The role of host immune responses in determining the outcome of HIV infection

The role of host immune determining the outcome o eis

Michael Westby, Fabrizio

Al /B8/DR3

haplotype

is associated

rapid disease progression, increased susceptibility

to infections-n,

a deletion of the complement lentivirus

subgroup

of retroviruses.

AIDS. The C4A deletion

ing autoreactive

immunopathology;

and

gene C4A is

associated with a more-rapid

Lenti-

viruses are associated with diseases involv-

with

as well as with

progression

studies in which the HLA-Al/B8/DR3

this is

to

may also explain as-

known to depend on the genetic background

sociation has not been as clearly associated

of the host since symptomatic

with the rate of progression

infection oc-

to disease, al-

curs in some strains of host but not in

though the frequency

others (e.g. visna-maedi infection in sheep)‘.

type in ethnic mixes is also likely to be an

Other

well-characterized

lentiviruses

important factoF4.

are

alleles encoding

slow at inducing disease, and it is possible that HIV and SW employ similar mechanisms of pathogenesis

tion in human populations immune

are consistent with this, particularly

apoptosis.

anergy, and the level of

Conversely, all of these features are absent in HIV-in-

fected chimpanzees, progress

the

to disease with the degree of

activation and antigen-specific

which can be infected with HIV but do not

to AIDS (Ref. 2). Although

Interestingly, when the

Al and B8 are split from

DR3 (a rare occurrence)

to these viruses. Many features of HIV infec-

association of the rate of progression

of the studied haplo-

recent data have revealed a

an increased

rate of progression

segregates

the susceptibility

with DR3 (Ref. 15). Other MHC class I alleles associated with rapid disease progression

include HLA-B35 and A-24 (Refs 9, 12, X-20);

MHC class II alleles associated

with

rapid

progression

HLA-DR2 and DR5 (Refs 12, 21, 22). However,

specificities encoded in MHC class II DR5 and DR6 correlated with a slow progression

to disease, which was proposed

to be due to a

skewing of the TCR repertoire

tied,‘, followed by high rates of virus replication and mutation dur-

tween the HIV gp120 V3 loop and the DR sequences23.

and progression

phase5c6, susceptibility

to disease cannot yet be explained

to infection solely on the

include

in another study,

high viral load in lymph nodes and spleen shortly after HIV infecing the clinically asymptomatic

as a consequence

Recently, there has been considerable

of mimicry be-

interest in searching for an

HLA association with long-term survivors of HIV infection. Previous

basis of the infecting HIV species. Many research groups have de-

reports associated HLA-Bw4 and HLA-DRBl*0702/DQAl*0201

scribed associations within HIV-infected

asymptomatic

certain major histocompatibility

cohorts between

disease,

complex (MHC) HLA types and a

restricted T-cell receptor (TCR) variable-gene

repertoire, arguing for

a positive role of the host’s immune system in determining outcome, as reviewed below.

clinical

to

with Al/BS, and not

with

HIV-l infection 13,1s.Many other HLA class I genes

have been shown to be ‘protective’, notably those encoding HLA-A25, A32, B18, B27, 851 and B57, which are rare in most human populations. Although the significance of these observations has been noted that these HLA types are predicted binding certain conserved

HIV peptide sequences

is unclear, it to be better at

than other HLA

types (D. Mann, pers. commun.). The HLA genes that have been re-

HLA and the response to HIV

ported as being associated

Genetic susceptibility to HIV could theoretically operate at three dif-

Overall, it is likely that there is a hierarchical

ferent levels: (1) the susceptibility

to infection upon HIV challenge;

tant associations

(2) the rate of disease progression

once productive infection has oc-

effect has already been noted within the class II alleles between

with HIV are summarized dominance

HLA-DQ and DR with regard to disease outcome24.

cell depletion. Examples of all three have been documented for HLA genes encoded within the MHC region of the human genome.

role in determining

disease susceptibility

appear inconsistent

with the data from chimpanzees,

of women

prostitutes

sistant to HIV-induced in Nairobi is

linked to HLA-A2 and HLA-DR13 (Ref. 7). By contrast, the HLACOW gbt$ ,996E’Wi E’Ec’e”ie Ltdai r gntlre;eWed jl67.5699’9615 I501:

The conclusion that the haplotype of an individual plays a major and clinical outcome may which are 98%

identical to Homo snpierrs at the genetic level and yet seem to be re-

I-M assaciation with HIV disease progression to HIV infection

of impor-

between MHC class I and class II alleles. Such an

curred; and (3) the conditions that define AIDS after severe CD4+ T-

Resistance

in Box 1.

disease*. However,

genes appear virtually homologous are subtle differences

whereas HLA class II

between the two species, there

in the HLA-B and HLA-III regions, the latter

IMMUNOLOGY

TODAY

disease

progression

of which encodes the tumour necrosis factor (TNF) genes. More-

Fast progressors

over, the chimpanzee

Al, A9, All, A23, A24. A28 + TAl’2.3, A29 + TAI’2.1,88 i DR3, 835 + Cw4, DR2, DR5

appears to have passed through an evolution-

ary ‘bottleneck’, since they lack homologues ated with fast progression

to HLA types associ-

to disease in humans, notably HLA-EW. It

Slow progressors/long-tern

is tempting to speculate that such a bottleneck was shaped by past infection with HIV!

non-progressors (LNTPs)

A9, A25 i- TAP2.3, A26, A32, BS, B14, B18, B27, B51,857, Bw4, DR5, DR6, DR7, DRB1*0702 + DQAl*OZOl, DR13 Frequently

Underlying mechanisms

A2, A28, DF.13

Several theories have been proposed

to explain the associations

tween haplotype

to HIV infection and disease.

