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Host Genetics & HIV
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Reported by Jules Levin
In his opening plenary talk at the 14th Intl HIV Drug Resistance Workshop SK Ahuja showed data suggesting the predisposed genetics related to the gene he researched showed individual differences in HIV transmissibility, response to HAART, viral failure to HAART, and development of AIDS. There is quite a bit of attention & research going into trying to predict outcomes in HIV with genetic predispositions. Ahuja presented quite a bit of information & research he has conducted associating genetics with outcomes, and there were additional presentations & discussion at the Workshop related to this subject. How much valid data & how strong the data is in finding these associations remain to be established. There has much discussion in the past several years about a number of topics related to this overall subject, but so far data has only been able to establish a few trends and not very much strong information to hang your hat on.
Host genetic determinants of HIV transmission and pathogenesis: should we care?
SK Ahuja
VA HIV/AIDS Centre, University of Texas Health Science Centre at
San Antonio, TX, USA
Borrowing from Shakespeare, (William Shakespeare,
King Richard II, Act ii, Scene 1):
'... this other Eden, demi-paradise, this fortress built by
Nature for herself against infection...'
Nature's fortress against infections such as HIV by necessity involves host factors that influence the early events of HIV-host interactions. In this seminar, I will show how we have used a genetic approach as a powerful tool to identify the host factors that underlie some of these early events. This approach has therefore permitted us to address the following clinical paradoxes:
--Why do some individuals when exposed to HIV-1 resist infection? Why do some individuals succumb to HIV-1 infection rapidly whereas others resist progression to AIDS?
Using this genetic approach we have (a) uncovered complex host gene-gene interactions that influence HIV-1 pathogenesis in vivo; (b) determined the relative
contribution of some of these host genetic determinants to the HIV-1 epidemic at the population level.
In previous studies we uncovered some of the CCR5 genetic determinants that contribute to inter-subject differences in HIV/AIDS susceptibility. Here, I will
show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding
CCL3L1 (MIP-1_P), a potent HIV-1-suppressive chemokine and ligand for the HIV coreceptor CCR5.
Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/AIDS susceptibility. This susceptibility
is even greater in individuals who also possess diseaseaccelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis. These findings should be considered in the broader picture of needing to consider genetic predispositions, particularly among ethnicity 7 geographically, in the broader context of issues relevant to the epidemic/ vaccines as well as individual-specific issues such as whether these variants have relevance for
understanding the inter-subject differences in response to HAART.
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