Perspectives on XMRV and Related Retroviruses John M. Coffin Endogenous proviruses Receptor usage Endogenous proviruses Receptor usage HIV Drug Resistance Program National Cancer Institute at Frederick Tufts University

What we know about XMRV 1. First reported in some prostate cancer samples in 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. 1. First reported in some prostate cancer samples in 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 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. 1. Inherited as endogenous proviruses (ca 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 1010 CFS pt 1042 PC VP 62 PC VP 42 PC 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? 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?