The breadth

and susceptibility

of protective cell-mediated

individuals

may depend

responses

be-

in HIV-infected

upon how many different peptides

de-

rived from key viral antigens (such as Gag, Pal, Env and Nef) are presented

by their HLA molecules. On the other hand, HLA genes

may simply be markers for, as yet undescribed, the key determinants

exposed HIV-seronegative (FESN) individuals

conferring

protection

genes that encode

or susceptibility.

Alter-

natively, viral protein products containing structural/sequence

mo-

The TCR is a heterodimeric

cell-surface molecule expressed on the

surface of helper fCD4’) and cytotoxic (CD8-) T cells, and interacts with foreign antigen

in the form of short peptides

presented

by

MHC class II or I, respectively, on the surface of infected cells. As such, the TCR represents a key elen,Gnt of the cell-mediated arm of

response

the immune

to pathogenic

challenge. TCRs comprise

tifs similar to HLA may elicit an allotype response capable of de-

either ~8 or ~6 chains, with 90% of the circulating T cells in the adult

pleting uninfected

expressing

determined

CD4’ T cells: the strength of the response being

by the ability of an individual’s

process and present the virally encoded

HLA molecules

alloreactive epitopes.

to The

up. TCRs belong to the immunoglobulin-gene

family, comprising

variable- and constant-region

arrange randomly during fetal developmenP9.

advent of molecular techniques for typing HLA genes within popu-

shown that HLA background

lations has already revealed previously

influence

unsuspected

associations

with several diseases. HIV-infected cohorts are only now being reinvestigated

using these techniques

yet to be published.

and most of the studies have

However, it would appear that recently identi-

the formation

Several studies have

and environmental

of the mature

super-

segments that refactors can both

TCR repertoire

in hu-

mans30mN,leading to the possibility that the TCR repertoire may contribute to HIV susceptibility/resistance. Interest in the TCR repertoire following HIV infection, and how

fied genes within the MHC region, such as those encoding the pep-

this relates to pathogenesis

tide transporter

has focused on two purposes: to determine the oligoclonality of the

associated with antigen processing

(TAP), can in-

and the rate of CD4- T-ceil depletion,

fluence the associations of HLA class I and II, affecting both fast and

host’s antiviral response and to seek evidence for a virally encoded

slow progressors.

superantigen

It is important to understand

the nature of HLA-associated nrotec-

tion from HIV infection for the design of effective vaccine strategies.

(SAgI. For example, TCR analysis has been used to

study the frequency

and longevity

clones in HIV-seropositive

of HIV-antigen-specific

CTL

individuals”“. It has also been possible to

One explanation

is that ‘protective’ HLA alleles present immuno-

determine the naive CD4’ T helper (Th)-cell repertoire for HIV anti-

dominant

peptides

gens, by repeated

viral

lymphocyte

that

generate

a strong

cytotoxic

T

KTL) response capable of neutralizing virus at the time

of exposure,

thereby

preventing

established

infection

and sero-

conversion. This mechanism has been proposed for HIV-exposed but uninfected

Gambian wome@

and described for the 653-associated

in nifm stimulation

of peripheral

nuclear cells (PBMCs) from HIV-seronegative latter studies may have implications

blood mono-

individualP’.

in designing

These

peptide-based

vaccine strategies, since effective Th-cell responses mediate both the Immoral and cell-mediated immune responses to pathogen. However,

resistance to severe malariazh. An alternative explanation for the HIV-

this article will focus on research that has looked for VP-family-

seronegative

specific TCR perturbations

Nairobi women prostitutes owes credence to the obser-

following HIV infection as evidence for

vation that host cell-surface molecules, including HLA, are incorpo-

an HIV-encoded

rated into the virion envelope?

maintain a stable TCR repertoire following HIV infection’“, and that

It is possible that allospecific immune

SAg. It is interesting

to note that chimpanzees

responses, raised and maintained by regular sexual contact, protect

anergy (a consequence

the women by recognizing as foreign antigen the HLA molecules that

with gpI20 in human but not chimpanzee

are incorporated

differences contribute to the absence of AIDS in chimpanzees.

supported

into the envelope of viral particles. This argument is

of superantigenic

challenge) can be induced Th cells?; perhaps

these

by the finding that protection correlates with the number

of sexual contacts, as well as by the fact that the haplotype of the protected women is rare for the Nairobi population (i.e. most sexual

SAgs and HIV

contacts would represent a form of alIo-immunization).

SAgs have been identified

host immunity

is thought

to explain

vaccination

This form of studies

macaque model of SIV infection, where monkeys immunized

in the with

uninfected human cells are protected from infection upon subsequent SIV challenge with virus grown in the same human cell line’“.

as essential components

in the patho-

genesis of several bacterial (e.g. Sfap/n~lococcrrs nr~rc~r~)and viral [e.g. mouse mammary

tumour virus (MMTV)] infectionsiq,“‘. 5Ags

classically stimulate a broad range of T cells by binding to the (Ychain of MHC class II and interacting with TCRs bearing specific

to the CD4’

bations of the TCR repertoire would be found. Indeed, using a PCR-

T-cell subset, although the SAg erythrogenic toxin A (ETA) from Streptococcus pyogerzes has been shown to activate CD4’ and CD8+

based technique, Imberti et nf.4”found a deletion in VP1420’ T cells

T cells4’. Following MMTV infection in mice, T-cell proliferation

Vp families in AIDS patients, although other workers have reported

Vp families. Thus, their activity is usually restricted

sults in the release of cytokines

promoting

B-cell expansion

reand

in patients with AIDS. Hodara et ~1.~’also found broad deletions of a random VP depIetion4s50. It now seems most likely that the de-

leading to increased viral load. T-cell activation is SAg mediated and

leted T-cell subsets identified by Imberti et al. and Hodara et al. in

is dependent on the MHC haplotype and TCR repertoire of the micea.

