The Vi­ral Se­leno­pro­tein The­ory

by Chi­tra Ra­jaku­beran

Just when you thought that HIV has bared all its se­crets, new ones come along. The HIV genome en­codes 3 main polypro­teins and six reg­u­la­tory pro­teins. Like all other vi­ruses, HIV re­lies ex­ten­sively on the host for repli­ca­tion; of course, what sets it apart from most other viruses is its re­markable abil­ity to in­te­grate into the host genome and lie dor­mant for long pe­ri­ods of time.

Fig­ure 1. In­dian paint­brush in bloom. These plants ab­sorb se­le­nium from the soil and con­cen­trate it in their tis­sues. The ed­i­ble, sweet flow­ers were con­sum­ed in mod­er­a­tion by var­i­ous Amerindian tribes as a cond­i­ment. The high se­le­nium con­tent, es­pe­cially in roots and green parts, makes it po­ten­tially toxic in large quan­tities. Source

Al­most all the iden­ti­fied ORFs of HIV have been im­pli­cated in its patho­gen­e­sis. How­ever, re­cent bioin­for­mat­ics re­ports sug­gest that HIV may in fact en­code for ad­di­tional frame-shifted pro­teins. This is a fas­ci­nat­ing story that didn't start with HIV. The frame-shift is brought about by RNA struc­tures called pseudo­knots. A pseudo­knot is de­fined as "an RNA sec­ondary struc­ture con­tain­ing at least two stem-loop struc­tures in which half of one stem is in­ter­ca­lated be­tween the two halves of an­other stem." The pseudo­knot struc­ture was first rec­og­nized in the turnip yel­low mo­saic virus in 1982.

Us­ing soft­ware that pre­dicts the ex­is­tence of RNA pseudo­knots, and hence the pos­si­bil­ity of frame-shifted pro­teins, the ex­is­tence of three new HIV pro­teins was de­duced. These frame-shifts oc­cur in the HIV pro­tease, re­verse tran­scrip­tase, and en­ve­lope pro­tein se­quences. Both the pro­tease and re­verse tran­scrip­tase are tar­gets of ex­ist­ing anti-retro­vi­ral drugs, which make study­ing these new frame-shift pro­teins ex­ceed­ingly im­por­tant.

Ex­am­ple of a nat­u­rally oc­cur­ring pseudo­knot found in the RNA com­po­nent of hu­man telom­erase. Source

Most sur­pris­ing is that all three frame-shift pro­teins are se­leno­pro­teins, that is, they con­tain se­leno­cys­teine re­sidues. Se­le­nium is a trace el­e­ment found in the soil and is a mi­cronu­tri­ent es­sen­tial for cel­lu­lar ac­tiv­i­ties. It is found in the ac­tive cen­ters of re­duc­ing en­zymes like glu­tathione per­ox­i­dase, thiore­duc­tase, and deio­di­niz­ing en­zymes. Se­leno­pro­teins are found in al­most all forms of life. In or­der to make se­leno­pro­teins, some UGA codons (oth­er­wise ter­mi­na­tion codons) must be read as en­coding se­leno­cys­teine, which re­quires an up­stream RNA struc­ture called the Se­leno­cys­teine In­ser­tion Se­quence (SECIS). Bioin­for­mat­ics stud­ies re­veal the pres­ence of these struc­tures in HIV's Long Ter­mi­nal Re­peats (LTRs).

Dis­tri­b­u­tion of se­le­nium in U.S. soils. Source

A cur­rent hy­poth­e­sis for the role played by se­le­nium in HIV in­fec­tion is that HIV se­leno­pro­teins se­quester se­leni­um and thus de­prive the body of it, re­sult­ing in chronic se­le­nium de­fi­ciency. Se­le­nium de­fi­ciency can cause wast­ing and low­er­ing of im­mu­nity and, most likely, the other clas­si­cal symp­toms of AIDS. Since se­le­nium mainly func­tions as an an­tiox­i­dant, the virus uses it to com­bat the cel­lu­lar im­muno­log­i­cal re­sponses like ox­ida­tive bursts. The vi­ral se­leno­pro­teins may also be reg­u­la­tory in na­ture and con­trol HIV tran­scrip­tion. Pre­lim­i­nary stud­ies in­di­cate that HIV in­fec­tion sig­nif­i­cantly low­ers the seleno­protein level in T cells. Even though this hy­poth­e­sis put for­ward by Will Tay­lor was ini­tially for HIV, re­cent ev­i­dence seems to in­di­cate that it could hold true for other retro­viruses and also for other viruses, such as some strains of cox­sackie viruses and even Ebola.

The vi­ral-se­leno­pro­tein the­ory, though con­tro­ver­sial, could, if proven, be a great turn­ing point in vi­rol­ogy. Not only would it high­light how ef­fi­cient the viruses are in uti­liz­ing their genomes but it could also have a huge im­pact on the lives of the mil­lions of HIV in­fected peo­ple all over the world. Just sup­ple­ment­ing their di­ets with se­le­nium might slow the pro­gres­sion to full-blown AIDS. Is this too sim­ple to be true? The fu­ture will tell!

Chi­tra was a stu­dent in the 2009 In­te­gra­tive Mi­cro­bi­ol­ogy grad­u­ate course at UCSD/SDSU. She is cur­rently pur­su­ing her Ph.D. stud­ies in the lab of Roland Wolkow­icz at San Diego State Uni­ver­sity.