disorders infected patients with acquired ...

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1985 66: 742-744

Antibody seronegative human T-lymphotropic virus type III (HTLV-III)infected patients with acquired immunodeficiency syndrome or related disorders JE Groopman, PI Hartzband, L Shulman, SZ Salahuddin, MG Sarngadharan, MF McLane, M Essex and R Gallo

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CONCISE

REPORT

Antibody Seronegative Human T-Lymphotropic (HTLV-III)-Infected Patients With Acquired Syndrome or Related Disorders By Jerome

E. Groopman, M.G.

The

human

primary (AIDS)

T-lymphotropic

cause of the and related

reported

that

ARC

manifest

HE

antibody

to

with

assays

primary

of the related

acquired disorders)

at risk

for the syndrome

observation especially

been virus.

instituted We have

manifest

individuals

exposed

antibody,

yet

this

and/or saliva.’0 risk individuals, enopathy HTLV-III.

to

had

are

the

Accurate require lack S

of

2.

I.

A

55-year-old

appeared Kaposi’s

one

infection

or tests may

for

and

with

negative.

in some

cases may In addition.

antigen.

indicate

one

antibody

an

atypical

clinical

Inc.

Again,

the findings

including

no treatment

evaluation

Kaposi’s

bisexual

generalized

for

was

sarcoma

man

was

lesions

evaluated

lymphadenopathy.

greater

than

four

of

for other were neg-

panendoscopy,

new

A 24-year-old for

there

of extensive

lesions,

present

2-cm

nontender

with

several

homosexual

man

nontender knee, which

skin lesion on he had noted

anal-genital contact. The results were otherwise entirely normal. until

AIDS but

months

in

This

had

was

not

and

associated with fever, malaise, weight loss, oral candidiasis, herpes zoster, or diarrhea. Physical exam revealed 1-cm

on two symptomatic highand the other with lymphad-

months previously. Biopsy revealed had a history of both receptive and

treatment

with

These

moveable

regions.

lymph

He was

experienced as

well

were

other bisexual men. intermittent Dexedrine history

as

not

active

but

vaginal

prostitutes

The

in cervical,

a sexually

oral-genital

men

women

nodes

not

of mononucleosis

bisexual

anal

man

intercourse

intercourse

with

and

contact

denied

patient was for temporary

to

inguinal,

women.

with

taking Mysoline and lobe epilepsy. He had

in 1980.

REPORTS

July 1982 with a violaceous lateral aspect of his right

any

culture

& Stratton,

1984

a prior Case

of HTLV-llI

antibody

sarcoma

had

with

one positive

There have been no for nearly two years.

axillary

infected

virus

and

who

but

cases.

unremarkable.

Kaposi’s

ative. noted

been

detectable

two

by Grune

1985

and

no

peripheral

Salahuddin,

Gallo

HTLV-Ill

HTLV-lIl

III

of AIDS.

October

to this healthy

Zaki

Robert

diagnosis direct virus

Case

have anti-

blood donors has recently

had

from

seronegative

CASE

are

the patient,

and

Syed

and

first

that

blood

who

recovered

antibody

report

otherwise

generalized

detect antibodies on asymptomatic

HTLV-III

We now report one with AIDS

who

prolonged

both asymptomatic HTLV-III infection

virus

We

(HTLV-

III

Essex,

course

pathogenesis

have been studied to HTLV-lII-related

using assays that previously reported

has

syndrome (AIDS) and AIDS as well as those

with

unexplained lymphadenopathy virtual uniformity of antibody

type in the

or

prior

to HTLV-lll.

virus agent

immunodeficiency Individuals

gens.59 Indeed, screening and high-risk persons for

AIDS

Shulman,

Myron

ARC.

have

with

This

etiologic

who

studies

for HTLV-lll, for antibody

T-lymphotropic

is the

Prior

HTLV-lll.

is the

syndrome

patients

Lawrence

F. McLane,

Ill (HTLV-lll)

(ARC).

to screen

HUMAN

III)

type

I. Hartzband, Mary

immunodeficiency

all symptomatic

engendered efforts to blood donation,

T

virus

acquired disorders

nearly

Pamela

Sarngadharan,

Virus Type Immunodeficiency

year

presented

in

Kaposi’s sarcoma. insertive oral-genital

the six He and

of his physical examination The patient did well without later

when

on the right arm. That sarcoma. His physical

another

one was exam

skin

MATERIALS

Sera

and

patients

hepaninized

at the

lymphocyte

time

count

also biopsy-proven at this time was

was

the

antibodies and

Piscataway, viously

NJ).8

smear.

Skin

virus tests

were obtained

periodically

by the

Peripheral

percentage

OKT3

(pan-T

cells)

Serum

immunoglobulins

Titers

to

performed

Co,

measured

virus

as pre-

capsid

measured

Candida.

using (suppres-

Pharmaceutical

Epstein-Barr

using

measured OKT8

were were

both Total

of lymphocytes

were

(Ontho

cytomegalovirus

from

thereafter.