AIDS, being low in number in normal individuals,

Thus, it seems reasonable to propose that the selective benefit of a

detectable limits of their assays due to random T-cell depletion in the

virally encoded SAg is to activate the immune system in such a way

AIDS group of patients. This is not surprising

as to provide the appropriate

occurs when protective

(cytokine) environment

pansion without stimulating virus-specific

was proposed

following

that certain murine retroviral infections known to

involve SAgs exhibit similarities with a number of clinical and experimental

host immunity

since clinical AIDS

has been irrevocably

de-

stroyed and CD4+ and CDS+ T cells are being lost. Opportunistic

host responses.

A role for a SAg in HIV pathogenesis the observation

for viral ex-

fell below the

features of the immune system following HIV infection

infections also cause transient lymphocyte stage, thereby further complicating Instead of studying clinical AIDS, several

lymphocyte groups

expansion

during this

the issue. populations

in patients

have compared

with

HWseropositive

(e.g. broad immune activation, HIV-induced T-cell anergy). Since all

asymptomatics

SAgs described to date interact with the VP region of the TCR, the

panel of VP mAbs suggested that there was a generalized activation

search for evidence of an HIV-encoded

of VP-bearing cells, with Vp5.3 being significantly

SAg has focused on analysis

with healthy controls. Early work using a limited

individuals

higher in HIV-

of the 24 VP families that, together, make up the TCR VP repertoire.

seropositive

At first sight, there appears to be great confusion over whether or

et aL5” also showed

not a SAg exists in HIV; however, by dividing the studies on the basis

case they found the proportion of T cells expressing the Vp5.1, VP12

perturbation

and Vu2 gene products

of criteria proposed below, the situation becomes a little clearer.

compared with the control groupsl. Bansal of the TCR repertoire,

in asymptomatic

duced relative to seronegative

homosexual

homosexual

but in this men was re-

controls. Most recently,

McCoy et aLs3 have shown that CD4+Vp19+ T cells are selectively The method of TCR analysis (PCR-based techniques versus

depleted during HIV pathogenesis.

cycofluorometry) The preferred method for analysis of the TCR VP repertoire is to use

phase of HIV infection54*55has revealed an activated but intact TCR

VP-specific

monoclonal antibodies

(mAbs) and fluorescence-acti-

vated cell sorter (FACS) analysis. This gives a reliable readout of the

Examination

of the TCR repertoire

during

the acute viraemic

repertoire. Other researchers have shown VP perturbations the acute stage to be the result of HIV antigen-specific

during

immune re-

percentage of T cells within a given population bearing a particular

sponses driving oligoclonal expansion of T cells, particularly CD8+

VP family; by double staining with anti-CD4 or anti-CD8 mAbs, the

CTLs (Refs 56,57). It seems that the level of T-cell activation per se

repertoire

during this stage is a good indicator of the rate of progression

within each T-cell subset can also be examined.

tunately, the number of VP-family-specific recent publication

using this technique

Unfor-

mAbs is still limited - a covered only 45% of the

ual examined by Pantaleo and co-workers

resulting in progression

repertoire4*. A more common technique has been to use VP-family-

to AIDS within 12 months of infections6. Interestingly,

specific oligonucleotides

ual’s haplotype

extracted

to amplify

all 24 families from mRNA

from PBMCs (Refs 43, 44). With this method,

it is also

ously as being associated

with rapid disease

well-documented

tion on magnetic beads or complement

suggest that a broad recruitment

chain reaction

method relies on semi-quantitative presumes

lysis prior to RNA extraction

(PCR) analysis.

However,

this

long-term

amplification

parameters

and

expansion.

that the relative proportions

species is representative

Edinburgh

immune

haemophiliac

of the proportion

of T cells is more desirable

for

of cells bearing each parFurthermore,

to amplify all subtypes within a given

VP family, which may be disadvantageous

if a putative

HIV-en-

MHC-matched

versus nonmatched

To avoid HLA-driven

et n1.5R compared

populations

influence on the TCR repertoire3&%, Rebai

the TCR repertoires

monozygotic

for the mouse endogenous SAg Mtu-7 or!, which activates mouse T cells bearing TCR Vp8.1 but not Vp8.2 (Ref. 45).

CD4’ but not CD8+ cells. Although

families VP13 (6/7 cases studied)

pansion observed The stage of disease SAg focused on AIDS

that the most dramatic

pertur-

and VP21 (4/7) expressed

by

the scale of the perturbation

it is comparable

with the VP14 ex-

in BALB/c mice following injection of infectious

MMTV(C3H)5q and the expansion

Early attempts to identify an HIV-encoded

of nine pairs of discordant

twins. They found small but significant changes in VP

initially seems unimpressive,

where it was suggested

in the

control of the virus than is mono/oligoclonal

coded SAg is subtype specific; this has been shown to be the case

patients,

progression

cohorts. These findings

of each VP-bearing mRNA

ticular VP family in the original T-cell population. primers are often designed

this individ-

was HLA-Al /BS, which had been identified previ-

possible to analyse CD4/CD8 T-cell subsets using either cell selecand polymerase

to

AIDS (Refs 54,56), with the most prolific activation in one individ-

in vitro following co-incubation nucleocapsid protei#.

of the CD4+Vp8+ T-cell subset of human

PBMCs with rabies

IMMUNOLOGY

Using another approach, TCR VP perturbations in a cohort of HIV-infected infected or uninfected

mothers

childre#.

were observed

when compared

SIV infectio#;

that any perturbations

ential activation of Vp12- cells rather than the preferential entry of

study in

HIV into these cells that contributed to the higher viral titre. These data are consistent with a virally encoded SAg.

