Perspectives on XMRV and Related RetrovirusesJohn M. Coffin

Endogenous provirusesReceptor usage

HIV Drug Resistance ProgramHIV Drug Resistance Program

National Cancer Institute at FrederickTufts University

What we know about XMRV1. First reported in some prostate cancer samples in 2005.2. Human infection is associated with 2 diseases:

1. Prostate cancer (ca 23% of biopsies) 2. Chronic fatigue syndrome (67% of cases)

3. Virus can be detected and cloned from prostate cancers (stromal or tumor cells?) Infection may be associated with Rnase L mutations (or not). 4. Virus can be detected in and isolated from PBMCs and plasma of CFS patients. 5. Detectable in ~4% of control samples (not really unbiased).6. Isolates from both diseases are very closely related to one another (most distant pair differs by 0.3%).

1. Suggests that very few cycles of replication separate viruses from distant locations.

2. Has implications for possible therapy, vaccination. 7. Very closely related to xenotropic MLV, an endogenous virus of inbred mouse strains and some wild mice. Related viruses cause many diseases in mice.

Xenotropic MLV

1. Inherited as endogenous proviruses (ca 10-20 copies) in all inbred mice.2. Many more proviruses in some wild Mus Musculus subspecies.3. Some proviruses (e.g., Bxv1) are intact and infectious.4. Can infect virtually all mammals, except some species of Mus, due to

receptor (Xpr1) polymorphism.5. Not directly pathogenic in mice (due to lack of receptor), but LTR is often

found in oncogenic recombinant MLVs.6. Pathogenicity in other species is unknown.7. Common contaminant of human tumor cell lines due to passage through

nude mice (which have Bxv1).8. Closely related to XMRV, but none is identical, probably excluding inbred

mice as the origin.9. Related MLVs cause a wide variety of diseases (malignant,

immunodeficiency, neurological) in mice.

• CFS pt 1010• CFS pt 1042• PCVP62• PCVP42• PCVP35 • XMVB Provirus• NZB Xenotropic MLV• BALB/c Xenotrpoic MLV• AKR MLV• Moloney MLV

Relationship of XMRV to Endogenous MLVs

CFS pt 1010CFS pt 1042 PC VP 62PC VP 42PC VP 35

XMV13 Provirus NZB Xenotropic MLV

AKR MLV

2%

BALB/c Xenotropic MLV

Moloney MLV

What we don’t know about XMRV

1. Role in CFS, prostate cancer, or other disease. Cause, passenger, or coincidence?

2. Incidence and prevalence in the human population.3. Distribution in the human population.4. Mode of transmission. 5. Origin (almost certainly from mice at some point). Single or multiple cross-

species transmission? How long ago?