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Debby den Uyl, et al.: Progression of HIV to AIDS
89
Progression of HIV to AIDS: a Protective Role for HLA-B27?
Debby den Uyl
1
, Irene E. van der Horst-Bruinsma
1
and Michiel van Agtmael
2
1
Departments of Rheumatology and
2
Internal Medicine, VU University Medical Centre Amsterdam, The Netherlands
Abstract
HLA-B27 is known for its strong association with inflammatory spondyloarthropathies (SpA), a group
of rheumatic diseases. Apart from playing its role in the onset of these inflammatory diseases, HLA-
B27 is so ubiquitous in the world that the carrying of this gene must have also have an advantage.
There are some indications that a beneficial effect can be found as a less severe course of viral in-
fections among B27-carriers. The literature on this subject was reviewed and revealed a favorable
course of infection with influenza virus, herpes simplex type 2 virus, Epstein-Barr virus and, even
more interesting, a protective effect of HLA-B27 in the progression of HIV infections. The course of
HIV infection differs among individuals and is thought to be partly related to host-factor variability,
reflecting broad genetic heterogeneity. The polymorphic human leukocyte antigens (HLA) are herein
analyzed intensively with respect to this relationship.
Cytotoxic T lymphocyte (CTL) responses, activated by HLA antigen presentation, are implicated in the
control of HIV replication. An immunological explanation for the protective role for HLA B27 in HIV
disease is that B27+ patients have a specific and strong CTL response against the p24 epitope, a
conservative HIV protein that does not easily mutate. Some HLA genes seen in long-term non-progres-
sors (LTNP) (>10 years disease free) are associated with a favorable prognosis. One of the alleles found
predominantly in LTNPs is HLA-B27. More genetic factors seem to influence disease progression in
HIV infections. Therefore, it would be interesting to further explore the influence of the genetic make
up of these HIV-infected individuals. Knowledge of the immunogenetic profile might give clues for the
individual course of the HIV infection, may influence the development of drug-resistant viruses and will
possibly lead to a tailored therapeutic strategy in HIV-infected persons. (AIDS Reviews 2004;6:89-96)
Key words
HLA-B27. HIV. AIDS. Spondyloarthropathy. Disease progression.
AIDS Reviews 2004;6:89-96
Correspondence to:
Irene E. van der Horst-Bruinsma
Department of Rheumatology, room 4A-42
PO Box 7057
1007 MB Amsterdam
The Netherlands
Phone: +0031 204443432
Fax: +0031 204442138
E-mail: IE.vanderHorst@vumc.nl
I
ntroduction
The natural course of HIV infection is characterized
by considerable variations among infected individuals.
The time between infection and progression to AIDS
varies per individual from 5-20 years and is believed
to be related to both viral and host factors, including
genetic differences. Prognostic viral factors for fast
progression are the level of the viral load and the pres-
e
nce of certain mutants. For instance, SI (syncytium-
inducer, or X4) viruses accelerate the immune decay
more than NSI (non-syncytium-inducer, or R5) viruses.
The intriguing relationship between viral and host fac-
tors has led to many studies to unravel the extent of
their respective roles.
Host factors are, among others, a strong cytotoxic T
lymphocyte (CTL) response against HIV, which is gen-
erally believed to play an important role in controlling
virus replication
1
. CTLs are activated by binding to
antigenic peptides, presented by human leukocyte an-
tigens (HLA), thereby initiating the immune response.
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without the prior written permission
of the publisher
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AIDS Reviews 2004;6
90
Because this CTL response is HLA-dependent, it is
believed that genetic factors influence the individual
response to HIV infection
2,3
. Over the years, there have
been studies reporting the effect of HLA polymorphism
on the progression to AIDS. Several studies have
reported associations between HIV disease progres-
sion and HLA antigens
3-7
. A subgroup of patients
(5-10%), called long-term non-progressors (LTNP),
remains asymptomatic and clinically healthy for more
than 10 years without therapy
8,9
. Different HLA anti-
gens have been correlated with rapid or delayed dis-
ease progression. HLA-A24, -A29, -B35, -C4, -DR1 and
-DR3 have been described as being associated with a
rapid progression to AIDS
4,6,10,11
, while patients with
HLA-B14, -B27, -B57, -C8 or -DR6 appear to develop
AIDS more slowly
4-6,10,11
.