T cells

(helper-inducer),

B, and

were

and

OKT4

described)0

hepatitis

METHODS

blood

determined

blood

sor-cytotoxic),

lesion

of diagnosis

on a peripheral monoclonal

AND

peripheral

antigen,

as described.8

mumps,

and

PPD

anti-

gens.8 From

the

Divisions

Department

of

Divisions

of

ofHematology/Oncology

Medicine.

Cell

Supported

ofCancer Medical

Biology, in part

Cancer from

No.

RD203,

Research

Fund

of the New England

May reprint

©

I 985

St.

Boston, by Grune

New MA

the

the Cancer

England

02215.

& Stratton,

0006-4971/85/6603---0045$03.00/0

742

Community

the

Bethesda,

American

Cancer

and

Deaconess

Immune

Inc.

Deaconess

Md. Deficiency

Hospital.

Hospital,

using

of 110

whole

H9

and

were established

clean

cells

on

these

cells

cell

in patient from

blood

mononuclear

healthy

individuals.’0 cells

similarly

l-1TLV-lll-negative

Identification

donors

of HTLV-III

Blood,

Vol

cultures

using

blood and

interferon

HTLV-III

established

Controls

consisted from

No 3 (September),

of

peripheral asymptom-

risk peripheral

1985:

was

T cell cub-

healthy

at no epidemiologic of patient

for

mononu-

stimulating

anti-alpha

Similarly,

in cultures

66,

HTLV-IlI-

Virus

gradient and

cultured

using

from

peripheral

factor

specimens

semipuni-

radioimmunopnecipitation lysates

described.”8’0

saliva

to HTL V-Ill: using

immunoblot.3’6 density

growth

previously

tunes atic

T

‘

by separating

a Ficoll-Hypaque

with

antibody (ELISA)

immunofluorescence

cell

Western

HTLV-lII

as

assay

indirect membrane H9 cells as targets;’

33S-cysteine-labeled

antibody cultured

serum

immunosorbent

whole virus;37 HTLV-lII-infected infected

Society,

Division

were used to measure

an enzyme-linked fled

Health

Institute,

20, 1985; accepted July 10, 1985. requests to Dr Jerome E. Groopman,

Hematology/Oncology, Francis

Hospital;

Biology, Harvard School of Public School, Boston; and the Laboratory

Contract Submitted Address

and

Four assays

Endocrinology,

Deaconess Harvard

National by grants

and

England

Hematology/Oncology.

Plan; the Department Health; the Harvard of Tumor

New

pp

for

AIDS. blood

742-744


HTLV-III-INFECTED

PATIENTS

WITH

AIDS

743

mononuclear cells on saliva was done by measuring scniptase activity and using a monocbonal antibody HTLV-III cone-related antigen p24.

reverse tranagainst the

DISCUSSION

HTLV-III immunodeficiency appears syndrome

RESULTS

Standard

laboratory

testing

revealed

normal

complete

blood count in patient 1 but leukopenia nia in patient 2 (Table 1). The bone

and thrombocytopemarrow aspirate

biopsy

2, and

results

were

blood

counts

ARC.

T cell studies

normal

were

T4 number

thought

Serum

immunogbobulins

detected

to previously

patient rect

consistent

revealed

in patient

using

were

the

was recovered

and

saliva

from

and

generalized

blood

are currently vention.

Both

these

Kaposi’s

sarcoma the

and

patient

with

from

without

both

of

thrombo-

AIDS

patients

subsets

Both

therapeutic

years.

mild

1 . Laboratory

two

the

a poor

cases,

Total

cells

lymphocyte

per mm3

6,200

count

1,425

per mm3

but with

patient

with

has

virus Kaposi’s

AIDS

with

generalized

and

and

leukopenia

detectable antibody.’#{176} Although normal by immunologic testing, show

skin

test

that

clinical

some

abnormality

reactivity

to recall

positive.

development outcome,

perhaps

is similarly

in peripheral

T cell

is correlated

to sufficient

Case 2

1

(ARC) 3,900 900

36

30 48 0.72

0.88

125.000

168,000 (mg/dL) 1,600

lgA gM

1,520

355

380

285

255

Testing

Skin

Mumps

+

Candida PPD Serum

Viral

Titers

Cytomegalovirus Epstein-Barr

virus

capsid

1:64

1:8

1:80

1:40

Hepatitis

B core

+

Hepatitis

B surface

+

HTLV-Ill

Antibody

ELISA IFA RIP

Western HTLV-III

blot Virus

Culture

32.000

Control Cultures ELISA,

expressed

enzyme-linked

9

day

PBL

day 14 130.000

173 as reverse immunosorbent

transcriptase assay;

activity IFA, indirect

(counts

per minute

immunofluorescence

802 per mL supernatant) assay;

for

lymphade-

persons cases of

due

41

Immunoglobulins

is

these these

of antibody

(cytoxic-suppressor)

lgG

The

sarcoma

antigens.

