Influence of host genes on HIV-1 disease progression

^a Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Département de Microbiologie et Infectiologie, Campus Notre-Dame, Montréal, Québec, Canada H2L 4M1

	ABSTRACT

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
The role of host genes in the course of HIV-1 infection has been examined in different populations and among all major risk groups. Two extended human lymphocyte antigen (HLA) haplotypes, HLA A1-Cw7-B8-DR3-DQ2 and HLA A11-Cw4-B35-DR1-DQ1, are found to be associated with a faster progression to AIDS. The complement C4 factor and tumor necrosis factor genes of the major histocompatibility complex, as well as the mannose binding protein gene, have also been suggested to influence the outcome of AIDS. The recent discovery that chemokine receptors could serve as cofactors for HIV-1 cell entry has prompted a search for polymorphisms in chemokine receptor genes. A 32 base pair inactivating deletion in the CCR5 gene and a point mutation within the CCR2b gene resulting in a conservative amino acid substitution have been examined and shown to be independently associated with delayed disease progression. Together, these observations strongly support a genetic component in AIDS pathogenesis. This article synthesizes the current state of knowledge about the influence of host genes on HIV-1 disease progression. It provides a summary of all significant association studies reported so far. The role of the allelic polymorphism in these genes is discussed with regard to the immunopathogenesis of AIDS.—Roger, M. Influence of host genes on HIV-1 disease progression. FASEB J. 12, 625–632 (1998)

Key Words: immunopathogenesis of AIDS • risk factors in HIV-1 disease progression

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
PROSPECTIVE STUDIES OF large cohorts of HIV-1-infected subjects have clearly indicated that the rates of progression of HIV disease may vary greatly among individuals. Although most individuals infected with HIV develop AIDS within a median period of 10 years, approximately 10% of HIV-infected subjects progress to AIDS within the first 2 to 3 years of seroconversion (rapid progressor), and approximately 5 to 10% remain asymptomatic and have stable CD4⁺ T lymphocyte counts 10 years after seroconversion (nonprogressor) (1–6). Risk factors that influence the development of clinical disease and survival time of HIV-infected individuals are poorly defined. The rate of CD4⁺ T lymphocyte counts decline (7); plasma HIV-1 RNA measurements (7–9) and the viral phenotype (10) are considered prognostic indicators of AIDS progression rather than risk factors in and of themselves. Differences in disease progression between transmission groups and of gender are not significant (11, 12). Age at the time of HIV infection has been suggested to be a determinant of outcome among adults (13), but adults of similar ages show highly variable rates of disease progression (1, 3, 4). Genetic variability of HIV-1 virus may influence the rate of disease progression. Deletions in the HIV-1 nef gene are associated with nonprogressing infections (14, 15), but nef alterations do not appear to account for most cases of nonprogressing HIV-1 infection (16).

A growing body of evidence suggests that host genetic factors play an important role both in susceptibility to HIV infection and progression to AIDS. Animal studies indicate that the resistance to murine-acquired immunodeficiency syndrome varies among host strains and maps to the H-2 complex (17), the mouse homologue of human lymphocyte antigen (HLA)² locus. In a large study of twins born to HIV-1-infected mothers, the concordance rate for infection status was higher among monozygotic than dizygotic twins (18). In a study of 95 pairs of HIV-1-infected hemophiliac brothers, sibling pairs sharing one or two HLA class II haplotypes were significantly concordant in the rate of HIV disease progression (19). Numerous investigations have suggested an influence of HLA alleles and closely linked genes of the major histocompatibility complex (MHC) on HIV-1 disease progression. Non-MHC genetic factors such as members of the family of receptors for ß-chemokine (CCR) genes and mannose binding protein (MBP) gene have also been proposed to determine the course of HIV-1 disease. Considerable progress has been made recently in determining the immunogenetic factors that influence HIV disease progression, which provides new insight in understanding the pathogenesis of HIV infection. This paper will review the most recent data on the host genetic factors controlling HIV disease progression.

