Genetic susceptibility

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Receptors

Certain gene mutations or polymorphisms may cause resistance to HIV infection by inhibiting the expression of CCR5 or CXCR4 or changing the way these receptors are expressed.

A mutation is a change in the nucleotide sequence of genetic material. It can be hereditary or acquired, caused by the environment, certain types of radiation, or by chance or error. Many mutations are caused by copying errors in cell division. Most mutations are neutral in their effect on the host; others can have a positive or negative effect. A positive mutation is a step in the evolutionary process.

A polymorphism is a permanent variation in DNA sequence that occurs in at least 1% of the population. Polymorphisms usually result from a single amino acid change in the protein structure, known as a single nucleotide polymorphism, or SNP. This single base change affects susceptibility to some conditions or diseases, such as HIV, malaria, glucose-6-phosphate dehydrogenase deficiency (G6PD), and thalessemia. A polymorphic (or abnormal) haemoglobin gene from both parents can result in sickle cell anaemia. Millions of SNPs have been identified in humans.

The CCR5-delta 32 mutation has been associated with up to a 31% lower risk of disease progression, and the CCR2 64I polymorphism with up to a 26% lower risk of progression.1 2

The CCR2 64I polymorphism is associated with a significantly longer time to achieve a CD4 cell count below 200 cells/mm3 in European patients.3 This polymorphism has been found to be more prevalent amongst Africans and Asians than amongst Europeans, whilst the CCR5-delta 32 mutation is largely confined to people of northern European descent. The CCR2 64I polymorphism has also been associated with an increased risk of male-to-female transmission of HIV.4

The interaction between chemokine receptor polymorphisms and HIV infection is complex, with effects on progression rates being linked to duration of infection, younger age, and injecting drug use.2 5 For example, CCR2 64I provides the greatest protection early in the course of HIV infection. In injecting drug users the CCR5-delta 32 and the CCR2 64I polymorphisms did not significantly affect progression.6

A CCR5 mutation called 356T increases CD4 T-cell susceptibility to HIV infection. This mutation occurs in 20% of African Americans and is common in people from West Africa. It may increase the likelihood of transmission and speed of disease progression. The chemokine receptor CX3CR1 contains a polymorphism called T/M280 that has been linked to accelerated HIV progression and a polymorphism called V/I249 that is associated with more rapid disease progression.7 8

Cytokines and chemokines

Genetic variations in cytokines and chemokines, such as interleukin-4 and interleukin-10, can affect the rate of disease progression.9 Similarly, levels of chemokines such as RANTES, MIP-1 alpha, and MIP-1 beta may also effect disease progression. The production of these chemokines is regulated by the production of interleukin-7, which may influence pathogenesis.10 11

Recently, researchers found a strong correlation between a genetic pattern associated with slower CD4 cell loss in untreated people and stronger CD4 cell gains after starting treatment, suggesting that these genes regulate the pathway determining susceptibility to immune depletion and impaired immune recovery.12

Host factor differences in the gene copy number of CCL3L1 (a potent HIV-suppressive chemokine that binds to CCR5) and in HIV co-receptor CCR5 polymorphisms can alter cell-mediated response to infection and independently influence HIV transmission, viral burden, disease course, and degree and durability of immune reconstitution.13 A low copy number of the gene for CCL3L1 is associated with a markedly increased risk of HIV disease progression.14 15

The CCL3L1-CCR5 genotypes favouring CD4 T-cell recovery are similar to those that retard CD4 T-cell depletion in the absence of HAART, indicating a common CCL3L1-CCR5 genetic pathway influencing both pathogenic and reparative processes from the time of HIV acquisition. Differences in the CCL3L1-CCR5 response provide a genetic basis for individual as well as population differences in response to infection and to antiretroviral treatment.12

One study that looked at response to ARV treatment between a cohort in the US and one in Uganda found that a low gene dose of CCL3L1 predicted poorer CD4 outcomes in the Ugandan cohort, regardless of viral load.12 Variations in the CCL3L1 gene dose and CCR5 genotype particularly influence immune reconstitution when HAART is initiated at less than 350 cells/mm3. Knowing the CCL3L1 gene dose could prospectively identify patients for whom HAART should be started earlier (before a CD4 count of less than 350 cells/mm3)and monitored closely. The use of CCL3L1 analogues might also promote immune reconstitution.13

In a further study, researchers categorised the copy number of the CCL3L1 gene and variations in the CCR5 gene into three groups designated as high, moderate, and low genetic risk groups. In estimating likelihood of disease progression, researchers found that CCR5 polymorphisms and gene dose of CCL3L1 had a predictive value equal to that provided by CD4 cell counts and viral load measurements.

