In our 5th monthly "Classic Papers in HIV" journal club, we discussed the discovery of the HIV-1 co-receptors  Paper 1:  HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872-7.

It was established early on that CD4 was the HIV-1 receptor.  However, mouse cells expressing human CD4 could bind virus, but the virus would not fuse with the cell membrane.  Also, HIV-1 strains had different tropisms that could be explained by the envelope but not the receptor.

The Berger lab performed a heroic screen for the "fusion" factor by testing pools of HeLa cell cDNAs in mouse cells that also expressed CD4 and looking for fusion with other mouse cells that expressed HIV-1 env. They identified a gene they called "fusin" as an HIV-1 co-receptor.

"Fusin" is a G-coupled protein with homology to chemokine receptors (which make lymphocytes migrate in response to binding chemokines).  Soon thereafter,  the ligand for this protein was identified and this HIV co-receptor was more properly renamed CXCR4.

CXCR4, however, is not the co-receptor of HIV-1 strains more commonly found in vivo. A previous study that identified a set of 3 different chemokines that inhibited entry of these strains of HIV-1 soon led multiple groups to show that chemokine receptor CCR5 is a co-receptor.

Paper 2: Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996 Aug 9;86(3):367-77.
https://bit.ly/3rUSCY5 

This paper showed that two participants in a cohort of multiply-exposed uninfected people had a 32 bp deletion in both alleles of their CCR5 gene that prevents the protein from getting to the cell surface and functioning as an HIV-1 co-receptor. The deletion is inherited.

This finding was remarkable in a definitive demonstration that HIV-1 strains that use CCR5 are the important ones for transmission and replication in vivo. Moreover, that humans do not, in fact, need CCR5.

Subsequent studies showed a role for CCR5 heterozygosity in disease progression and some fascinating population genetics of the distribution of the deletion. There is also a direct line from these basic studies to the cure of Timothy Ray Brown, whose life was celebrated today.

Next month in Classic Papers in HIV journal club we will talk about the discovery of the co-factors for the HIV-1 transcription factor, Tat.