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Archive for January, 2016

What causes HIV-induced immunodeficiency?

regfbec11 January 2016

Chronic HIV infection almost always leads to a progressive immunodeficiency. The manifestations of the immunodeficiency are quite characteristic to HIV infection. Specifically, commensal or non-pathogenic environmental micro-organisms, which are generally contained by the immune system asymptomatically, lead to uncontrolled infections, morbidity and, if untreated, death. Interestingly, although HIV infection leads to a specific loss of CD4 cells, many of the major HIV-associated infections are caused by intracellular organism, both viral (e.g. KSHV, HSV, CMV), bacterial (e.g. Mycobacterium) and fungal (e.g. Cryptococcus), infections in which the CD8 T cell response has an important protective role. The mechanisms which underlie HIV pathogenesis continue to be hotly debated. Functional defects have been reported not just in the primary target of HIV (CD4 T cells) but in almost every other facet of immunity. But unravelling which changes cause immunodeficiency, and which are the indirect consequence of it remains an unsolved challenge.
We have recently re-examined the T cell repertoire in chronic untreated HIV infection using high throughput sequencing to generate a global picture of alpha and beta gene usage (Frontiers in Immunology). We observe multiple levels of immune dysregulation, including a decrease in overall diversity, which seems to be driven both by a reduced CD4 cell repertoire, but also by a very extensive over expansion of individual CD8-associated T cell clones which take up a progressively larger proportion of the available repertoire space. We repeated our analysis on samples taken from the same patients three-four months after they started ART treatment, by which time viral load was very low or undetectable in all patients. Clinical experience has established that this short treatment period leads to dramatic improvements in patients suffering from HIV-associated infections at the time of treatment initiation, suggesting that even this brief time is sufficient for significant functional repair of immune function. As expected, CD4 T cell numbers were still very low at the time of the second sample, and we observed only a very small increase in overall repertoire diversity. However, the ability to quantitatively track the frequency of individual alpha and beta genes in the two sequential samples, showed a remarkably dynamic picture underlying the apparent stable overall T cell numbers and diversity (see fig 5 in paper). Many of the TCRs which were highly expanded in the HIV+ samples showed decreases in abundance of 100 fold or more, while other TCRs increase in abundance. These dramatic changes in T cell receptor abundance are much larger than are observed when comparing paired samples taken at similar time intervals from healthy volunteers. Although the repertoire method we used does not allow pairing between alpha and beta chains, we were able to identify a number of TCR genes present in the HIV+ samples which had been characterised as forming part of HIV specific TCRs in previous studies. These sequences generally showed a fall in abundance following three months of therapy, in agreement with the rapid decrease in HIV specific T cells previously observed to accompany the ART induced fall in viral load.
On the basis of these observations, we propose a model linking dysregulation of TCR repertoire to immunodeficiency. The model remains speculative, but we hope it will stimulate further discussion and experimental verification. We propose that HIV infection drives an unregulated expansion of specific CD8 T cells, responding either directly to chronic exposure to HIV antigens, or to gut microbial antigens which enter the circulation as a result of HIV induced damage to the gastrointenstinal barrier . The overexpansion of these clones distorts the CD8 T cell repertoire, and may specifically out-compete some of the CD8 T cells responsible for containing the growth of microorganisms to which we are commonly exposed or by which we are already chronically but asymptomatically infected. As a result, organisms which are normally harmless can no longer be adequately controlled and lead to overt infection and morbidity. The rapid fall in viral load following ART leads to a rapid decrease in the abundance of these over-expanded clones (as antigen load diminishes). This in turn leads to a normalisation of the CD8 effector repertoire, and hence reversal of functional immunodeficiency and control of facultative pathogens long before the slow regeneration of the CD4 compartment can take place.