However, a prospective

although,

Rebai et ~1.~~have suggested

in the macaque

restricted to specific VP subfamilies,

repertoire,

able to replicate inside the T cells, indicating that it was the prefer-

with their

macaques failed to show any changes in the Va or VP repertoires following

TODAY

should they be

may have been missed in this

study due to the PCR techniques employed.

An altered proliferative response to some but not all bacterial SAgs has been reported in HIV’ individuals. PBMCs from HIVseropositive asymptomatics

respond normally when cultured i?zz$tro

with staphylococcal enterotoxin A (SEA) or SEB (Refs 50,66) but have a significantly different VP usage compared with control groups ir, response to SED or SEE (Refs 67,68X Furthermore,

Sourceof T cells (peripheral blood versus lymph node)

responsiveness

The lymph nodes have been shown to be the site of most active viral

from HIV-serop>sitive

proliferation

sponse to ETA (Ref. 68). The nonresponsiveness

during the asymptomatic

phase of HIV pathogenesis.

selective non-

of Vp8+ (but not VplZ-) CD4’ and CDS+ T cells individuals

has been demonstrated

in re-

of the VpS+ subset

of T cells from the lymph nodes to the periphery

was not recoverable with interleukin 2 (IL-2) or IL-4. Although this

(and vice versa) upon HIV infection account for the apparent pertur-

V/38+ T-cell anergy was only observed in 56% of the patients and

Can redistribution

bations described in peripheral blood? To investigate this, Soudeyns

has yet to be correlated with progression,

et ~1.~ have compared with the peripheral

it has been confirmed by

the TCR VP repertoires

in the lymph nodes

another group who used rabies nucleocapsid

blood of two HIS-infected

patients. Consistent

Vp8-specific SAg, to stimulate

twins and mother-

infected PBMCs with rabies nucleocapsid protein also induced Th2-

with their findings in discordant

monozygotic

protein, which is a

cells i!z zjiW’. Treatment of HIV-

child studies (described above), they found significant perturbations

type cytokines (IL-4 and IL-IO) and led to B-cell activation, resulting

in the TCR repertoire, with a 24fold

in the production of anti-HIV and autoantibodies,

reduction of Vp6+ and Vp21*

T cells in the lymph nodes of one infected individual, the peripheral

blood. A more-thorough

tomatics and six healthy control& ences in the VP repertoires

relative to

study of five HIV+ asymp-

confirmed

that there are differ-

of lymph nodes and peripheral

blood

during HIV infection. Despite there being random partitioning

of

both of which are

associated with HIV infection. Perturbations ing stimulation

in the TCR repertoire have been observed followof HIV-seronegative

individuals

with either crude

viral extracts or purified envelope preparations”‘-“. of the patterns were complicated,

VP3

Although many

T cells were consistently

VP-bearing cells both in healthy and infected individuals, there were

stimulated

consistent

with HIV-derived antigen. Furthermore, this stimulation was MHC

differences

in the CD4+VP5.3+ and CD4+VP21’ T-cell

subsets between the two compartments

of the infected group. More

in CD4’ and CD8’ subsets after incubation

cIass II dependent

of PBMCs

and did not require antigen processing, both of

surprisingly, there were also differences within Vp5.2/5.3, VP12 and

which are characteristics

VP21 families of the CD8+ subsets.

One study, finding no evidence of mixed lymphocyte reaction (MLR) using PBMCs from two monozygotic twins discordant for HIV infection, concluded that it is unlikely that a SAg is involved in HIV pathogenesis 73. However, the HIV-infected twins studied were

Manipulation in vitro prior to TCR analysis(‘functional’studies) As intimated above, the peripheral blood may not provide the ideal lymphocyte

population

it is the only convenient

for studying the TCR repertoire. However, population

of a SAg.

and is often the only practical

source of cells for these studies. Given this limitation, the question

both in CDC (Centers for Disease Control) stage IV, and 98% of ihe phytohemagglutinin (PI-IA)-treated, irradiated PBMCs used as stimulators were CD8+ and therefore would either not be infected or would have low levels of MHC class II: in this instance, it is not

then arises as to whether one should pm-incubate the cells in vitro

surprising

prior to analysis; this is a common practice in studies of, for exam-

eration.

ple, the cytokines produced

Srap~yl~cocct~sSAgs (SE) was observed in the infected twins, which

during a Thl to Th2 switch following

HIV infection@. The arguments

for and against manipulation

of

samples in vitro prior to analysis are equally as valid: the main argument for in vitro culture is that it helps us to understand tional state of cells; whereas an argument that manipulation

very interesting

forces

in vitro have produced

some

results.

One imaginative

in vitro

approach

with the SE-induced

prolif-

to a cocktail

of

selective VP anergy found by

other gro~p@‘*~.