This review highlights the role of HLA-B27 on HIV
progression and raises the following intriguing ques-
tions: a) does the worldwide pattern of HLA-B27
prevalence coincide with the worldwide differences in
HIV progression, and b) can HLA-B27 positivity be
used in single individuals as a predictor of disease
progression.
HLA-B27 and human diseases
The human major histocompatibility complex (MHC)
maps to the short arm of chromosome 6 and contains
the polymorphic HLA genes. These HLA genes are
fundamental for the acquired immune response. HLA
class I products bind to endogenous antigenic epit-
o
pes and present them to CD8+ CTLs, while HLA
class II products present exogenous antigenic pep-
tides to CD4+ helper T-cells. The binding groove of the
HLA alleles binds to specific peptides. These peptides
anchor in the groove by one or two amino acids at key
points. Because of the polymorphism of HLA genes,
many different peptides can be presented to the im-
mune system.
Numerous diseases are associated with the HLA
loci and a number of them are autoimmune diseases.
HLA-B27 is associated with the spondyloarthropathies
(SpA), including ankylosing spondylitis (AS), Reiter’s
syndrome, reactive arthritis, inflammatory bowel dis-
ease and psoriatic spondylitis
12
. HLA-B27 is highly as-
sociated with AS (98% is positive), whereas the preva-
lence in other forms of SpA varies between 50-80%
13
.
The B27-antigen is present in 8-20% of healthy Cau-
casians, depending on their geographic distribution,
with the highest prevalence being in the northern zones
(Fig. 1).
Research on the pathogenesis of B27 has lead to
several theories, all of which cite the unique structure
of the binding groove of HLA-B27 as the cause of this
autoimmune reaction
14,15
. Spondyloarthropathy patients
have an adequate HLA-B27 restricted CTL response,
showing that their HLA-B27 functions normally
12
. There
is evidence that infection with Chlamydia, Yersinia, Sal-
Figure 1. Prevalence (%) of HLA-B27 among different indigenous population groups in the world.
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without the prior written permission
of the publisher
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Debby den Uyl, et al.: Progression of HIV to AIDS
91
monella, Shigella, Campylobacter and Klebsiella, trig-
gers the local chronic inflammation causing reactive
arthritis
16
.
Animal models support the importance of an infec-
tious agent triggering disease. Rats maintained in
germ-free environments did not develop arthritis; how-
ever after being transferred out of the pathogen-free
colony, arthritic changes were seen within several
weeks
17
. Different bacteria involved in SpA pathology
were found to have sequence homology with certain
regions of the B27 molecule
18
.
The “molecular mimicry” hypothesis explains that
bacteria would cause SpA as antibodies cross-react
with self-peptides. Another theory suggested that
bacteria bind to an empty HLA-B27 molecule, there-
by activating autoreactive T-cells
14
. Empty HLA-B27
molecules are relatively stable compared to other
HLA subtypes, and are able to bind to several pep-
tides
19
.
Finally,
the role of CD4+ T-cells is believed to be of
importance. MHC class II–, HLA-B27+
transgenic mice
still develop spontaneous disease
20
. This can be ex-
plained by the hypothesis that CD4+ T-cells can rec-
ognize MHC class I molecules
15
. Some investigators
believe that the empty B27 molecule forms an abnor-
mal complex with itself, causing a local autoimmune
response by activating CD4+ cells
14,15
. The enhanced
CTL response in B27+ HIV-infected patients should
explain their better prognosis.
Twenty subtypes of HLA-B27 exist, but not all are
associated with human disease. B2706 and B2709 are
not disease-associated, while B2702, B2703, B2705
(the most common subtypes) and B2707 are clearly
associated with disease
21
. It is believed that the diver-
sity of the HLA antigens is maintained through natural
selection by local infectious diseases
22
. But if HLA-B27
is strongly associated with SpA, why is it more common in
the northern than in the southern hemisphere (Fig. 1)?
Figure 2. Number of children and adults with HIV/AIDS at the end of year 2003.
No part of this publication may be
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without the prior written permission
of the publisher
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AIDS Reviews 2004;6
92
Could there be advantages of having HLA-B27, there-
by causing an evolutionary selection?
HLA-B27 viral infections
Demographic data indicate that the incidence of
some viral infections is higher in the northern hemi-
sphere. Hepatitis C is found predominantly in countries
of the northern hemisphere
23
and outbreaks of influ-
enza viruses and SARS are also mainly associated with
countries of the northern hemisphere where HLA-B27
is more prevalent
24
. Could there be an evolutionary
connection?
