HIV infection changes the genes that affect development of tuberculosis

The human leukocyte antigen (HLA) genes affect the development of tuberculosis (TB) differently in people with and without HIV-1 infection, according to research published in the March 15^th edition of the Journal of Infectious Diseases.

The authors, from California, the US and Harare, Zimbabwe, found that having certain HLA genes increases both the risk of developing active TB and the severity of the disease’s symptoms. They show that HIV infection changes which genes influence the development of TB.

The HLA genes are the most variable in the human genome. Everyone has over 40 HLA genes, with each having up to 130 possible variants, or alleles, which are passed down from parents to their offspring. The HLA molecules form an important component of the immune system, since one of their functions is the presentation of foreign material to T-cells, to initiate immune responses.

While HIV-positive patients with certain variants of the HLA genes were more likely to develop pulmonary TB, the researchers showed that other alleles were associated with TB in those without HIV.

Additionally, HIV-positive people who had inherited two copies of the same HLA allele (homozygotes) had a reduced risk of disease development. However, homozygosity was also associated with a rapid progression of the disease to the pleural effusion stage.

This study suggests that genetic susceptibility to TB is different in people with and without HIV infection. This may prove important to the effort to curb the spread of TB. “Stimulating effective immune responses among HLA homozygous individuals and those who are already infected with HIV-1 will be important to consider in TB vaccine development,” state the authors. “Strategies to control TB must also consider the risks of acquiring HIV-1 infection and of progression to AIDS.

Previous research has suggested that the HLA genes influence the speed of progression to diseases including AIDS and TB. Although these genes are known to affect progression to TB in HIV-positive patients, this study is the first to compare this effect in people with and without HIV infection.

The researchers sequenced the DNA of 586 Shona Africans from Harare, Zimbabwe, an area with high rates of HIV-1 and Mycobacterium tuberculosis infection.

They found that alleles of the ‘class I HLA-A and -C genes (A*3601 and C*0407) were more common in HIV-positive patients with pulmonary TB than those without the disease, whereas A*6802 showed the opposite trend. Additionally, fewer people in the TB group were homozygous for the HLA genes, particularly the ‘class II genes DRB1 and DPB1.

In the HIV-negative participants, the presence of different alleles of the HLA-C gene (such as C*1200) was associated with pulmonary TB, and there were no significant effects of variation in the HLA-A gene. There was also no association between homozygosity of the HLA genes and the risk of development of TB.

The researchers also recruited 45 HIV-1-infected patients with pleural effusion TB, to examine the effect of the genes on disease progression. More of these patients possessed the A*6802 allele and were homozygous for DRB1 than the HIV-positive patients with pulmonary TB.

The authors point out that the HLA genes have opposite effects on the two stages of TB: the development of active pulmonary TB following M. tuberculosis infection, and the progression of pulmonary TB to pleural effusion TB. They speculate that different immunological mechanisms are at work at these two stages, at least in HIV-positive individuals. While a more effective immune response against M. tuberculosis may cause the symptoms of active TB in people who lack A*6802 or are homozygous for the DRB1 gene, this response may keep bacterial replication under control and prevent the rapid progression of the disease.