	MHC GENE COMPLEX

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
The MHC gene complex, located on chromosome 6, contains many individual genes that regulate the immune function. This complex is composed of HLA class I (A, B, C, E, F, G)/class II (DM, DP, DQ, DR) alleles and genes encoding for transporter for antigen processing (TAP), low molecular weight polypeptides of the proteasome, complement component factors (Bf, C2, C4), and tumor necrosis factors (TNF-, TNF-ß) (20). The role of host HLA genes in AIDS progression has been examined in different populations and among most major risk groups ( Table 1). Two extended haplotypes, HLA A1-Cw7-B8-DR3-DQ2 (21–31) and HLA A11-Cw4-B35-DR1-DQ1 (23, 25, 32–35), were found in several studies to be associated with a faster progression to AIDS as measured by various outcomes including CD4 T cell decline, AIDS vs. HIV-1 + AIDS-free, and time to AIDS. However, one study (25) reported an association between DR1 and slow CD4 T cell decline. Associations were also reported between faster HIV-1 disease progression and other HLA types: A23 (30, 31), A24 (22), A26 (30, 31), B21 (25), B38 (31). Conversely, some studies have shown associations between delayed AIDS progression and DR4 (25, 26), DR7 (30–32), B17 (36), B27 (28, 30, 31), B51 (30), and B57 (30, 31). Certain class II DR5 and DR6 alleles are associated in some studies with rapid progression to disease (26, 30–32), but correlate with slow disease progression in another study (37).

The exact role of HLA haplotypes in AIDS progression remains elusive. Several theories have been proposed to explain the associations between HLA haplotypes and HIV-1 disease progression (38, 39). One possible mechanism is the variable ability of different HLA molecules in presenting the HIV-1 antigen and inducing a strong immune response. One can speculate that HLA molecules such as HLA B35, associated with the accelerated progression of AIDS, fail to present HIV-1 cytotoxic T lymphocyte (CTL) epitopes. In a recent study, Tomiyama et al. (40) demonstrated that although HLA B35 molecules were able to present many HIV-1 CTL epitopes, natural mutations of HLA B35-restricted HIV-1 CTL epitopes affect the recognition of CTL by mechanisms that reduce peptide binding and T cell receptor (TCR) recognition. Another proposed mechanism is based on HLA mimicry of the HIV-1 gp 120 region. Considerable homology between DR5 and DR6 products and the COOH-terminal region of the HIV-1 envelope V3 loop has recently been observed (37). In this study, DR alleles were associated with delayed progression to AIDS, and it was proposed that these alleles may bias the anti-HIV TCR repertoire through a mimicry mechanism. They suggested that HLA mimicry could influence the outcome by deletion of self-reactive CD8 T cells that would otherwise be injurious to the host by destroying HIV-infected CD4 T cells.

