Hepatitis C virus pathogenicity: The corner pieces of the jigsaw puzzle are found

April 1994

EDITORIALS

cellular

injury

for injury.> plant

to rule out the virus as the sole mechanism Furthermore,

recipients

alanine

infected

with

aminotransferase

ters. ‘-* How alanine mains

both

often

unresolved,

normal

HCV often

levels

chronic

aminotransferase

of chronic

liver and kidney

HCV

of infectious

despite

Second,

carriers

viral

with

ti-

normal

histology

a few well-documented

recases

up for a few years with

blood donors have normal

alanine

levels.”

monocytes

and macrophages

vivo “,”

and can be infected

chronic

HCV carriers,

cytokines,

high

on liver biopsy.‘.‘” After all, two thirds

volunteer

aminotransferase

have normal

levels have normal

HCV carriers followed

histology

despite

besides providing

trans-

increased

such as tumor

are infected

in

in vitro. ‘* In the livers of levels of inflammatory

necrosis factor a, tumor necrosis

factor p, and interferon y, could be a cause of hepatocyte injury. This could be confused with direct viral-mediated cytotoxicity monocyte mined. Third,

histologically. and macrophage

Whether

or how HCV affects

function

remains

to be deter-

a biological

gence of “escape” mutations. tions in the neutralizing complexed

and should

susceptible clinical

cells.

disease

observation periods could

mechanism

epitopes could

cause a biochemical for the long

that the disease “sputters” quiescence occur

known

between that

often;

varying

vertical

when

of and

and activity.2i

the observation

does not

muta-

would not be immune-

flare and account

of biochemical

transmission

for the emer-

A virus that contains

infect a whole new population

This

also explain

1119

This HCV

it does,

the

neonate becomes infected with only one viral sequence even though the mother may be infected with more than one virus. 24,25Presumably, ized immune

complexes

most viruses exist as neutralin the mother

that cannot

infect

the infant. One could speculate that the virus that infects the neonate contains an “escape” mutation to which no neutralizing

antibodies

This hypothesis of HCV infections

yet exist.

may explain

the aggressive

in agammaglobulinemic

behavior

patients

and

can be identified and cloned from liver tissue and peripheral blood.‘s,l” Whether T cell-mediated toxicity to spe-

immune-suppressed patients who fail to mount an antiHCV immune response. Kumar et al. observed five patients with agammaglobulinemia who became infected with HCV from a contaminated source of intravenous

cific viral epitopes

immune

cytotoxic

T cells reactive to HCV determinants

is related to disease activity

or outcome

globulin

(personal

1993). All five patients

communication,

had an accelerated

November disease course

is yet to be ascertained. Last, HCV contains a hypervariable region in its viral envelope glycoprotein, the EZlNSl region.‘71’8 The high

and a number died of end-stage liver disease in < 5 years. We have also observed one HCV-infected cardiac trans-

mutation rate in this region may allow the virus to elude the host’s defenses, assuming that antibodies to epitopes

plant recipient who died within 18 months of infection who failed to mount a humoral response to the virus.‘”

in this region are neutralizing. This may in part explain the variable nature of the chronic infection with occa-

In at least one of the five patients

sional flares of disease activity that might correlate with the emergence of a new mutation that escapes neutralitation.” The observations

in the report

by Kumar

this issue of GASTROENTEROLOGY extend servation. mutations

et a1.20 in

the fourth ob-

They found that during a 2 ‘/*-year period, no in the hypervariable region coding for the

observed

by Kumar

et al., the virus was not observed to mutate at all in the hypervariable region. The fact that this patient had continued flares of disease but eventually became clear of his infection after interferon therapy also implies that the virus is not under selective pressure to mutate because of a cellular immune response or mechanisms associated with hepatocellular injury (personal communication, No-

body-dependent T cell cytotoxicity is not needed to cause hepatocellular injury in HCV infection. Liver injury is occurring either because of direct viral cytotoxicity or an immune response that is incapable of clearing virus.

vember 1993). Evidence that is consistent with this hypothesis was recently presented at the annual American Association for the Study of Liver Diseases meeting by Farci et al.” They obtained serial blood specimens from a patient with posttransfusion HCV for a 13-year period. Sera obtained 2 years and 13 years after infection were heat inactivated,

HCV exists in the blood as two forms: free virus and virus complexed to antibodies2’.** A possibility exists that the antibody-bound virus is neutralized. Perhaps early in infection, neutralizing anti-HCV antibodies arise that limit the extent of virally infected cells or limit infection of uninfected cells. The formation of immunecomplexed viruses may slow the pace of the infection,

then mixed with plasma obtained during the initial hepatitis. While chimpanzees developed hepatitis after receiving the initial plasma alone or the initial plasma mixed with the 13-year postexposure sera, a chimpanzee was not infected when the plasma was preincubated with the 2-year postinfection sera. Presumably, the 2-year sera contained neutralizing antibodies to the initial virus. The

major viral envelope protein of an HCV-infected agammaglobulinemic patient occurred. This implies that anti-

1120

GASTROENTEROLOGY Vol. 106. No. 4

EDITORIALS

concentration

of neutralizing

postinfection

sera was probably

because of antigenic occurred

in this patient

that

HCV

competent

or self-limit

humoral

13.

HCV that

interacts

with

its host is

14.

the host would have a mechathe infection.

does not hypermutate

a significant genicity

too low or not present

over time. a virus

If it were simple,

nism to prevent

in the 13-year

drift in the predominant

The way in which complex.

antibodies

By showing

in the absence

response, Kumar

of a

15.

et al. have provided

piece of the jigsaw puzzle that is the patho-

16.

of HCV. JEROME PHILIP

B. ZELDIS, JENSEN,

M.D.,

Ph.D. 17.

M.D.

Gastroenterology Division University of California

Davis Medical Center

Sacramento, Calzyornia

18.

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Address requests for reprints to: Jerome 6. Zeldis, M.D., Ph.D., Research Building I, Room 1004c, 4815 2nd Avenue, Sacramento, California 95817. Fax: (916) 4567727. 0 1994 by the American Gastroenterological Association 00165085/94/$3.00