JOURNAL OF VIROLOGY, June 2006, p. 6056–6060
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Vol. 80, No. 12
Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency
Virus Type 1 Infection in Native Africans
Aleksandr Lazaryan,1Elena Lobashevsky,1Joseph Mulenga,4Etienne Karita,5Susan Allen,6
Jianming Tang,2and Richard A. Kaslow1,2,3*
Departments of Epidemiology,1Medicine,2and Microbiology,3University of Alabama at Birmingham, Birmingham, Alabama;
National Blood Transfusion Service, Lusaka, Zambia4; Project San Francisco, Kigali, Rwanda5;
and Department of Global Health, Emory University, Atlanta, Georgia6
Received 8 October 2005/Accepted 5 April 2006
Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared
peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naı ¨ve human
immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and
HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective
associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for contin-
uous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous.
In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P ? 0.01) or
B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P ? 0.02) or B*5802-Cw*0602 (P ?
0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P ? 0.05), whereas B*5801
as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with
slow (P ? 0.06) and rapid (P ? 0.003) disease progression, respectively. In neither population were B*1516-
B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an
HLA-B–HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As
presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every
The concept of human leukocyte antigen (HLA) supertypes,
categories of alleles that share common peptide-binding mo-
tifs, offers a simplification of the complex HLA nomenclature
by consolidating the huge spectrum of individual alleles into
relatively few groups. Individual alleles assigned to each super-
type have either proven or predicted ability to present anti-
genic peptides with similar anchoring residues at the second
and C-terminal positions of peptide ligands. Initially proposed
in the late 1990s, four HLA-A and five HLA-B supertype
categories encompass the majority of known HLA class I al-
leles (24, 25). There have been subsequent efforts to improve
supertype categorization (8, 22). However, independent of the
supertype assignment method, the HLA epitopes for just a few
of the major supertypes have been estimated to provide sub-
stantial population coverage for antigenic peptides. If con-
served peptides that cross-react with representative HLA class
I supertypes can be identified, a supertype-guided approach
could simplify the development of human immunodeficiency
virus type 1 (HIV-1) subunit vaccines. Furthermore, designing
a multiepitope HIV-1 vaccine candidate to target a few super-
types would be considerably easier than tailoring one to highly
population-specific allelic differences. However, the success of
such a strategy would depend on numerous factors (13, 15),
including the degree of uniformity in the nature and magnitude
of the CD8?cytotoxic T-lymphocyte (CTL) responses to viral
The associations of CTL responses and control of HIV-1
viremia appear to differ from one HLA class I supertype to
another (20, 23, 31). However, shared epitope recognition by
alleles within a single supertype would be expected to produce
relatively uniform associations of immunologic or clinically
relevant CTL responses. On the other hand, if functional dif-
ferences among alleles within a single HLA supertype are
substantial, then the knowledge of those differences would be
crucial for predicting responses to vaccines designed on the
basis of supertype. Since not all HLA class I supertypes have
been uniform in their associations with HIV-1 outcomes (4,
31), the systematic assessment of alleles within the same su-
pertype may identify important differences in their epitope-
The HLA-B58 supertype (B58s) is associated with a favor-
able response in Caucasians infected with HIV-1 clade B and
in Africans infected with clade C (20, 23, 31). Among B58s
alleles (all B*57 alleles, B*5801-*5802, and B*1516-*1517)
(25). The HLA-B*57 alleles have consistently been associated
with a favorable disease course in populations with different
HIV-1 viral subtypes and ethnic backgrounds (1, 6, 11, 28, 30).
However, assessment of the other B58s alleles has been rela-
tively sparse (4, 10, 14). We evaluated the degree of control of
HIV-1 infection exerted by the different B58s alleles in two
cohorts of infected native Africans. Our findings of contrasting
associations for certain B58s alleles, along with apparent effect
modification by their accompanying HLA-C alleles, highlight
* Corresponding author. Mailing address: Department of Epidemi-
ology, University of Alabama at Birmingham, 220A Ryals Bldg., 1665
University Blvd, Birmingham, AL 35294. Phone: (205) 975-8698. Fax:
(205) 934-8665. E-mail: email@example.com.
the distinctive contributions of individual B58s alleles and their
MATERIALS AND METHODS
Subjects. We analyzed data from participants in two cohorts whose available
biologic materials permitted resolution of HLA B58s: one included HIV-1-
infected Zambian sex partners, and the other included sexually active HIV-1-
infected Rwandan women. The design and conduct of these studies have been
described elsewhere (9, 18, 28). The selection of mostly HIV-1 subtype C-
infected Zambians (n ? 423) was based on the availability of HIV-1 RNA
measurements. The selection of mostly HIV-1 subtype A-infected Rwandan
women (n ? 202) was based on the availability of clinical and hematological
indicators of disease progression.
