14th International HIV Drug Resistance Workshop 7-11 June 2005, Québec City, Canada

HOST GENETIC DETERMINANTS OF HIV TRANSMISSION AND PATHOGENESIS: SHOULD WE CARE?

Antivir Ther. 10, Suppl 1:P3

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. Specifically, in this seminar, I will focus on the role of CCR5 and its ligands in HIV/AIDS pathogenesis. 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-1aP), 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. I will then place these findings 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.

The work presented here is the culmination of a fruitful collaboration/partnership between members of the VA HIV/AIDS Center/UTHSCSA and three groups at (i) Wilford Hall Medical Centre, San Antonio, TX, PI: Matt Dolan, MD; (ii) Barcelona, Argentina, PI: Luisa Sen, MD; (iii) UCSD (AIEDRP), San Diego, CA, PIs: Susan Little, MD and Doug Richman, MD.

PRESENTING AUTHOR: SK Ahuja

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2005-06-07
P1

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