A genome armed against HIV

Steve OBrien of the NCI reviewed the understanding gained by his group and others over the past decade on human genes which either reduce or increase the transmission of HIV and the progression of HIV infection to AIDS.

The best known protective human genetic trait is the delta 32 deletion in the chemokine receptor CCR5. Along with the CD4 receptor, HIV requires a chemokine co-receptor, most often CCR5 to enter cells. About 1% of white Northern Europeans carry a 32-base pair deletion (termed delta 32) of CCR5 on both copies of their CCR5 genes that does not impair immune function but prevents infection by CCR5-using strains of HIV. Phylogenenetic have shown that this mutation occurred after migration of humans from Africa to Northern Europe.

Linkage disequilibrium analysis suggests that the delta 32 event happened about 700 years ago, around the time of the Black Death, an epidemic of plague in Europe. Studies in transgenic mice in whom the CCR5 gene has been disrupted and expression of CCR5 is knocked out have shown that yersinia pestis, the plague bacteria, replicates with 30-fold lower efficiency in the macrophages of these mice. So it is argued that the Black Death exerted a selective pressure on Northern Europeans, resulting in some who carry a gene that generations later provides protection against a second, viral, plague.

Since the discovery of the delta 32 CCR5 mutation, at least 4 other mutations have been described that affect CCR5 receptor, and several other human leukocyte antigen (HLA) markers have been found that regulate T cell function and either increase or decrease risk of acquisition or progression of HIV. Six variations in genes related to the innate immune system (primitive immune responses not enacted by T or B cells) have also been described that alter the risk of HIV infection or disease.

OBrien and others have searched for relationships between known human genotypes or haplotypes for relationships to the risk of HAART failure, post-HAART survival, and HAART-related toxicities. Many genetic markers have been found that have a statistical relationship to increased or decreased risk of progression to AIDS after HAART. However, thus far, these relationships are very complex, and it is not yet possible to guide clinical practice by genetic screening. However, this is certainly the goal of this work in the future.

OBriens group is now studying 332 single nucleotide polymorphisms (single site DNA variations in the human genome) within 8 known ARGs in a sample of over 2600 HIV-infected patients. The group hopes to construct a genetic map to predict risk of HIV disease and complications. The group is working out methods and controls for this endeavor, but OBrien is optimistic that a genome-wide scan for useful ARGs can be performed.

Overall, various genetic markers, or AIDS restriction genes (ARGs) can be shown to increase the relative risk (>2.0) of morbidity and mortality in HIV infection. That is to say that those with such genes have a 2-fold increased risk of morbidity or mortality despite HAART. However, only about 10% of the total risk is explained by ARGs. This is similar to studies attempting to predict the risk of lung cancer, in which factors such as smoking increase the risk of lung cancer greatly, despite the fact that most smokers do not get lung cancer.

OBrien S. AIDS Restriction genes: discovery, assessment and implications. Plenary lecture Tuesday 7 February, 13th CROI, 2006, Denver. Webcast available on conference website.