Anyhow, this was a long journey with an amazing group of collaborators (71 authors and beyond) that wouldn't have been possible without the incredible people living HIV who consented to be in this study /fin 🙏

Final thoughts: It can't be over-stated that we need more diversity in #GWAS. Not only to make more discoveries but to make sure that the benefits of genomics are seen by those most impacted

So, where does that leave us? We've got a new locus of HIV control, on that I'm (as I'm told the kids say). We've got the gene too (I think) but the mechanism is still very much up in the air. I'm really excited to see where this all leads now that it's officially out.

Although, the role that macrophages play in maintaining the HIV reservoir has gotten increasing attention recently. And other myeloid cell types might also be under-appreciated for their contribution

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That was something of a surprise. It's been known for a long time that macrophages are infected by HIV, but they certainly weren't the first thought on our mind

Oddly enough we didn't see the same effect in a T cell line (Jurkats), suggesting it might be a cell type (or cell state) specific effect

We saw a similar thing in monocytic THP1 cell lines (ED figure 4) and in iPSC-derived macrophages (where less CHD1L meant more HIV)

To try to get to the bottom of that, we used #CRISPR to knock out CHD1L in a model cell line (U2OS) and saw a pretty big jump in HIV infection in KO cells. An effect that was reduced when we added CHD1L back

Functional and statistical fine-mapping pointed to the nearby gene CHD1L. A helicase involved in DNA repair and loosely linked to HIV integration through its interaction with PARP1

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Anyhow, why didn't we find this in earlier (larger) studies in people living with HIV of European ancestry? pnas.org/doi/10.1073/... Because the associated variant(s) aren't present in non-African ancestry populations!

For those keeping score, this brings the grand total of known loci for HIV viral load to three. That larger peak on chromosome 6 is HLA (as expected). We don't see the CCR5 peak (Chr3) in this population for reasons I still need to get to the bottom of (but I digress...)

We did a #GWAS of viral load in the African component of the International Collaboration for the Genomics of HIV #ICGH We discovered (n=2,682) and replicated (n=1,197) a new locus on chromosome 1 that strongly associates with reduced HIV viral load (p=6.4x10-10)

HIV viral load (the amount of virus in the blood) during untreated chronic infection is a strong predictor of rate of disease progression and transmission potential. It is highly variable in people living with HIV for a lot of reasons (including host genetics)

Quick bit of background, HIV is still huge problem, with ~39 million people living with HIV globally, >1 million new infections every year, and >600k deaths due to HIV. With the highest burden in Southern Africa unaids.org/en/resources...