HIV-1 outcomes. HIV-1 RNA levels (viral loads [VLs]) were measured by a
Roche Amplicor 1.0 assay (Roche Diagnostic Systems Inc., Branchburg, N.J.).
Logarithmic (log10) transformation allowed modeling of VL as a continuous,
normally distributed variable. Categorical VL analysis involved groups with
?10,000, 10,000 to 100,000, and ?100,000 copies/ml VL. Rwandan women were
monitored from the date when infection was first documented until death or
for ?8 years and categorized as relatively slow (n ? 101), intermediate (n ?
86), or rapid (n ? 15) progressors (27).
HLA class I typing and haplotype assignment. HLA class I alleles were
detected by PCR with sequence-specific primers (Pel-Freez Clinical Systems,
Brown Deer, Wis.) for both cohorts. B58s alleles were resolved to their four-digit
specificities by automated reference-strand conformation analysis. HLA-B and
HLA-C haplotypes in Zambians were manually assigned after linkage disequi-
librium analysis (28).
Statistical analysis. For the Zambian cohort, the Mann-Whitney test was used
to compare the median log10VLs among subjects with various B58s alleles. For
Zambian couples with a previously established correlation between VL levels in
epidemiologically linked transmitters and seroconverters (29), we used general-
ized estimating equation (GEE) methodology (32) to assess the association
between B58s alleles and VL. Because VLs in subjects with preexisting seropos-
itivity at enrollment or seroconverters during follow-up could also reflect time-
sensitive effects of HLA alleles, we stratified the subjects by serostatus to account
for such differences in the analysis of the effects of B58s alleles. In separate
stratification, we also aimed to dissect the effects of individual B58s alleles from
those of their closely linked HLA-C alleles.
For the Rwandan cohort, the Jonckheere-Terpstra test was used to compare
the proportions of subjects in the HIV-1 disease progression categories. Propor-
tional odds regression analysis was used to measure the proportional odds ratios
(POR) and 95% confidence intervals (CI) for the B58s alleles.
SAS version 9.01 (SAS Institute, Cary, N.C.) and GraphPad Prism version 4.0
were used for all statistical analyses and graphs.
B58s alleles and HIV-1 outcomes in Zambians. Of those
Zambians whose specimens were typed at the HLA-B locus,
127 (30%) carried at least one B58s allele. Compared with
Caucasians, Zambians were more likely to carry B58s alleles,
including B*5802. Frequencies of individual B58s alleles in this
population (2N ? 846) ranged from 1.7% for B*1516-*1517 to
5.8% for B*5703 (Fig. 1). The mean log10VL for all seropos-
itive individuals was 4.67 (?47,000 copies/ml). Overall, sub-
jects with B58s alleles showed a slightly lower log10VL than
those without it (?log10VL ? ?0.12, P ? 0.18). However, VLs
differed markedly across groups carrying certain individual
B58s alleles. HLA-B*5703 was associated with low VLs in both
linear (mean VL ? 4.36, ?log10VL ? ?0.34, P ? 0.01) and
categorical (P ? 0.004) analyses (Fig. 2a). Conversely, B*5802
was associated with higher VLs in both linear (mean VL ?
4.97, ?log10VL ? ?0.33, P ? 0.02) and categorical (P ? 0.007)
analyses. For subjects with B*5801, the median log10VL (4.61)
was not appreciably different from that found for subjects with
B*5703 (4.49) (P ? 0.54) and not significantly lower than the
median for subjects with non-B58s alleles (P ? 0.23). The
small number of individuals with B*1516-*1517 had a nonsig-
nificantly higher mean VL (mean VL ? 4.77, ?log10VL ?
?0.12, P ? 0.53) than those without any B58s allele.
To assess the effect of duration of HIV-1 infection on our
findings, we compared transmitting partners who were HIV-1
positive at study entry (i.e., seroprevalent subjects) with part-
ners who seroconverted after entry (i.e., seroconverters). The
contrasting effects of B*5703 and B*5802 on VL were consis-
tently apparent following stratification (Table 1), although the
magnitude and significance of the B*5802 disadvantage were
diminished among seroconverters. The protective effect for
FIG. 1. Viral load distribution of HLA-B58 supertype alleles in Zambians. Horizontal bars correspond to median viral loads. The P values were
derived from the Mann-Whitney test, and only P values of ?0.1 are shown.
VOL. 80, 2006HLA-B*58 SUPERTYPE ALLELES AND HIV-1 6057
B*5801 was suggested among seroprevalent subjects (mean
VL ? 4.5, ?log10VL ? ?0.28, P ? 0.06) and particularly
among those with the B*5801-Cw*03 haplotype (mean VL ?
4.19, ?log10VL ? ?0.65, P ? 0.02) but absent in seroconvert-
ers. However, low numbers of seroconverters with B58s alleles
may have accounted for the observed differences in the mag-
nitude of the effects. The association with VL could not be
meaningfully assessed in B*1516-*1517 seroconverters (n ? 4).