pressing for caution is

of cells in the absence of counteracting functional studies

is consistent

a hyporesponsiveness

the func-

from the immune system can give artificial results. These arguments notwithstanding,

that this study failed to detect any SAgspecific Nevertheless,

has shown that laboratory-

If VP-specific consensus? The perturbations

perturbations

exist, why is there no

of the TCR repertoire described

above are sum-

marized in Table 1. The difficulty in identifying

a single, consistent

SAg-reactive

individuals

subset of T cells in HIV-infected

might

adapted strains of I-IN preferentially grow in T cells expressing VP12

be a consequence

rather than VB6.7, regardless of the donor origins. T-cell activation

changes in the VP specificity of the putative HIV-encoded SAg. On

was MHC class II dependent

but not haplotype restricted. Further-

more, if Vp6.7+ cells were first stimulated

with mitogen, virus was

of the high mutation rate of the virus promoting

the other hand, other cofactors may be involved. Recently. Dobrescu and colleagues found an explanation

for their earlier observations

IMMUNOLOGY

TODAY

59,801, suggesting

that Nef plays an impor-

tant role during

the interaction

of HIV-

infected cells and CD4+ cells. Evidence supporting the importance of Nef in HIV pathogenesis

has

been

recent discovery

by

provided

the

of an HIV quasispecies

with a 124deletion that is present in six HIVseropositive long-term survivorsa’. Although experiments fied gp16O/gp120

in vitro using puri-

have shown

induced TCR VB perturbations,

envelopemore-con-

vincing data have been generated crude preparations ing that other

using

of HIV, possibly indicatvirus

molecules

are in-

volved71. Therefore, it is possible that gp120 could act as an accessory

molecule

for

of preferential growth of HIV in VB12’ T cells when they showed

presentation of Nef in the same way as the MMTV envelope protein

that cytomegalovirus

is known to be necessary for SAg presentation

infection of monocytes was responsible

for

in miceB2. Other

the SAg-like effects74. Their findings do not explain the other VB

regions of the HIV genome have also been implicated as encoding

perturbations

SAgs, but little experimental

described above, such as the VP&specific anergy ob-

evidence is available to datea3.

served by Dadaglio et RI.6R,but do support the hypothesis that there is a SAg involved in maintaining a T-cell reservoir of HIV in viuo, Mimicry

although the SAg may not be HIV encoded.

There am many other ways in which HIV infection could lead to a skewed TCR repertoire. For instance, the ability to activate the imCandidates for an HIV-encoded SAg

mune system preferentially

gp120.gp I60 and Nef The envelope protein gp160 and its outer envelope

like regions encoded by HIV Molecular modelling component

in some hosts may be due to the HLAof gp120 pre-

dicts that several regions of HLA mimicry may contribute to the

gp120 have received the most attention in the search for an HIV-en-

envelope being recognized

coded SAg. These proteins bind strongly to the CD4 receptor, which

has been shown that soluble gp120 can bind selected peptides that

as an allo-HLA molecule. Recently, it

lies in close proximity to the B chain within the TCR complex on the

can also be bound by specific soluble HLA molecules, and that this

T-cell surface. Anti-gpl60-reactive

CTLs raised in mice of unrelated

binding can be specifically competed out with the same peptide@.

haplotype showed restricted VB usage, with the clones expressing

This argues for a functional mimicry that may be rendered more

VBS or VB14 TCRs (Ref. 751. Similarly, usage of VB12,13,14 and 15

effective by the incorporation

TCRs was observed in a study of gpl20-specific human CD4’ T-cell

of the budding

clones raised from two individuals by repeated in vi&o stimulation

clivity to protection from challenge by SIV in macaques that have

with soluble gp120 (Fig. 1; M. Westby, A.G. Dalgleish and E Manta,

made a good immune response to allogeneic cellP.

unpublished). autologous

These clones reacted to whole gp120 presented antigen-presenting

cells (AI%)

by

but not to synthetic

of HLA molecules into the envelope

virus and which could, therefore, explain the pro-

Another way HLA mimicry might contribute to SAg-like effects, and hence to disease, is by the furnishing of HI&like

peptides en-

peptides. This anomaly was initially attributed to T-cell recognition

coded by the HIV genome to compete with the normal self-HLA

of nonlinear

peptide repertoire that is viewed as normal by the host. If the virus

epitopes

or the importance

of flanking sequences

within the antigen, as had been observed previously76. However, an

furnishes similar (but not identical) HLA peptides, then tolerance to

alternative explanation is that gp120 binds to MHC class II and

self-peptides

interacts with the TCR in a non-antigen-specific

HIV gpl20, when presented

manner analogous

tr. SAg-mediated or allogeneic stimulation.

them susceptible

Another candidate for an HIV-encoded SAg is Nef, whose open reading frame (ORF) within the HIV genome corresponds

could be broken. In support of this, the C-terminus of

to the 3

as a peptide by target cells, renders

to killing by their own allogeneically

activated

CTLs (Ref. 85). This effect is not observed in all cells, but appears to be mom prevalent in HLA-88 donors (A.G. Dalgleish, unpublished).

