Epidemiological studies of genetic polymorphisms in human populations have enabled new ways to understand antiviral response and immune activation during HIV infection. The natural course of HIV infection is characterized by considerable variations among infected individuals, and is related to both viral and host factors, including genetic differences.
One of the first studies addressing this question was the description of almost complete protection from HIV infection conferred by homozygosity of a 32 base deletion in CCR5 (CCR5-l32) or a mutation in CCR2 (CCR2-64I) [110
]. They provide strong protection and are found more frequently in LTNP than in rapid progressors.
Moreover, certain HLA alleles are associated with control of virus replication and slower progression to AIDS [111
]. For virus replication control, a strong CTL response is crucial. CTLs are activated by binding to antigenic peptides presented by HLA, initiating the immune response. Many studies report the effect of HLA polymorphisms on the progression of AIDS [112
]. Many HLA alleles have been correlated with rapid disease progression, as HLA-A24, -A29, -B35, -C4, -DR1, and -DR3, whereas patients carrying HLA-B14, -B27, -B57, -C8, or -DR6 appear to develop AIDS more slowly [114
]. It is known that LTNPs remain asyntomatic and clinically healthy for more than 10 years without therapy [116
]. A number of studies [118
] have shown a higher frequency of the HLA-B27 and HLA-B57 alleles in this group of patients, suggesting also a role of these alleles in the pathogenesis of HIV [111
]. It has been shown that CD8+
T cells of individuals expressing HLA-B27 or -B57, targeted a defined and highly conserved region within the HIV-1 p24 Gag (amino acids 240 to 272) early in infection, and responses against this region contributed over 35% to the total HIV-1-specific T cell responses in these individuals. In contrast, this region was rarely recognized in individuals expressing HLA alleles associated with rapid disease progression [121
The HLA genotyping could help identifying those patients with either a mild or aggressive course of their natural HIV-1 infection. This might influence the timing to start HIV therapy and allow a risk stratification that could be relevant in countries with limited access to antiviral drugs. Moreover, under antiretroviral therapy, HLA type may influence the risk of developing drug-resistant viruses, and therefore address the choice of drug regimens in naïve patients. Finally, since HLA loci vary by ethnic groups and regions, it may affect the response to specific vaccines in different parts of the world.
Recently, the association between polymorphisms in the inflammasome component NLRP3 and susceptibility to HIV infection has been demonstrated and adds to other studies linking inflammasome activation and IL-1/IL-18 production with HIV pathogenesis [122
For the association of TLRs polymorphisms and HIV-induced inflammation, somewhat more insight exists. One study reported an association between two single nucleotide polymorphisms (SNP)s in TLR9 and rapid HIV progression as measured by CD4+
T cell decline [123
], although the investigators did not evaluate the precise effect of these SNPs on TLR9 signalling. In contrast, a different TLR9 polymorphism has been linked to slow disease progression and found less frequently among individuals with high viral set point [124
]. In addition, a frequent functional TLR7 polymorphism resulting in significantly less IFN-α
production has been associated with accelerated disease progression and may also be associated with increased HIV susceptibility, since this mutation was present more frequently in patients than in controls [125
]. The importance of TLR7 signalling was further supported by a recent article demonstrating sex differences in the TLR7-mediated response of pDCs to HIV: pDCs from women produce markedly more IFN-α
in response to HIV-derived TLR7/8 ligands than pDCs from men, resulting in a higher degree of immune activation in women for a given viral load [126
]. At the genetic level, this may be explained by the fact that TLR7 is X-linked and therefore women may have higher expression of this receptor due to unbalanced X-inactivation. Clinically, the more robust IFN-α
response in women is translated into women exhibiting lower viral loads early in infection but progressing faster to AIDS for any given viral load [127
]. Taken together, these studies support the idea of type I IFN having dual functions, including antiviral activities and immune activation.
Combination therapy with Peg-IFN plus ribavirin is the standard treatment for patients with chronic HCV infection [128
]. However, it eradicates HCV in only about half of the patients infected with genotype 1. The outcome of IFN-based therapy for HCV is dependent on the genetic systems of both the human host and the virus. Host genetic factors that influence the outcome of therapy include gender, race, and variation in genes of the immune system.
