Human Immunodeficiency Virus (HIV) is a retrovirus, infection with which causes Acquired Immunodeficiency Syndrome (AIDS). HIV infection occurs via transfer with bodily fluids and is characterised by progressive failure of the immune system and life threatening opportunistic infections. The virus primarily infects cells of the immune system including CD4+ T cells, macrophages and dendritic cells. The mechanism of action involves direct killing of infected cells, increased rates of apoptosis of infected cells and killing of infected CD4+ cells by CD8+ cytotoxic T cells. The opportunistic infections are as a result of CD4+ T cells falling below critical levels for maintaining cellular immunity.
HIV infection is treated with combinations of antiretroviral drugs such as Nevirapine and Abacavir. Abacavir is a guanosine analogue which works by competitive inhibition of the reverse transcriptase enzyme. Abacavir has been shown to be associated with drug hypersensitivity in patients who carry the HLA class I allele HLA-B*57:01. Two recent large scale Abacavir drug studies which incorporated skin patch tests have shown that 100% of patients who develop Abacavir drug hypersensitivity carry the HLA-B*57:01 gene. This predictive value supports the use of HLA-B*57:01 genetic screening of patients prior to commencement of treatment with Abacavir even though a proportion of HLA-B57:01 patients do not develop hypersensitivity. Current guidelines in the UK recommend that HLA-B*57:01 patients be put on alternative regimes.
Genetic variations amongst humans have been shown to be associated with either protection against HIV infection, slow progression to AIDS once infected or rapid progression to AIDS. Several studies of highly exposed seronegative individuals, such as sex workers and the healthy newborns of HIV infected mothers, have shown that the HLA molecules HLA-A2 and A68 are associated with reduced risk of seroconversion. Generally concordance of HLA class I alleles between a HIV infected patient and their uninfected sexual partner results in increased likelihood of HIV transmission. Where HIV infection has taken place, a number of studies have shown that some patients do not progress on to full blown AIDS. A correlation has been shown to exist in these long term non progressers between the HLAB*57 and B*27 molecules and delayed AIDS onset. In general, patients heterozygous for HLA class I have delayed progression compared to homozygous individuals. The B*35 allele and the HLA-A1, B8, DR17 haplotypes have conversely been shown to be associated with a more rapid disease progression.
Non HLA genes associated with delayed or rapid progression include the delta 32 variant of the CCR5 chemokine receptor which is associated with resistance to infection and delayed progression once infected and P1 variant of the CCR5 chemokine receptor which is associated with rapid progression.
Genetic screening in HIV infection is therefore of value both as a screen for patients who may exhibit drug hypersensitivity but also helps identify patients who may be as risk of more rapid progression. In addition, an understanding of the genetics and mechanisms involved in non seroconversion in some individuals and slow progression in others may hold some promise for the development of HIV vaccines.
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