ORF of the MMTV SAg. The SIV homologue of nef has been shown

This would be consistent with the proposal by Habeshaw& that the

to be essential for development

difference in disease progression

of AIDS in SIV-infected rhesus

between

HLA-B8 and 827 indi-

macaques, particularly with respect-to high viral load and disease

viduals is explained by their different presentation

induction=, and has been shown to be sufficient to induce irnmuno-

with B8 presenting

deficiency in transgenic mouse models7s. The C-terminus of Nef has

HLA-peptide

been identified on the cell surface of HIV-infected T-cell lines dnd

would suggest that the situation is unlikely to be this simple, and

EBMCs (Ref. 791, as is the case for the MMTV-encoded SAgs (Refs

several other HLA-like sequences that are encoded by HIV may play

MARCH

1996

of this region,

the peptide in such a conformation

that the

complex mimics allo-HLA. However, our studies

IMMUNOLOGY

TODAY

CDR3 region

FAB line C

TGTGCCAGCAGT C

FAB line D

S

GCCCTGGGGGGC

S

TGTGCCAGCAG

VJ312.4

C

FAB line E Vj312.3 FAB line F

S

R

P

Q

G

GCCCTGGGGGGC

A

S

C

A

S

C

A

T

P

S

C

A

NQPQHF

L

G

Y

Y

D

S

F

Jp2.7

Jf31.5

NQPQHF

Jpl.5

CAATGAGCAGTTCTTC G

N

E

Q

F

F

Jp2.1

ACAATGAGCAGTTCTTC

DLPTTSGM

DNEQFF

TTCGAGGGGTCAAGGG

S

Y

AATCAGCCCCAGCATTTT

GATTTGCCAACGACTAGCGGGATGG

S

Q

SNQPQHF

G

A

E

AGCAATCAGCCCCAGCATTTT

G

G

Jj31.5

TACGAGCAGTACTTC T

TACGACGCTAGCGG

TGTGCCAGCA

vp13.3

V

A

S

TGTGCCACCAGT

vp15.1

AATCAGCCCCAGCATTTT

G

ACGGCCACAGGGAACC R

TGTGCCAGCAGT

MAR 8

G

TGTGCCAGCAGT

VP1 2.3 FAB line Ii

L

CCGGTCGGGGGT

C

FAB line G

A

A

TGTGCCAGCTCC C A S S

vp14

Fig.

A

Jp2.1

CACCGGGGAGCTGTTTTTT

IRGVTG

TGELFF

Jp2.2

I. Comparison ofTCR sequences ofCD4+, MHC class Il-restricted, anti-gp720 T-cell clones raised in vitro frown HIVserorregotiue donors. Abbrmintions:

CDR3, complemeiztaritzJ_clefemitlillg

a role, particularly

region 3; HN lzzmzn immzzrzorleficiel?nJe/?cie~~~~ aims; MHC, rnnjor lristocovzy~tibilit~/ cm~~lex; TCR, T-cell receptar,

the two HLA-like regions in Nef (Refs 87,88). A

similar model has recently been proposed for the ability of exogenous agents to induce autoimmune

disease in hosts with a particular

Michel Me&xl

HLA-typeX9. This model proposes that ‘three-way mimicry’ between

&h~a

sequences

Of

in a target receptor, an exogenous

agent and an HLA se-

quence can lead to the induction of autoreactivity priate infection. Indeed, similarities

d

otlcO~Ogll,

hgzls ce~hdnr

SC~IOU~, Cmtmer

Dalgleisiz and

T?rrnir, Gotirzg,

is fit the Dept of hmrrriology,

Geiron nird Admnced

(~~lgleis~sgizrlzs.ac.z~~j me

MoIecII!nr .%&ces,

Sf &or@s

nt the

Hospit”/

UK SW j GRE; Fabrizio

Snn Mnrtirzo Hospitd,

Uuizrersity

Bivtr,chrlolg~!/ Cmtre, 1.76132, Gemn, ]tnlz/.

following appro-

have been noted between

the

pal gene of HIV and the (Ychain of HLA-DR (Ref. 89), and between gpl20 and HLA-DRP (Ref. 90). Interestingly,

Westby

~~z&w Of

the latter sequence has

References 1 Haase.A.T., Stowing, L., Narayan, O., Griffin, D. and Price, D. (1977) S&Ice 195, 175-I 77

2 Heeney, J.L. (1995) ~I)IIUII~~.xrdny lb, 515-520

also been reported elsewhere as containing an alloepitope”.

3 Pantaleo, G., Graziosi, C. and Dernarest, J.F. (1993) 4 Cheynier, R., Henrichwark, 5 Ho, D.D., Newman,

Concluding remarks

It would appear that there are several ways in which sequences

en-

coded by HIV could enhance lymphocyte

proliferation to the benefit

of the virus. This article has particularly

focused on the possibility

Nntwc362, 355-358

S., Hadida, F. of nl. (1994) Cc// 78,373-387

AU., Perelson, AS., Chen, W. and Markowitz, M

(1995) A’nfrrre 373, 123-127 6 Wei, X., Ghosh, S.H., Taylor, M.E. et nl. (1995) Nahv? 373, lli-I22 7 Gozlan. M. (1995) Lmcrt 346, 1290 8 Steel, C.M., Ludlam, C.A., Beatson, D. of nl. ii988) inrtcrf i, 1185-118~

that HLA-like sequences contribute an allo-like effect in order to in-

9 Cameron, EU., Mallal, S.A., French, M. and Dawkins, R.L. (199@)Hum.

duce immune activation and anergy. In an accompanying

Irrrmwml. 29, 282-295

article in

this issue, S&al and colleagues focus on the other types of homology within the HIV genome, and speculate that it is the perturbation

of

the antibody pattern to self-ligands that contributes to the collapse of

19 Kaplan, C., Muller, J.Y., Doinel, C. t’f nl. (1990) Hlrr~. Herd 40. 290-298 11 Kaslow, RA., Duquesnoy, R., Van&den,

the immune system by interfering with the regulation of the idiotype

(1989) J. AIDS 2,28-32

network92. However, these mechanisms

13 Louie, L.G., Newman,

as demonstrated graft-versus-host

are not mutually exclusive,

by their combined presence in patients

with chronic

disease, whose clinical similarities with HIV infec-

tion were first noted by Gene Shearer over 12 years agoyg.

M. d RI.(1990) LOIILT~ 335,927-935

12 Jeannet, M., Sztajzel, R., Carpentier, N., Hirschel, B. and Tiercy, J.M.

14 Hentges, F., Hoffmann,

B. and King, M.C. (1991) /. AIDS 4,814-X18 A., OliAreira de Araujo, F. and Hemmer, R.

(1992) Clirr. Esp. ftrmno~ol. 88, 237-242 15 Mann, D.L., Carrington,

M.N. and Krower, B.L. (1994) AIDS 8, 53-60

16 Itescn, S., Mathur-Wagh,

LJ., Skovron, M.L. cI nl. (1992) /. All1.j i. 37--1?