(helper-inducer)

Serum

one who

We have previously reported on asymptomat risk for the acquired immunodeficiency carry HTLV-III in peripheral blood and/or

0KT8 Platelets

to

blood viru.

has been asymptomatic of any new lesions

OKT4

ratio

led

among to this

Percentage

OKT4/OKT8

It the by

lymphadenopathy,

negative, patient

(AIDS/KS) blood

one

in that he appearance

The

This

Evaluation

Case

White

acquired

disorders.

particularly serum antibody

thrombocytopenia,

ARC

and

with Table

of

It is possible

inter-

of the

assays.3’9

of prolonged

interesting without

two

and

first

blot

antibody

course

saliva without were entirely

peripheral

leukopenia, any

not

blood

the

asymptomatic. atic individuals syndrome who

1gM

Western

disorder

HTLV-IlI

nopathy,

or

were

the peripheral

lymphadenopathy.

asymptomatic

and

and

report

a related

almost

mdiblot,

IgG

techniques

from

in either

Western

now

or

particularly and untreated

cases. assay,

assay,

techniques.

with

in both

was not detected

agent related

that virtually all symptomatic patients with manifest antibody to I-ITLV-III, detected to screen for HTLV-III, using assays that detect

clinical

were

and

ELISA

are

patients.

antibodies

immunosorbant

using

patient

in absolute

etiobogic

syndrome

efforts donors, with

of

primary

either

We

diagnosis

in both

and

viruses

antigens

sought

HTLV-III

cytopenia,

normal,

immunofluorescence

were

the

ratio

and

his abnormal

abnormalities

encountered

radioimmunoprecipitation

found.

with

in T4/T8

the enzyme-linked

membrane

antibodies

mild

2 and

to HTLV-III

Antibody

in patient

is the

day 9 26,000

168 on days 9 and 14.

and RIP, radioimmunoprecipitation.

day 14 175.000

712

in vivo


744

GROOPMAN

proliferation

of HTLV-lII

that elicit an antibody reported an acquired to

neoantigen

ARC.’2

to expose response. B lymphocyte

challenge

Although

the

in

two

total

serum

immunogbobulins,

ate

antibody

response

the host

to viral

persons

cases

with

the

reported

related antigens is unable could explain the antibody

newly

AIDS

here

it is possible to

antigens

Lane and co-workers have abnormality in response had

that

an appropri-

encountered

to develop. This seronegativity

and

normal

patients are nearly We are currently over

a six-month

uniformly following period

since

recovery

of virus,

in either

in such

closely,

and

antibody

has

of them.

Preliminary

data

antibody serum conversion to 16 weeks after exposure

to HTLV-III in both man

zees

(M.

Bionetics,

Sarngadharan,

personal

Litton

communication,

indeed,

B cell dysfunction of these two cases

antibody positive.3’6 these two patients

developed

that four

individuals

HTLV-III-

but certainly does not explain the response to HTLV-III the vast majority of patients with AIDS or ARC since

not

may

require

never

seroconvert.

may

patients

March

with

AIDS

or

HTLV-III infection viral antigens rather might

periods

ARC

to

be of importance

suggest

for both

in screening

blood donors. have prognostic

Furthermore, significance

Md, or,

such

on

that

symptomatic

some

seroconvert as ours

diagnosis

may require direct assay than antibody in certain

well as possibly

indicate

Nonetheless,

Observations

of

for virus or hosts. This individuals

of asymptomatic

AL

occurs within and chimpan-

Kensington,

1985).

long

ET

persons

antibody seronegativity in HTLV-III-infected

as

such

as

may persons.

REFERENCES 1

.

Popovic

isolation

M, Sarngadharan

and

(HTLV-III) 224:497,

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production

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AIDS

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RC:

Detection, retrovinuses

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1984

Schupbach J, Popovic M, Gilden RV, Gonda MA, Sarngadharan MG, Galbo RC: Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS. Science 224:503, 1984 3. Sarngadharan MG, Popovic M, Bruch L, Schupach J, Galbo RC: Antibodies reactive with a human T-lymphotropic retrovinus (HTLV-lII) in the serum of patients with AIDS. Science 224:506, I 984 4. Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan, Haynes BF, Palker Ti, Redfleld R, Oleski J, Safai B, White G, Foster P, Markham P: Frequent detection and isolation of cyto2.

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8. Groopman iE, Salahuddin SZ, Sarngadharan MG, Mullins ii, Sullivan iL, Mulder C, O’Hana Ci, Cheeseman SH, Haverkos H, Forgais P, Riedel N, McLane MF, Essex M, Gallo RC: Vinobogic studies

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10. Salahuddin SZ, Groopman JE, Markham PD, Redfleld RE, Essex M, Sarngadharan MG, McLane MF, Sliski A, Gallo RC: HTLV-III in symptom-free seronegative persons. Lancet 2:1418, 1984

for AIDS. Science 224:500, 1984 5. Goedent ii, Sarngadharan MG, Biggan Ri, Weiss SH, Winn DM, Greene MH, Mann DL, Gallo RC, Grossman Fi, Bodner Ai, Strong DM, Blattnen WA: Determinants of retnovinus (HTLV-III) antibody and immunodeficiency conditions in homosexual men. Lancet 2:71 1, 1984 6. Safai B, Sarngadharan MG, Groopman iE, Popovic M, Schupbach J, Arnett K, Sliski A, Gallo RC: Senoepidemiobogic

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