The dominant role of the immune-modulator IFN-α
in treating HCV infection has driven an extensive search for genetic associations between components of the immune system and outcome of therapy [129
To date, the most prominent human genetic associations with outcome of therapy are SNPs within the IL28B gene. The strongest association was found for SNP rs12979860, located about 3
kb upstream of the IL28B coding region. Patients with a CC genotype at this SNP were more than twice as likely to achieve sustained virologic response (SVR) as patients with a CT or TT genotype [132
]. Suppiah et al. [133
] estimated that the cumulative effect of the favorable allele at the IL28B locus is to increase SVR by 32% relative to a population in which the allele is absent. The favorable association of the CC genotype was found in patients of both European and African-American descent, and differential prevalence of the CC genotype explained approximately half of the twofold poorer response rate to treatment found in African Americans. Several reports have associated failure of response also with the presence of SNP rs8099917 and rs12980275. All these associations were shown to be significant for genotypes 1 and 4 but not for genotypes 2 and 3 [134
The IL28B gene encodes the type 3 IFN, namely, IFNλ
that has been shown to inhibit HCV replication; so the variations in the IL28B gene mutations presumably affect the efficacy of the innate immune response against HCV during therapy [134
Interestingly, the pretreatment expression levels of genes involved in IFN-stimulated genes (ISGs) have been found to be related to treatment outcome. The allele OASL rs12819210 constitutes an important independent factor that is significantly associated with SVR in peg-IFN-plus-ribavirin treatment, notably improving the predictive value of IL-28B rs12979860. In addition to OASL and IL-28B, the IFIT1 rs304478 A/A genotype favors a better therapy outcome, especially in patients with HCV-1 [136
The most common associations with clearance after primary infection has been with the class II alleles, DQB1*0301, and DRB1*1101 which are in close linkage disequilibrium. It has been demonstrated that immunodominant HCV epitopes are presented by DRB1*1101 [137
] and that T cell lines recognize HCV peptides presented by DQB1*0301 [138
]. Similarly, another allele that has been associated with HCV clearance, DRB1*0101, was associated with a greater magnitude and broader range of epitope responses in an HCV-specific T cell proliferation assay [139
By contrast, only very few of class I HLA allele associations have been described in association with clearance of HCV viremia. KIR2DL3 and its ligand, HLA-C1 has been associated with an increased likelihood of spontaneous and treatment-induced HCV clearance [140
]. It has been postulated that this gene combination is protective because the KIR2DL3 binds HLA-C with a lower avidity than other inhibitory KIR and thus NK cells expressing this specific inhibitory receptor have a lower threshold for activation [143
NK cells are also inhibited by the heterodimeric receptor CD94
NKG2A, which has the oligomorphic MHC class I molecule HLA-E as ligand. In a genetic study, homozygosity for the HLA-ER
allele has been shown to be protective against chronic infection with HCV genotypes 2 and 3 [145
]. This protective effect was thought to be due to an effect on HLA-E-restricted T cells, although the HLA-ER
allele may have a lower affinity for peptides and hence be expressed at lower levels. This could, therefore, lead to less inhibition of NK cells via the CD94
NKG2A receptor [146
]. The presence of HLA-B27 allele has also been associated with viral clearance [147
] and a functional mechanism for this effect has been reported with the recognition of an HLA-B27 restricted CD8 epitope [148
Genetic associations with outcome of therapy have also been reported for the genes encoding KIR2DL5, IL-6, IL-12B, IL-18, CCL5, TNF-α
, osteopontin, GNB3, and CTLA4. Several SNPs of TLR, relevant adaptor molecules and cytokines mediated by TLR signaling can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute infection has not been elucidated [149
]. However, other studies have failed to find associations with many of these genes. The inconsistencies in these data appear to be due to differences among the studies in racial make-up and HIV co-infection status of the cohorts, the definition of therapeutic response, the therapy employed (IFN-α
monotherapy, IFN plus ribavirin, or pegylated IFN plus ribavirin), and the HCV genotype infecting the study participants.
Other immunogenetic polymorphism have recently been reported to influence outcome of HCV infection such as polymorphisms of the promoter region of the IL-10 gene with the IL-10-592 AA genotype associated with self limiting infection, and the IL-10-1082GG genotype associated with persistent infection [150
]. Another study demonstrated an association between the IL-10 ATA haplotype (IL-10-1082A, -819T, -592A) and spontaneous HCV clearance [151
]. The authors postulated that the reduced production of IL-10 associated with this haplotype may result in a Th1-polarized CD4+
T cell response, which may be associated with enhanced viral elimination.
The presence of polymorphisms of the TGF-β
1 gene promoter that reduce expression of TGF-β
1 is also associated with increased rates of clearance of HCV infection [152
Simultaneous genotyping for all these SNPs could be a useful tool for individualizing antiviral therapy for chronic hepatitis C.