17 Scorza Smeraldi, R., Fabio, G., Lazzarin, A., Eisera, N.. Moroni. M. and Zanussi, C. (1986) Lnrzcrf ii, 1187-1189 We are endebted

to B. Marriott for critical reading of this manuscript,

and to

the Wellcome Trust, Medical Research Council, Italian Ministry of Health and

It3 Scorza Smeraldi, R., Fabio, G., Lazzarin, A. E! nl. (19X8) I~rrrt~.IIW!IUIO/ 22,73-79

Glaxo Research and Development Ltd, who are funding our ongoing research

19 Sahmoud, T., Laurian, Y., Gazengel, C., Sultan, Y., Gautrean, C. and

in this area.

Costagliola,

D. (1993) AIDS 7, 497-500

MARCH

1996

IMMUNOI.OGY

20

TODAY

Raffoux. C., David, V., Couderc, L.D. A nl. (1987) TissrrcArrtiReus 29,

60-52 21

Enlow, R.W..Nunez Roldan, A., LoCalbo,I’.,Mildvan, D., Mathur, U.

55 Cossariua, A., Ortolani, C., Mussini, C. et a!. (1595; AIDS 9,547-553 56 Pant&o, C., Demarest, 1.9 Soudeyns, H. et al. (1994) Nature 370,463-467 57 Chen,Z.W., Kou, Z.C., Lekutis, C. et 01.(1995)J.Erp. Med. 182,21-31

and Winchcstcr. R.J. (19B.3) Lnr/rrl ii, 51-52

58

22

Kuntt, B. and Bruster, l-1.(19891 Fisstr; AII~~RP”S 34, l&1-169

USA 91,1529-1533

23

Itcscu, S., Rose, S., Dwyer, E. and Winchester, R. (1994) Pm. NotI Acnd.

59

Sri. US/1 91,11472-11476 24

Rebai, N., Pantaleo, G, Demarest, JX et al. (1994) Pm. Natt Acad.Sci. Held, W., Shakhov, A.N., Waanders, G. el al. (1992) J. Exp. Med. 175,

1622-1633

Donald, J.A., Rudman, K., Cooper, D.W. er ~1.(1992) TissueAntigem 39,

60 Lafon, M., Lafage, M., Martinez-An&+,

A. et ai, (1992) Nntun 358, $4%510

241-248

61 Soudeyns, H., Rebai, N.,

25

Rowland-Jones, S., Sutton, J., Ariyoshi, K. cf nl. (1995) Nat. Med. 1,59&l

17%.185

26

Hill, A., Elvin, J,, Willis, AC. ct nl. (1992) Nntrrw360.434-439

62 Chen, Z.W., Kou, Z.C., Shen, L, Retmann, K.A. and Lehrin, N.L. (1993)

27

Arthur, L.O., Bess, J.J., Sowdcr, R.I. ct nl. (1992) Scirrrcc 258, 1935-1938

28 Chan, W.L., Rodgers, A., Grief, C. rfnl. (1995) AID.5 9,223-228

29 Moss, P., Rosenberg, W. and Bell, J.I. (1992) Awnr. Reu. Iirrma~rol.10, 71-96 38 Akolkar, P.N., Gulwani-AkoIkar, B., Pergotizzi, R., Bigter, R.D. and Silwr, I. (1993) I. Irrwwiol. 150, 2761-2773 31

Usuku, K.. Joshi, N., Hatem, C., Alper, C.A., Schoenfeld, D.A. and

Pant&o,

G.l? ef ~1.(1993)Semin.Immud.

5,

1. Immunol. 151,2X%2187 63 Soudeyns, H., Routy,J.P.and Sekaly, R.P.(1994)Leukonia8 (Suppt.f), 595-597 64 Ctedci, M., Via, CL, Lucey, D.R., Roilides, E., P&o, F.A. and Shearer, G.M. (1991) Eur. 1. Immunol. 21, &Z-670 65 Laurence, J., Hodtsev, AS. and Posnett, D.N. (1992) Natrtre356,255-259

Hauser, S.L.(1993) Ir,l~~l~~,ro~~~~rtirs 38,193-198

66 Eylar, E.H., Rivera, Q.C., Laroche, H.I. and Yamamura, Y. (1994) 1. AIDS

32 Malhotra, U., Spielman, R. and Concannon, l? (1992) 1. Immurrof.149,

7,124-128

1302-1808

67 Bissct, L.R., Opavtl,

33 Geursen, A., Skinner, M.A., Townsend, L.A. et nl. (1993) Clin. Exp.

Hum. Refrwjnrses 9,241-246

InlrIrllol.

94, 201-207

34 Gulwani-Akolkar,

M., Ludwig

E. and Fterz, W. (1993) AIDS Res.

68 Dadaglio, G., Garcia, b., Montagniec B., Posnett, D.N., &on,

C.H. ef al. (1991)1. Exp. Med.

L. and Gougeon, M.L. (l!XX)

I. Exp. Med. 179.413-424

174,1139-1146

69 Scott-Algara, D., Lafon, M., Vuillier, E, Pialoux, G, Dauguet,C.

35 Moss, P.A., Rowland-Jones, S.L., Frodsham, P.M. cl al. (19%) Pm. Nat1

Dighiero, G. (1994) Eur. J. Immunof. 24,2595-2601

Acnd.Sri. USA 92,5773-5777

70

36

Manta,

Ref Rx irology

F.,

Fenoglio.D, Vallc, M.T. et nl. (1995) 1. AIDS H~tm.

9.227-237

Akolkar. P,N., Gulwani-Akolkar,

fmn~rrrrol. 25,

B., Chirmule, N. et d. (1995) Ann. New

York Acud. Sci. 756,176-178

71 Akolkar, P.N., C&mule,

37 Manta, E. Fenoglio, D.. V&e, M.T. et nl. (1995) Eur. I.

and

lmmunol.

