Nef: Savior and Satan

Vpu has kinda been my accessory protein of choice here at ERV, but its not the only one with a super cool evolutionary history and super cool evolutionary implications.

Another particularly fun one is Nef.

This eeeeeeeety bitty HIV-1 protein (27 kDa) has a lot on its plate. Contrary to the 'expert' opinion of Michel Behe, who thinks viral proteins just 'gum up the works', Nef has several exceedingly specific functions--

1. Down-regulating CD4 from the host cell plasma membrane-- This is basically 'pissing on the fire hydrant'. HIV-1 requires CD4 on the surface of susceptible cells to initiate infection. HIV-1 doesnt want to share a cell with other HIV-1s, so one of the first things it does is haul all the CD4 receptors off the cell surface via clathrin coated pits (animation).
2. Down regulating MHC Class I from the host cell plasma membrane-- A simple Creationist might think that both CD4 and MHC are pulled off of the plasma membrane the same way. Since Nef just 'gums up the works', gumming up one surface receptor should gum up any surface receptor. This is soooooo not the case. MHC Class I molecules are essential components of a normal cell plasma membrane. They send up flags that say 'Everything is fine here! So dont kill me, k?' Viruses like to take down these flags, because they also can signal 'HEY! Im infected here! Better tell me to kill myself!' Viruses dont want that, so they take down the flags. Minor problem-- If no MHC Class I flags are there, another immune cell notices they are missing, and kills the cell. What Nef does, is specifically targets HLA-A and B, but leaves HLA-C and E alone, effectively keeping other immune cells from knowing anything is wrong with the infected cell. These are very very very specific interactions! Teeeeeeeeny tiny viral protein knows the difference between HLA-A and HLA-C. Thats nuts. Also, it takes these receptors off the surface an entirely different way than the CD4-- Its clathrin independent.
3. Inhibiting apoptosis--
Your immune system doesnt technically 'kill' infected cells. It tells them to commit suicide (apoptosis). Infected cells do not want to die. They want to produce progeny virus, and kill the cell in the process. Thus Nef also has the capability to inhibit a couple of the ways your immune system tries to induce apoptosis, FAS and TNF.

EEEEEEEEETY BITTY protein, all those functions.

At one point, Nef had the potential to be our savior. Between 1981 and 1984, eight people in Australia were infected with HIV-1 via blood transfusions from the same donor. This donor happened to have a mutation, where none of their viruses contained Nef. HIV-1, no nef. While this was during the height of the HIV-1 epidemic, people dying left and right, these eight patients were doing real damn good. Better than good. They were fine! None of them were progressing to AIDS, even without antiretrovirals! Scientists had hope that this meant we could make a live attenuated vaccine with delta-nef HIV-1!

Unfortunately, these patients never cleared the virus. And, three of them eventually progressed to AIDS (but responded to anti-retrovirals!) (one died from unrelated causes). Theres no way we could use that for a vaccine. *sigh*

Nef also turned into our nightmare. Know how HIV-1 always has the 'same genes that act the same way', according to Perfesser Behe? Nothing real exciting, he says? Yeah, this one time, back in the late 80's, we accidentally evolved an acutely lethal SIV.

Yes, you read that right. Acutely lethal SIV. As in, it kills you <13 days after youre infected. Not 10 years, less than 13 days.

Yeah.

Yeah.

Oops.

Scientists were passing SIV from sooty mangabeys in pig-tailed macaques. Its a stock-standard way of generating a live attenuated vaccine. Take the pathogen out of its native host, passage it in a non-native host, return the attenuated virus to the original host. The original host can usually fight it off better than the virus you started with.

Yeah, this didnt work with SIV. The 'new' SIV, 'smPBj'* had altered cell tropism, caused super friggen hyperactivated immune systems, and the monkeys basically shat their guts out and died.

All because Nef evolved a new function.

One amino acid mutation turned Nef into an ITAM, and all kinds of hell broke loose.

Happily, this variant of SIV is not found in nature, nor would we expect it to survive in nature (if you are pooping out your guts, you arent having sex to pass on the virus), but the artificial conditions we used in the lab allowed this variant to thrive.

Vpu aint the only cool eeeeeeeety bitty HIV-1 protein to have a fun evolutionary history :)

* An acutely lethal SIV, and its name makes my mind scream "ITS PEANUT BUTTER JELLY TIME! PEANUT BUTTER JELLY TIME!!!!"