HLA-B27 is thought to positively influence the out-
come of viral infections like influenza, herpes simplex
virus type 2 (HSV-2) and Epstein-Barr virus (EBV)
12,25-27
.
The importance of HLA B27 in influenza is clear from
the recent description of a new escape mutant influ-
enza A virus with a mutation of a HLA B27 specific
epitope
25
.Also B27+ individuals infected with EBV
show high, specific CTL responses against viral epit-
opes, suggesting a protective role
26,27
. The evalua-
tion of three cohorts showed an association of B27
with asymptomatic infection of HSV-2
27
. B27 is as-
sociated with a benign clinical course of hantavirus
infection
28
. In addition progression of HIV infection
in particular appears to be positively effected by
presence of HLA-B27
12,14
.
Definition of HIV progression
HIV progression can be measured in two ways: by
the level of viral antigens (viral load) and by the de-
crease in CD4+ cells (CD4 count).
Viral load and viral escape
AIDS is the result of an ongoing infection of the im-
mune system. CTLs have been implicated in the con-
trol of HIV infection by several mechanisms, including
direct killing through lysis, or by inhibiting viral replica-
tion by production of cytokines and chemokines
2
. In-
fected patients produce strong CTL responses to
HIV
29
. Ogg, et al.
1
observed an inverse correlation be-
tween HIV-specific CTL frequency and plasma RNA
viral load. Characteristic of HIV is its ability to escape
CTL responses. This is due to the high mis-incorpora-
tion rate of HIV and its transcriptase, which lacks proof-
reading activity
29,30
.
In longstanding, progressed, HIV infection not just
one HIV-epitope but a cloud of mutated epitopes was
found in patients with increasing viral load levels
29,31,32
.
This mechanism seems an effective survival strategy
of the virus. CTLs exert a selective force on HIV,
giving an advantage to epitopes mutated in critical
amino acids in the dominant epitopes. This viral es-
cape causes an increase in viral load
29,32,33
. An epi-
tope which escapes from CTLs has a selective advan-
tage and this escape mutant will eventually dominate
the virus population
29,32,33
. The consequence of this
antigenic variation is a shift of immunodominance of
CTL response to other epitopes, resulting in an irre-
versible immunodeficiency. Thus, high levels of plasma
HIV-RNA levels are associated with rapid disease pro-
gression. Effective therapy will prevent viral escape
because a high viral replication is needed for HIV to
mutate. However, suboptimal therapy will lead to es-
cape variants, which can be transmitted sexually,
theoretically leading to a spread of non-responsive
epitopes over the world
34
(Fig. 2).
CD4 count and CTL response
Failure to control the virus will cause CTL escape.
Moreover, CD4+ T-cells have direct antiviral effects
35
and because of their antigen-presenting role, T-helper
cells are important in the priming of CTLs, maintaining
CTL memory, and for maturing CTLs
36
. T-helper cells
are needed to initiate new CTL responses against the
mutated epitopes
3
. However, with ongoing HIV infec-
tion there is a gradual loss of these CD4+ T-helper
cells, as they are the main targets of the HIV virus.
The decline in the CD4+
count will weaken the CTL
response and is therefore a second cause for viral
escape. An effective suppression of the virus with
antiretroviral therapy will protect CD4+ cells, result-
ing in a better control of HIV
36
. By reducing the
replication of the virus to a minimum, thus halting
the destruction of CD4+ T-cells, a strong CTL response
is maintained.
HLA B27 and slow HIV progression
With the HIV pandemic evolving in low-resource
countries with limited access to antiretroviral drugs,
there is growing interest in identifying the 5-10% of
patients with a relatively natural course being called
“long-term survivors” (10-20 years). A number of stud-
ies have shown a higher frequency of the B27 haplo-
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of the publisher
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Debby den Uyl, et al.: Progression of HIV to AIDS
93
type in this subgroup of patients. Table 1 summarizes
the associations between B27 and HIV progression
resulting from several observational cohorts and so-
called “extreme patient” studies
4-6,8,9,30
. These studies
suggest that HLA-B27 is involved in the pathogenesis
of HIV.
Kaslow, et al.
4
correlated in 1996 one of the first in-
dividual HLA-B27 profiles with slow progression. This
observation was confirmed by Magierowska, et al.
6
.
McNeil, et al.
5
showed a significant association of B27
with a delayed progression to AIDS. Hendel, et al.
