RETROVIRUSES AND RESISTANCE TO EXOGENOUS RETROVIRUS INFECTION
Stoye, M.W. Yap, C. Lynch
National Institute for Medical Research, Mill Hill, London, U.K.
Endogenous proviruses have
been accumulating in the human genome over a period of tens of millions of years
and currently comprise around 8% of human DNA. It seems reasonable to suppose
that during this time a process of co-evolution has occurred, with the
development of host mechanisms to control virus expression and a series of virus
counter-measures. In addition, it would not be surprising if specific proviral
products might take on niche functions benefiting the host, perhaps in providing
additional means for preventing virus infection.
In the mouse, a number of
genes for resistance to retroviral infection have been described. One of these,
Fv1, acts in a cell autonomous manner to block infection at a post-penetration,
pre-integration stage in the viral life cycle. We have cloned Fv1 by positional
means. It is related to sequences encoding part of the gag gene of the
MuERV-L/HERV-L family of endogenous proviruses. More recently, phenotypically
similar activities have been detected in cells from a variety of primates,
including humans. These genes, called Ref1 or Lv1, remained uncloned.
In light of the apparent
similarities between Fv1 and Ref1/Lv1, it is tempting to speculate that the
latter genes are also of endogenous proviral origin. In collaboration with Drs.
Jonas Blomberg and Michael Tristram we are developing a candidate gene strategy
for attempting the cloning of Ref1/Lv1. A large collection of ERVs with open
reading frames in gag has been identified by bioinformatics means. They are
currently being cloned into an expression vector for functional testing of
antiretroviral activity. Progress and programs with associating specific
proviruses with given biological functions will be discussed.