Do HLA genes influence disease progression or do they simply reflect the associations of other unknown linked loci? Investigators have seldom considered the complex interrelationships produced by linkage disequilibrium among HLA genes themselves or with other non-HLA genes of the MHC (41). Linkage disequilibrium arises when alleles at different loci occur more frequently than would be expected from random association. This phenomena was emphasized by recent studies in which two North American cohorts and one European cohort typed serologically for HLA class I antigens and molecularly for HLA DR, DQ, and TAP antigens were analyzed (30, 31). The researchers were able to extract information from combinations of MHC genes that is missed by traditional allele or haplotype-based analysis. Association with rapid disease progression was observed for certain class I alleles when TAP alleles were present and with different class I alleles when TAP alleles were absent. Conversely, TAP 2.3 was associated with a prolonged disease-free interval when it occurred in conjunction with yet another set of class I markers or certain class II alleles ( Table 1). The identification of combinations of TAP variants and class II alleles as risk factors in disease progression is surprising, because TAP gene products are not known to play a direct role in facilitating events in class II processing as they do for class I. Furthermore, the TAP polymorphisms found in these combinations are not associated with any functional deficiency of the transporter (42). Consequently, the TAP alleles may simply be surrogate markers for closely linked disease genes. The same situation could apply for the association of HLA DR1 and DR3-containing haplotypes and the increased rate of HIV-1 disease progression to AIDS. The TNF- and TNF-ß genes have been shown to be in linkage disequilibrium with the HLA DR3 haplotype (43–46). Several groups have demonstrated a variation in TNF inducibility in individuals with different HLA types (47–49): the DR3 + phenotype is associated with increased levels of TNF-. Tumor necrosis factors play an important role in the immunopathogenesis of AIDS. They can induce expression of HIV through activation of the transcription factor NF-B (50), and increased levels of TNF- have been demonstrated in many patients with AIDS (51). The direct role of TNF genes in HIV disease progression has recently been assessed ( Table 1). A microsatellite (TNF-c2) located in the first intron of the TNF-ß gene was recently associated with slow progression to AIDS (52). Another study found no association between four polymorphisms in the promotor region of the TNF- gene and HIV-1 disease progression (53); however, this study was not powerful enough to draw any solid conclusions from it. The HLA DR3 and DR1 haplotypes associated with faster disease progression also contained the complement C4A and C4B null alleles, respectively (23), which result in relatively low total C4 plasma concentrations and impaired antibody responses (54). Both C4 null alleles have been shown to be associated with rapid progression to AIDS (23, 55) ( Table 1). However, among HIV-1-infected persons, plasma C4 levels do not appear to correlate with disease status (56).

	CHEMOKINE RECEPTORS

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
The chemokines are classified into two major families, C-X-C (or ) and C-C (or ß), according to the configuration of a conserved two-cysteine motif in their primary sequences. The ß-chemokines RANTES, macrophage inflammatory protein 1 (MIP-1), MIP-1ß, and the -chemokine stromal cell-derived factor 1 (SDF-1) are potent in vitro inhibitors HIV-1 virus (57–60). The exact role of these chemokines in HIV-1 disease progression remains unclear. In a recent study (61), no significant associations were observed between plasma levels of RANTES, MIP-1, MIP-1ß, and progression to AIDS in terms of viral burden, levels of neopterin, and levels of CD8 T cells. However, several chemokine receptors have been shown to serve as HIV-1 cell entry cofactors. The CCR5 chemokine receptor that selectively binds RANTES, MIP-1, and MIP-1ß appears to be the main coreceptor for macrophage tropic or nonsyn~cytium-inducing (NSI) HIV-1 strains (62, 63), whereas the T cell tropic or syncytium-inducing (SI) strains preferentially use the SDF-1 chemokine receptor CXCR4 (59, 60). Some HIV-1 isolates are dual tropic in being able to use both CCR5 and CXCR4 receptors (64, 65). A limited proportion of strains can also use additional chemokine receptors: CCR3, CCR2b, and possibly CCR1 (63–66). A longitudinal study of children with progressive HIV-1 infection demonstrated that viral isolates obtained during asymptomatic stages generally used only CCR5 as coreceptor whereas the majority of the strains derived after the progression of the disease have acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage (67).

