Flare-ups of past infections with herpes viruses, hepatitis C and mycobacterial infections after commencing Highly Active Antiretroviral Therapy, known as immune restoration diseases, may be associated with particular genetic patterns, say Australian researchers.
The findings, published this week in the online edition of the journal AIDS, show that mutations in genetic regions that code for several inflammatory cytokine are associated with the development of CMV retinitis and other clinical events associated with herpes viruses soon after commencing HAART, and with inflammatory reactions to mycobacterial infections such as tuberculosis.
The study compared DNA sequences from five genes in 36 patients who experienced inflammatory reactions after commencing HAART, together with a control group of 33 patients who experienced immune restoration without inflammatory reaction on HAART. An HIV-negative control group of 154 HIV-negative bone marrow donors was also included.
The five gene sequences selected for analysis were IL1A-889, IL1B+3935, IL6-174, TNFA-308 and IL12B—3’UTR. Polymorphisms in IL1A-889 and IL1B+3953 were not found to differ between the three groups, but a polymorphism in the TNF alpha gene (308*2) was found to be significantly associated with herpes virus-related illnesses after the initiation of HAART (25 individuals, including 5 cases of CMV retinitis) (p=0.042).
An allele in the interleukin-6 gene was found to be rarer in people who experienced inflammatory reactions to mycobacterial infections (MAI and tuberculosis) (p=0.05), and these reactions occurred only in individuals who were homozygous for TNFA-308*1. Homozygosity at this allele together with non-carriage of IL6-174 was associated with a threefold increased risk of immune restoration disease (p=0.014).
The authors suggested that carriers of the TNF-alpha polymorphism may have less capacity to produce TNF-alpha and clear residual mycobacterial infection, leading to a T-cell response that becomes pathogenic in this group of patients.
Individuals who developed herpes virus-associated illnesses after starting HAART were 80% less likely to carry the *2 allele in the IL12B-3’UTR region compared to other HIV patients (p=0.0043), and hepatitis C flare-ups (defined as > 3-fold increase in serum ALT) were also more common in those without this allele (p=0.024).
The findings illustrate the potential importance of immunogenetics (the study of genetic variations between the immune systems of humans) in predicting responses to therapy. Earlier this year the same research group identified the genetic correlates of abacavir hypersensitivity reaction in Australian patients.
Click here for further information on immune restoration diseases in HIV, and details of previous research.
Price P et al. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 16: 2043-2047, 2002.