibrosis does not allow consistent conclusions to be drawn

Trypanosoma cruzi (Chagas' disease)

• HLA-A30 antigen confers increased susceptibility
• HLA-DQB1*06 allele confers protection, irrespective of whether its form of presentation is cardiac or digestive [66].
• a greater frequency of HLA-B39 and -DR4 antigens was found in patients with Chagas' disease [67]. The patients with cardiomyopathy exhibited a greater frequency of HLA-B35 antigens [67]. In these same patients, there was an increased frequency of the HLA-DR16 antigen when compared with asymptomatic patients and with healthy controls. Thus, the HLA-DR4 and -B39 antigens may be associated with infection by T. cruzi; -DR16 with susceptibility to the cardiac condition, and -A68 with protection against cardiomyopathy [67]. In Venezuelans, a greater frequency of the HLA-C*03 allele was observed in patients with the cardiac form of Chagas' disease [69], and a low frequency of the HLA-DRB1*14 and -DQB1*0303 alleles was found in seropositive patients, inhabitants of an endemic region, suggesting the protective effect of these alleles against chronic infection [70]. Among seropositive patients, when comparing those with and without cardiomyopathy, high frequencies of the HLA-DRB1*01, -DRB1*08 and -DQB1*0501 alleles and low frequencies of-DRB1*1501 [69] were found in the cardiomyopathic group. Another study on this population in an endemic region revealed an association of the HLA-DRB1*01-DQB1*0501 haplotype with cardiomyopathy [71]. The HLA-DRB1*01-DQB1*0501-DPB1*0401 haplotype is mentioned by Fernández-Mestre et al. (2002) as a marker of susceptibility to Chagas' disease in Venezuela [72], while HLA-DRB1*14-DQB1*0301 was associated with non-infection by T. cruzi in individuals inhabiting a highly endemic area in Peru [73]. Overtvelt et al. (2002) demonstrated that HLA class I also participates in the escape mechanism of T. cruzi from the immune response, associating greater expression of some of these molecules with longer persistence of the parasite in the host organism without eliciting an immune response [74]. In Chile, high levels of HLA-B40 and -Cw3 antigens were found in seropositive patients without cardiac disease, suggesting a protective function of the HLA genes responsible for the expression of these antigens [75]. When comparing chronic cardiomyopathy patients with others that presented with cardiac transplant rejection and with a third group, made up of patients with dilated cardiomyopathy secondary to another etiology, greater expression of HLA class I was perceived in the cardiomyocytes of the first two groups [76]. In contaminated but asymptomatic patients, when compared with those that developed Chagas' disease cardiomyopathy, a greater frequency of the HLA-A68 and -B39 antigens was observed in the former

Podoconiosis :

• HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701–DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis.

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