Three independent groups identified a mutant allele containing a 32 base pair deletion in the open reading frame of the CCR5 gene (32-CCR5) that induces a frame shift, a premature stop codon, and loss of a HIV-1 coreceptor activity (68–70). The frequency of this mutant allele is approximately 1% in the homozygous state and 10 to 20% for the heterozygous state among Caucasians in North America or Europe, but is lower or absent in subjects of African, Asian, and Latin American heritage (68, 69, 71–76). Genetic analysis of more than 5000 persons from multiple AIDS cohorts has suggested that individuals homozygous for the mutant allele are resistant to HIV-1 infection (68, 69, 71–75), although three cases of infection have recently been described in such subjects (77–79). The HIV-1 strains were characterized in two of three patients and found to display the SI phenotype, which can use the CXCR4 receptor (77, 78). Heterozygous individuals do not appear to be more resistant to HIV infection than those bearing two functional CCR5 alleles (68, 71–75). Only Samson et al. (69) found a significantly lower frequency of heterozygosity among HIV-1-infected individuals. Several studies in different populations and among all majors risk groups have suggested a protective effect of the deletion on HIV-1 disease progression ( Table 2). Dean et al. (68) examined the course of HIV infection (time to AIDS) in six U.S. AIDS cohorts with different exposure to HIV (homosexuals, intravenous drug users, hemophiliacs) and found that individuals with one copy of the deleted CCR5 gene had a significant delayed (2 to 4 years) progression to AIDS when compared with those harboring the homozygous wild-type genotype. Similar findings in HIV-infected homosexual men have been reported by three other groups (72, 73, 75). Two other studies have shown a tendency toward delayed progression, but a significant level was not found (71, 74). The protective effect of the deletion on disease progression was significant only during the first 7 years of follow-up in some studies (71, 74, 75), whereas in other studies the slower progression persisted over a follow-up period of 12 years (72, 73). The proportion of heterozygotes among long-term nonprogressor groups was greater compared to the progressor group. This observation was significant in homosexual cohorts (68, 72, 73) but not in a hemophilia cohort (68). The rate of CD4 T cell decline was significantly lower in heterozygous homosexual individuals (71, 75). Heterozygous patients had a slightly but significantly lower viral loads during the post-seroconversion plateau phase (71, 74). Together, these observations strongly suggest that the CCR5 genotype influences the course of HIV-1 infection. However, this mutation accounts for only a small proportion of long-term survivors who continue to resist AIDS-defining illness 10 to 20 years after seroconversion. The great majority of highly exposed HIV-seronegative persons tested in these studies are not homozygous for this deletion, and more than 60% of long-term survivors are homozygous for the wild-type allele (68, 71–73).

The importance of chemokine receptors in HIV-1 infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A point mutation in the CCR2b gene (CCR2b-64I) has recently been identified. Compared to the 32-CCR5 mutation, which is unique to Caucasian ethnic groups and results in a nonfunctional chemokine receptor, the CCR2b-64I polymorphism is found in many different ethnic groups and encodes a conservative amino acid substitution (80). Genetic analysis of five AIDS cohorts revealed that although the CCR2b-64I polymorphism exerts no influence on susceptibility to HIV-1 infection per se, HIV-1-infected individuals heterozygous for this allele progressed to AIDS 2 to 4 years later than subjects homozygous for the wild-type allele (80) ( Table 2). The researchers who previously analyzed the CCR5 mutation with the same cohorts of patients (68) showed that CCR2b-64I protection is as strong as and independent of 32-CCR5 influence. According to Smith et al. (80), the survival of approximately one-quarter of HIV-1-infected, long-term survivors who avoid AIDS for more than 16 years can be attributed to their CCR2b/CCR5 genotype. However, Michael et al. (81) failed to detect the CCR2b-64I association with delayed onset of AIDS with the San Francisco Men's Health Study AIDS cohort ( Table 2). Some argue (82) that the failure of Michael's group to detect CCR2b association relates to cohort structure and study design.

	MANNOSE BINDING PROTEIN

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
The MBP is a calcium-dependent lectin with an important role in innate immunity: it activates complement and phagocytosis. It acts as an opsonic factor and can bind various pathogens, including HIV virus (83). Low serum concentrations of MBP can lead to an opsonic defect (84, 85) and are the result of three independent nucleotide substitutions in exon 1 (86, 87) and polymorphisms in the promotor region of the MBP gene (88). Genetic analysis of MBP variants in Caucasian Danish homosexual men showed an association between homozygosity for the variant alleles at the three exon 1 loci and increased susceptibility to HIV-1 infection (89). These variant alleles were also significantly associated with a shorter survival time after diagnosis of AIDS. The rate of disease progression could not be assessed accurately because the investigators did not know the date of seroconversion for any of the HIV-infected patients. Although the serum lectin concentration correlated with the MBP genotypes, it did not differ significantly among patients in different stages of the disease. Because MBP-associated serine protease uses C4 to activate the complement system (90), the researchers proposed that variant C4 null alleles associated with faster progression to AIDS (23, 55), together with MBP variant alleles, are cofactors in HIV disease progression.

