Intrinsic Immunity - Activities of Canonical Intrinsic Immune Proteins

Activities of Canonical Intrinsic Immune Proteins

• TRIM5α (Tripartite interaction motif five, splice variant α) is one of the most studied intrinsic immune proteins due to its connection with human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). This constitutively expressed protein recognizes the capsid proteins of entering retroviruses and prevents viral uncoating and reverse transcription through an unknown mechanism. The rhesus monkey TRIM5α variant is able to recognize and prevent HIV infection, whereas the human TRIM5α protein can prevent SIV infection. This variation helps explain why HIV and SIV infect humans and monkeys respectively, and probably reflects a previous epidemic of what we now call HIV among ancestors of current rhesus monkey populations.

• APOBEC3G (Apolipoprotein editing complex 3 G) is another intrinsic immune protein which interferes with HIV infection. APOBEC3G is a cytidine deaminase against single stranded DNA which introduces transversion mutations into the HIV genome during reverse transcription by randomly changing cytidine basepairs into uracil. Though this will not necessarily stop viral integration, the resulting progeny viral genomes are too riddled with mutations to be viable. APOBEC3G expression is disrupted by the HIV vif protein which induces its degradation through the ubiquitin/proteasome system. If an HIVΔvif deletion mutant is created it will be able to infect a cell, but will produce non-viable progeny virus due to the action of APOBEC3G.

Other intrinsic immune proteins have been discovered which block Murine leukemia virus (MLV), Herpes simplex virus (HSV), and Human Cytomegalovirus (HCMV). In many cases, such as that of APOBEC3G above, viruses have evolved mechanisms for disrupting the actions of these proteins. Another example is the cellular protein Daxx, which silences viral promoters, but is degraded by an active HCMV protein early in infection.