N., Gulwani-Akolkar,

& et al. (1995) Sund.

1.

41,487-498 B., McKinley, M., Fisher, S.E. and

1217-1223

72 Akolkar, P.N., Gulwani-Akalkar,

38 Boldt-Houle, D.M., Nigida, S.M., Rinaldo, CR. and Shrlich, C.D. (1994) 1. Med. Primfd. 23,432-U]

Silver,J. (1995) Cfin. Immunof. Immunoplthof. 76,255-265

39

74 Dobrescu, D., Ursea, B., Pope, M., Asch, AS and Posnett, D.N. (1995) Cell 82,x+763

Irwin, M.J., Hudson, K.R., Am-,

K-T., Fraser, J-D_ and Cascoigne,

N.R.J. (1993) h~~nwroI_Rm. 131.61-78

73

Nisini, R., Aiuti, A., Matricardi, P.M. et at. (1994) AIDS 6,113-449

10 Held, W., Acha-Chbea, H., MacDonald, H.R. and Waanders, G.A. (1994) In1tnrtrroi.7&/q 15,184-190

75 Shirai. M., Vacchio, MS., HotIes, R.J. and Benofsky, J.A. (1993)

41 Braun, M-A., Gerlach, D., Hartwig, U.E cl of. (1993) I. Immrrrral. 150,

76 Manta, I?, Habeshaw, J. and Dal&&h, A. (1991) 1, Immunaf. 1%,1964-Im

2457-2166

77 Kestler, H.W., III, Rtngler, D.J., Mori, K. et af. (1991) Cell 65,651-662

42 Ramwoui, S., Joucnbeads,

F., Michot, E, Borsalebas, F., Humbert, G.

I. Immunol.

78

151,2X&2295

Lindemann, D., Wtlhe,ln, R., Renard, P., Al&age, A., Zinkemegel, R.

and Tron, E (1995) Clijr. Exp. br~a~r~~cll. 99, 182-188

and Mous. 1. (19941 I. hp.

43 Hall, B.L. and Finn, O.J. (1992)Biof~c!~clrr~iqrres 13.248-257

79 Otake, K., Fujii, Y., Nakaya, T. et al. (1994) J. fmmwnol. 153,5826-5837

Med. lL9,797+IO7

44 Panzara, M.A., Gussoni, E., Steinman, L. and Oksenberg, J.R.(1992)

80 Winslow, G.M., Schenr, M-T., Kappler, J.W. and Marrack, P. (1992) Cell

Biu~cchrriqacs 12, 728-735

71,719-730

45

Kang. I., Ido, E., Rwling.

I., Beutner, U., Huber, B,T. and Hozumi, N.

81

Deacon, NJ., Tsykin, A., Solomon, A. et ol. (1995) Science 270,9&991

(1994) 1. Inrrn~tr~ol.152, 1039-1046

82 Golovkina, T.V, Chervonsky, A., Prescott, J.A.. Janeway, CA., Jr and

46 hnbcrti. L., Sottini, A., Bettinardi, A., Puoti. M. and Primi, D. (1991) Sckw 2%. 8bUfib2

Ross, S.R. (1994) 1. Exp. Med. 179.439446 83 5iss4

48 pmnelt, D.N.. Kabak, S., Hodtsev. AS., Goldberg, E.A. and Asch, A.

L.R. and Fierz, W. (1992) AIDS Res. Hum. R&n&uses 6,154&15&l 84 Sheikh, M.J., Ongradi, J., Austen, B.M. and Dalgleish, A.G. (1995) AIDS 9,122~1235

(1993) AIDS

85 Ckrtci, M., Shearer, G., Hounsell, E.E, Jameson, B., Habeshaw,J. and

47

49

Ho&m, V.L.. Jcddi. T.M., Gnmewald,

1, cl al. (1993) A/D5 7,63.3-638

7,625-431

Boldt-Houle. D.M., Rinaldo, C.J. and Ehrlich, G.D. (1993) I, Lfl~kocy~p

Biuf. 54.4861Yl 50 Bayer, V., Srnlth. L.K., Ferre, E et nl. (1993) Clitr. Exp. b~~t~~~l. 92, 437-441 51

Dalgleish. A.G.. Wilson, 5.. Gompels, .M.cl nl. (t992) Lnrrccr 339,824-828

52

Bans& A.% Grwn. L.M., Khoo, S.H.. Pumphrey, R.S., Haeney, M.R.

and Mandal, B.K. (1993) Clirt. Exp. Im~nrr~rof.94, 17-20 53 McCoy, I.P., Overton. W.R., Blumstein. L,, Baxter, I.D., Gekowski, KM. and Donaldsun, M.H, (1995) Cymwtry 2,1-9 54 Cossarizza, A, Ortolani,C.. Muss& C.cf nl. (1995) 1,l+cr. IX. 172,105-112

Dalgleish A.G. (1993) Eur. J. Immunol. 23,2022-2025 86 Habeshaw, J.A. (1994) Immm~ol. Todny 15,39+0 87 Vega, M.A., Guigo, R. and Smith, T.E (1990) Nature 345,26 88 Hobohm, U. and Sander, C. (1993) FE6.S Mt. 333,211-213 89 Baum, H., Davies, H. and Peakman, M. (1996) Immunol. T&y 17,64-70 98 Young, J.A. (1988) Nalure 333,21.5-216 91 Atassi, H. and Atassi, M.Z. (1992) Hum. Immnunol.3431-38 92 Sbsal, C., Daniel, V. and Opelz, G. (1996) Itumunol. T&by 17,114-l-9 93 Shearer, G.M. (1983) Neu~Eql. 1%Med.

308,223-224