	CONCLUSION AND FUTURE DIRECTIONS

TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 
The association of AIDS outcome with certain HLA haplotypes and mutations in the chemokine receptors genes supports a genetic component in AIDS pathogenesis. However, numerous discrepancies were observed among the studies, and may reflect the heterogeneity of HIV disease and host genes as well as biases in study designs. HIV disease displays the characteristics of a complex trait in that there are increased risks to relatives that increase with the closeness of relation (twin studies), and there is no clear simple inheritance pattern. Therefore, the observed phenotype could be influenced by multiple genes working independently (heterogeneity) or in interaction (epistasis) and by nongenetic factors (91). Evidence for the interaction of genetic host factor and viral phenotype in determining HIV disease progression is provided by Michael et al. (72), who found a distinct survival advantage against disease progression in 32-CCR5 heterozygotes with NSI isolates. Apparent incongruities between studies may occur simply because the distribution of alleles differs from one population to another, and thus one allele could not be associated in one population because it is simply too rare to detect. This is probably the case in MHC studies, where the genes are highly polymorphic and the sample sizes are usually too small to produce reliable associations. Genetic association studies in mixed population can lead to spurious associations because of unrecognized differences in allele frequencies among population subgroups that are represented unequally in the samples compared. Such population stratification is the major confounding factor in association studies and can be due to either recent admixture of different populations or by inappropriate matching of cases and controls (91, 92).

These are some of the problems that can hamper the genetic dissection of a complex trait such as AIDS. As suggested by Lander and Schork (93), we need to investigate more homogeneous populations of different ethnicities. In fact, genomic search for association may be more favorable in young, genetically isolated populations because linkage disequilibrium extends over greater distances and the number of disease-causing alleles is likely to be less (94). Almost all studies in this field have been of Caucasian populations in developed countries, even though most infected individuals worldwide live outside these areas and almost nothing is known of genetic susceptibility in developing countries and in other races. Future studies that examine HLA association with AIDS progression need to use larger sample sizes than those reported so far and should include a more thorough analysis of genes closely linked to HLA in order to more precisely locate the disease-causing locus. Given the importance of the chemokine receptors in AIDS pathogenesis, they should be investigated further and correlated with the virus phenotypes. In the near future, the application of new technologies, such as the genome-wide scan, could unravel new loci and allow for a better understanding of AIDS pathogenesis.

	ACKNOWLEDGMENTS

 
The author thanks Dr. François Coutlée for critical reading of the manuscript. The author is a chercheur-boursier from Fonds de la Recherche en Santé du Québec (FRSQ).

	FOOTNOTES

 
¹ Correspondence: Département de Microbiologie et Infectiologie, Campus Notre-Dame-CHUM, 1560 rue Sherbrooke Est, Montréal, Québec, Canada H2L 4M1. E-mail:

² Abbreviations: HLA, human lymphocyte antigen; MHC, major histocompatibility complex; CCR, ß-chemokine; MBP, mannose binding protein; TAP, transporter for antigen; CTL, cytotoxic T lymphocyte; TCR, T cell receptor; MIP, macrophage inflammatory protein; SDF, stromal cell-derived factor; NSI, nonsyncytium-inducing; SI syncytium-inducing; TNF, tumor necrosis factor.

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TOP ABSTRACT INTRODUCTION MHC GENE COMPLEX CHEMOKINE RECEPTORS MANNOSE BINDING PROTEIN CONCLUSION AND FUTURE DIRECTIONS REFERENCES

 

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