9
studied a cohort of individuals representing extremes
of fast progressors and non-progressors and they also
found a protective effect of B27 on the progression to
AIDS. In contrast, the results of Carrington, et al.
37
showed an association of B27 with rapid progression.
This was found among the 144 African-Americans
studied, whereas the positive effect of B27 in other
studies had been seen among Caucasians. Smith,
et al.
38
found an overall lower CD4 count among black
HIV-infected persons compared with white HIV-infect-
ed persons, while Trachtenberg, et al.
30
found that
black men had lower viral loads than white men. These
data suggest an influence of ethnic background on HIV
progression; therefore the association of B27 with rap-
id progression among African-Americans could be a
result of selection bias.
Although most studies implicated B27 prevalence
with slow progression, some associations of B27 with
HIV progression only indicate a trend
10,30,39
. The incon-
sistencies seen in B27 data could be explained by the
study design or by the fact that B27 is a rare HLA
subtype in these research-groups. To study HLA influ-
ence on HIV progression it is important to know the
date of seroconversion and to choose an exact end-
point (death, AIDS or CD4+ decline)
7
. Also, a short
interval of HLA-typing is important to ensure that no
HLA types are missed because of early death
7
. The
effects of multi-allelic associations may be difficult to
interpret. The extensive polymorphism of HLA, linkage
disequilibrium and cohort size can complicate the in-
terpretation of results
7,8,40
. For example, small numbers
of patients in a study lead to weaker associations be-
cause of the multiplicity of the HLA alleles, while large
numbers of alleles need multiple-comparison correc-
tion (Bonferroni) to consider other HLA effects that
Table 1. Results of studies associating HLA-B27 with slow progression of HIV-1 infection
Reference Study Risk group Race Cohort size Definition of Antiretroviral RR
design (% B27) disease progression treatment B27
Kaslow ’96
4
Cohort*
Homosexual Caucasian 241 (7%) AIDS-free interval (50%) 0.23
McNeil ’96
5
Cohort IDU ? 313 (8%) Rate CD4+ decline AZT (66%) 0.3
in time
Carrington ’99
37
Cohort IDU African- 144 (?) AIDS-free time ? 6.86
American Time till death
Keet ’99
10
Cohort Homosexual Caucasian 375 (8%) Rate CD4+ decline Single or 0.4
in time combination
AIDS-free interval
Magierowska ’99
6
Extremes
†
Homosexual Caucasian 153 (11%) LTNP: LTNP: no therapy 0.2
IDU asymptomatic ≥ 8 years
+ CD4 > 600 µl
last 5 years
Hendel ’99
11
Extremes ? Caucasian 276 (13%) LTNP: LTNP: no therapy 0.34
asymptomatic ≥ 8 years
+ CD4 > 500 cells/mm
3
Trachtenberg ’03
30
Cohort Homosexual ? 481 (2%) Rate CD4+ decline HAART ?
in time (guidelines)
Viral load level
*Cohort: prospective follow-up cohort with known seroconversion date;
†
extremes = extreme patient study: comparing the extremes of disease progression (slow progressors
and fast progressors); IDU: injection drug users; RR = relative risk; >1 = short AIDS-free interval; <1 = prolonged AIDS-free interval.
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of the publisher
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AIDS Reviews 2004;6
94
could mask the influence
7,40
. Ideally a study is per-
mormed in hundreds of HLA-characterized patients,
but this is difficult to establish in practice.
Mechanism of Gag-specific
CTL response
Although not all results of the role of B27 in HIV
progression seen in cohort and cross-sectorial studies
are consistent, there is a molecular basis to explain the
protective role of B27 in HIV progression. It is believed
that HIV-infected patients carrying HLA-B27 control the
virus better due to their strong immune response. Stud-
ies show that patients with HLA-B27 maintain stable
CD4 counts for many years and present high levels of
HIV-specific CD8+ T-cells during the asymptomatic
phase. It is known that HIV can escape from selective
pressure of CTLs. Patients with HLA-B27 have CTLs
specifically selected for a Gag p24 epitope (amino
acids 263-272, sequence KRWIILGLNK), a core pro-
tein of HIV
31,41
. This Gag p24 epitope is strongly im-
munodominant
32
. Although oligoclonal T-cell responses
are believed to give a better protection against viral
escape
35
, B27+ patients clearly show an immune re-
sponse against one epitope. How can this been ex-
plained?
