XMRV infection of Rhesus macaques

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References:

XMRV Can Cause Persistent Infection in Monkeys

Help ME Circle, 17 February 2011

Rhesus macaques exposed to human

gammaretrovirus XMRV

Help ME Circle, 17 February 2011

~jvr

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virology blog

ABOUT VIRUSES AND VIRAL DISEASE

XMRV infection of

Rhesus macaques

By Racaniello

17 February 2011

The first detailed study of infection of nonhuman

primates with the retrovirus XMRV reveals that the

virus establishes a persistent infection characterized

by infection of multiple tissues.

Viremia (virus in the blood) is low and transient, with

proviral DNA detectable in blood lymphocytes.

The results show that the Rhesus macaque can be

used to study XMRV infection, transmission,

vaccines, and antiviral drugs.

The subject of this study, the Rhesus macaque

(Macaca mulatta), was selected because of its

evolutionary proximity to humans and a comparable

immune system.

The monkeys used did not have antibodies to the

capsid protein p30 of XMRV, indicating that they

were not previously infected.

Animals were inoculated intravenously with 3.6

million TCID50 of purified XMRV – a good amount of

virus, to ensure infection.

The virus used, VP62, was produced by transfecting

cells with cloned viral DNA isolated from human

prostate.

Virus in the plasma fraction of blood was assayed by

quantitative RT-PCR.

Of three animals infected, virus was detected in one

animal at day 4 and not after day 14; and in a

second animal from days 14-20.

The third animal did not develop detectable viremia.

Proviral DNA was found in peripheral blood

mononuclear cells (PBMC) of all three monkeys for

3-4 weeks, indicating successful infection.

At one month post-infection proviral DNA was no

longer detected.

Plasma virus was again detected in one of the

positive animals on day 291, 16 days after being

immunized with a mixture of XMRV proteins.

This means that viral DNA had been present in this

animal but was not detected. XMRV was detected in

CD4+ and CD8+ T cells and NK cells, but not in B

cells or monocytes.

Rhesus macaques infected with XMRV did not display

obvious clinical symptoms. Analysis of peripheral

blood revealed increases in the number of circulating

B and NK cells.

Anti-viral antibody titers were detected after

infection and re-infection of animals but soon

decreased.

Other infected animals were sacrificed during the

acute phase of infection to identify pathological

changes and sites of virus replication.

No pathogenic consequences were observed except

for the formation of germinal centers in spleen and

lymphoid organs, changes that are expected after

immune stimulation.

Virus was detected in a wide variety of tissues,

including spleen, lymph nodes, the lining of the

gastrointestinal tract, prostate, testis, cervix,

vagina, and pancreas, but not in others including

brain, heart, kidney, and bladder.

Different types of cells were infected in different

tissues: lymphocytes in lymphoid organs,

macrophages in lung, epithelial or interstitial cells

in other organs. The authors note that:

*this viral behavior appears specific to this virus*.

Here are some other comments

and conclusions drawn from this

study:

* The authors suggest that in Rhesus macaques,

XMRV causes first an acute infection, followed by a

persistent chronic infection. A persistent infection

lasts for long periods of time; a chronic infection is a

persistent infection that is eventually cleared. Since

the monkeys in this study were all sacrificed, it's not

possible to determine if the infection was cleared.

* The presence of XMRV in certain blood cells

resembles the pattern in a cohort of ME/CFS patients

* Virus is present in the prostate early in acute

infection – XMRV was identified in prostate tumors

* The presence of XMRV in reproductive tract

tissues is consistent with sexual transmission of

infection

* After the acute phase, virus levels are very low,

but there could be a different outcome in individuals

with immune dysfunction

* One animal produced virus after immunization;

perhaps immune activation results in cycles of virus

production

* The virus has an initial acute phase followed by

reactivation. The authors comment:

< While our study has not linked XMRV infection with

pathogenic mechanisms that might lead to prostate

cancer or chronic fatigue syndrome, we submit that

such link, assuming it exists, would be a temporally

distant one.>

* It would be informative to determine if XMRV is

present in some of the same tissues in humans that

were observed to be infected in rhesus macaques

Because the study involved only a small number of

monkeys (8), the experiments should be repeated

with additional animals, and in different laboratories,

to verify the findings.

I also wonder if the choice of the intravenous

inoculation route had an effect on the pattern of

infection and tropism.

It is well known that viral pathogenesis can be

determined by how the virus enters the host.

For example, the same virus may replicate in

different tissues, or have different virulence, when

inoculated in different ways.

This question can be readily addressed by inoculating

rhesus macaques via different routes.

Studying viral pathogenesis (the series of events

that occur during viral infection of a host) in animals

is essential for understanding how viruses cause

disease in humans.

However, the results of such studies must always be

interpreted with caution, because what is true in an

animal is not always true for a human.

For example, simple differences in size, metabolism,

and development can have substantial effects on

pathogenesis.

In interpreting the results of animal studies, we

must keep in mind the adage, *Mice lie, monkeys

exaggerate*.

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Onlamoon, N, DasGupta, J, Sharma, P, , K,

Suppiah, S, Rhea, J, Molinaro, RJ, Gaughan, C,

Dong, B, Klein, E, Qui, X, Devare, S, Schochetman,

G, Hackett, J, Silverman, R, & Villinger, F (2011).

Infection, viral dissemination and antibody

responses of Rhesus macaques exposed to

the human gammaretrovirus XMRV Journal

of Virology