No abstract

Selection of HIV-1 variants resistant to antiretroviral therapy is well documented. However, the selection in vivo of HIV-1 mutant species that can escape host immune system HLA class I restricted cytotoxic T-lymphocyte responses has, to date, only been documented in a few individuals and its clinical importance is not well understood. This thesis analyses the observed diversity of the HIV-1 reverse transcriptase protein in a well characterised, stable, HLA-diverse cohort of HIV-1 infected patients with over two thousand patient-years of observation. The results show that HIV-1 polymorphism is selected within functional constraints and is associated with specific HLA class I alleles. Furthermore, these associations significantly cluster along the sequence and tend to occur within known corresponding HLA-restricted epitopes. Absence of polymorphism is also HLA-specific and more often seen with common HLA alleles. Knowledge of HLA-specific viral polymorphisms can be used to model an individual's viral load from their HLA type and viral sequence. These results suggest that cytotoxic T-lymphocyte escape mutation in HIV-1 is critical to the host at an individual and population level as well as to short and long term viral evolution. This work provides new insights into viral-host interactions and has clinical implications for individualisation of HIV-1 therapy and vaccine design.

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.