Results from several studies have shown that Gag
p24 does not mutate easily and therefore it is believed
to represent a conservative HIV protein
31,42,43
. Most
mutations lead to a non-viable virus, because they
result in a changed conformation, causing the peptide
to lose its function
31
. But even when a mutation variant
survives, peptide-binding experiments have shown
that B27-specific CTLs still recognize these mutated
Gag p24
31,42
. Crystallographic analysis showed the
importance of arginine at position 2, which binds
strongly with the B-pocket of the B27 molecule, creat-
ing a stable complex
44
. An amino acid substitution from
arginine (R) to lysine (K) or glycine (G) leads to a
peptide that binds poorly to B27
31,42
. Kelleher, et al.
31
proved that Gag p24 escapes from HLA-B27 only after
a particular array of mutations.
The functional impor-
tance of p24 and the genetic tolerance of B27 explain
why HIV escape from B27-specific CTLs occurs late in
the course of infection.
Unfortunately, the mutational escape variant is found
to be sexually transmittable
45
. Children sharing the
HLA-B27 with their mother failed to control HIV replica-
tion. These children showed a rapid disease progres-
sion because they targeted an epitope that had already
escaped from B27-specific CTLs. Other studies sup-
port the theory that advantageous mutated epitopes
may be transmitted frequently to other individuals with
the same HLA type
30,45,46
.
Other genetic factors
and progression to AIDS
HIV is found to progress faster in individuals homo-
zygous for HLA loci, because CTL escape occurs
easier
10,37
. Patients heterozygous at the HLA loci are
able to present a higher variety of antigenic epitopes
Table 2. Genetic factors involved in HIV-1 disease progression
Genetic factors Function Influence on HIV progression
HLA homozygosity MHC Rapid progression
HLA-B35 MHC Rapid progression
HLA-Cw04 MHC Rapid progression
HLA-B27 MHC Slow progression
HLA-B57 MHC Slow progression
CCR2-64I Chemokine receptor Slow progression
CCR5-Δ3
2 Chemokine receptor Slow progression
CX3CR1 Chemokine receptor Rapid progression
SDF1-3’A Chemokine Slow progression
RANTES Chemokine Slow progression
IL10-5’A Cytokine Rapid progression
MBL Mannose-binding lectin Rapid progression
CCR2 and CCR5 are coreceptors for HIV-1. CX3CR1 is rarely used as coreceptor for HIV; a mutated form was associated with rapid progression in one study. SDF1 is the
chemokine receptor for CXCR4, an important coreceptor for HIV-1 in the late disease course. RANTES is the CCR5 chemokine ligand and could suppress HIV-1 infection by
blocking CCR5. IL10 is a TH-2 cell cytokine that is shown to inhibit HIV-1 replication in macrophages. MBL activates complement and phagocytosis and a genetic variant is
associated with rapid progression to AIDS.
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Debby den Uyl, et al.: Progression of HIV to AIDS
95
to CTLs and studies suggest that this results in a more
productive immune response
30,37
.
A fast growing number of host genetic associations
have been identified as correlating with HIV disease
progression (Table 2). The role of chemokine receptors
CCR2 and CCR5 especially have been studied inten-
sively. These receptors are found to be used as core-
ceptors for HIV-1 together with CD4
47
. A mutation in
these genes, CCR5-
Δ
32 and CCR2-64I, has been
shown to provide strong protection and is found more
frequently in LTNPs than in rapid progressors. Both are
found to be associated with slow progression in many
cohorts
6,9,40,47,48
. Altogether, the results of many asso-
ciation studies illustrate the complexity of host genetic
interactions with the HIV pathogen.
Conclusion
The role of HLA in HIV disease progression should
be further elucidated to identify those patients with
either a mild or aggressive course of their natural
HIV-1 infection. HLA genotyping might influence the
timing to start HIV therapy, for example postponing
therapy in the long-term survivor group. This risk strat-
ification could be relevant in countries with limited ac-
cess to antiviral drugs. Under antiretroviral therapy,
HLA type (like drug levels) may influence the risk for
developing drug-resistant viruses. Thus, HLA typing
could play a role in the choice of antiretroviral regi-
mens, mainly in drug-naive patients. Knowledge of the
immunogenetic background may enable us to calcu-
late a composite genetic risk, which will be of increas-
ing importance in the tailored management of HIV-in-
fected patients. Moreover, since HLA loci vary by
ethnic group and region, it may affect the response to
specific vaccines in different parts of the world.
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