Using gene risk grouping, researchers were also better able to predict progression to AIDS, even when lab markers did not.13 In an analysis of two other cohorts, using results from an additive risk-scoring system and classification and regression tree, the combination of laboratory and genetic markers offered more prognostic information than either set of markers alone.16 

Human leukocyte antigens

The specific combination of genes for human leukocyte antigens (HLAs) a person has, known as their HLA type, can also effect HIV disease progression. HLA plays an important role in triggering immune responses.

As much as a six-fold difference in the rate of disease progression may result from HLA type. In addition, people with identical gene pairs for HLA-A and HLA-B progress to AIDS more rapidly.17 18 Furthermore, a diverse range of HLA variations may slow disease progression. HIV adapts to the most frequent HLA alleles, providing an advantage to people with rare alleles. Dubbed HLA ‘supertypes’, rare alleles are associated with superior immune responses to HIV.19

People with HLA class I genes B14 and C8 tend to experience slow or non-progression of HIV, whereas those with HLA class I genes A29 and B22 are likely to experience rapid progression.20 In addition, A1, B14, B44, B27, and B57 or B5701 are associated with non-progression.21 B5701 is highly associated with long-term non-progression. However, it seems that this HLA-type is not the single determinant of non-progression, given that in another study, 19 of 200 progressors also had B5701.22 In contrast, rapid progression of HIV disease has been linked to HLA B54, B55, and B56.23

It is not fully understood how HLA influences disease progression, but it is likely that HLA molecules associated with slow disease progression may allow for recognition of a wider range of viral antigens by CD8 cytotoxic T-cells. ref]

Other factors

The human protein APOBEC3G is an antiviral protein that inhibits viral replication by altering the HIV DNA produced by reverse transcriptase. HIV’s viral infectivity factor (Vif) protein specifically inhibits APOBEC3G’s activity. Variations in the human APOBEC3G gene affect the speed of HIV disease progression. One variant, H186R, is common in African Americans and associated with increased disease progression.24

References

  1. Ioannidis JP et al. Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis. AIDS 17: 1631-1638, 2003
  2. Mulherin SA et al. Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection. AIDS 17: 377-387, 2003
  3. Easterbrook PJ et al. Chemokine receptor polymorphisms and human immunodeficiency virus disease progression. J Infect Dis 180: 1096-1105, 1999
  4. Lockett SF et al. Mismatched human leukocyte antigen alleles protect against heterosexual HIV transmission. J Acquir Immune Defic Syndr 27: 277-280, 2001
  5. Inversen AK et al. Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus. J Infect Dis 187: 215-225, 2003
  6. Schinkel J et al. No evidence of an effect of the CCR6 delta32/+ and CCR2b 64I/+ mutations on HIV-1 disease progression among HIV-1-infected injecting drug users. J Infect Dis 179: 825-831, 1999
  7. Faure S et al. Deleterious genetic influence of CX3CR1 genotypes on HIV-1 disease progression. J Acquir Immune Defic Syndr 32: 335-337, 2003
  8. Singh KK et al. Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load. J Infect Dis 191: 1971-1980, 2005
  9. Vasilescu A et al. Genomic analysis of Th1-Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression. Genes Immun 4: 441-449, 2003
  10. Koning FA et al. Decreasing sensitivity to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization of CC chemokine receptor 5-using, non-syncytium-inducing virus variants in the course of human immunodeficiency virus type 1 infection. J Inf Dis 188: 864-872, 2003
  11. Llano A et al. Interleukin-7-dependent production of RANTES that correlates with human immunodeficiency virus disease progression. J Virol 77: 4389-4395, 2003
  12. Ahuja SK et al. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nat Med 14(4): 413-20, 2008
  13. Dolan MJ et al. CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 8(12):1324-1336, 2007
  14. Mackay CR CCL3L1 dose and HIV-1 susceptibility. Trends Mol Med 11: 203-206, 2005
  15. Gonzalez E et al. The influence of CCL3L1 gene-containing segmental duplications on HIV/AIDS susceptibility. Science 307: 1434-1440, 2005
  16. Kulkarni H et al. CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals. PLoS ONE Sep 8;3(9): e3165, 2008
  17. Kaslow RA et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2: 405, 1996
  18. Tang J et al. HLA class I homozygosity accelerates disease progression in human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 15: 317-324, 1999
  19. Trachtenberg E et al. Advantage of rare HLA supertype in HIV disease progression. Nat Med 9: 928-935, 2003
  20. Hendel H et al. New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 162: 6942-6946, 1999
  21. Guerin J et al. Nonprogressors in the Australian long-term nonprogressor cohort: proportions and predictions. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 454, 2003
  22. Migueles SA et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A 97: 2709-2714, 2000
  23. Dorak MT et al. Influence of human leukocyte antigen-b22 alleles on the course of human immunodeficiency virus type 1 infection in 3 cohorts of white men. J Infect Dis 188: 856-863, 2003
  24. An P et al. APOBEC3G genetic variants and their influence on the progression to AIDS. J Virol 78: 11070-11076, 2004
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