There were 143 haplotype combinations consisting of a B58s
allele and its imputed linked HLA-C allele identified among all
Zambians studied, each with two presumed haplotypes (2N ?
844). Notably, (i) the association of B*5703 with lower VLs was
strong in the presence of Cw*18 but entirely lost in its absence;
(ii) B*5801 commonly formed haplotypes with both Cw*03 and
Cw*07, but only the B*5801-Cw*03 haplotype was associated
with appreciably lower VLs (Table 2); and (iii) the association
of the B*5802-Cw*06 haplotype and that of B*5802 overall
with higher VLs were strong and indistinguishable due to the
very strong disequilibrium between these B and Cw alleles.
Because the carriage of Cw*18 appeared statistically to modify
the effect of B*5703 in the Zambian population, we explored
the role of Cw*18 further. Its carriage was associated with
lower VLs among all subjects (mean VL ? 4.3, ?log10VL ?
?0.43, P ? 0.0001) as well as in the subsets of those with and
without B*5703 (mean VL ? 4.25, ?log10VL ? ?0.72, P ?
0.01, and mean VL ? 4.39, ?log10VL ? ?0.34, P ? 0.03,
FIG. 2. (a) Distribution of HLA-B58 supertype alleles within three
VL categories in Zambians. The vertical bars represent the propor-
tions of subjects with a particular B58s allele within each category. The
number of subjects with a B58s allele is shown at the top of the bar for
each category. P values were calculated with the Jonckheere-Terpstra
test. (b) Distribution of HLA-B58 supertype alleles within three HIV-1
disease progression groups of Rwandans. The vertical bars represent
the proportions of subjects with a B58s allele within each group.
The number of subjects with a B58s allele is shown at the top of the
bar for each category. P values were derived from the Jonckheere-
TABLE 1. Effects of HLA-B58s alleles on HIV-1 VL, stratified according to heterosexual HIV-1 transmission categories in Zambiansa
Seroprevalent subjectsb(n ? 276)
Seroconvertersc(n ? 147)
Combined groups (n ? 423)
aAll estimates are from the univariate GEE models.
bSeroprevalent subjects, seropositive index partners who were HIV-1 positive at the time of study entry.
cSeroconverters, partners of discordant couples who seroconverted during follow-up.
d?VL values correspond to beta coefficients from the GEE models.
e—, not reported due to instability of estimates.
TABLE 2. Linear associationaof HLA-B58s and HLA-C alleles
with HIV-1 viral load in Zambians
B58s and Cw
alleles carried by group
B*5703-Cw*18 haplotype (n ? 38)d
Cw*18?B*5703?(n ? 38) vs.
Cw*18?B*5703?(n ? 28)
Cw*18?B*5703?(n ? 8) vs.
Cw*18?B*5703?(n ? 348)
B*5703?Cw*18?(n ? 38) vs.
B*5703?Cw*18?(n ? 8)
B*5703?Cw*18?(n ? 28)fvs.
B*5703?Cw*18?(n ? 349)
B*5802-Cw*06 haplotype (n ? 30)d
Cw*06?B*5802?(n ? 30) vs.
Cw*06?B*5802?(n ? 59)
Cw*06?B*5802?(n ? 2) vs.
Cw*06?B*5802?(n ? 332)
B*5802?Cw*06?(n ? 59) vs.
B*5802?Cw*06?(n ? 332)
B*5801-Cw*03 haplotype (n ? 13)d
Cw*03?B*5801?(n ? 13) vs.
Cw*03?B*5801?(n ? 39)
Cw*03?B*5801?(n ? 27) vs.
Cw*03?B*5801?(n ? 344)
B*5801?Cw*03?(n ? 13) vs.
B*5801?Cw*03?(n ? 27)
B*5801?Cw*03?(n ? 39) vs.
B*5801?Cw*03?(n ? 344)
aAssessed by GEE.
bCorresponds to mean log10VL of haplotype or the first group of comparison
cCorresponds to beta coefficients from the GEE models.
dCompared to the absence of haplotype.
eNot reported due to instability of estimates.
fSix Cw*18-positive subjects had lower VLs (mean ? 4.4, ?log10VL ? ?0.33,
P ? 0.3) after exclusion of 22 B*8101-positive subjects
6058 LAZARYAN ET AL.J. VIROL.
respectively). However, because Cw*18 also shows linkage dis-
equilibrium with B*8101, another allele associated with lower
VLs in Zulu/Xhosa populations (14) and in our Zambian pop-
ulation (mean VL ? 4.34, ?log10VL ? ?0.35, P ? 0.03), the
independent Cw*18 effect could be assessed only in the ab-
sence of both B*5703 and B*8101. Even in that small subgroup
(n ? 6), Cw*18 showed an effect (?log10VL ? ?0.33), albeit
statistically insignificant (P ? 0.3), of a magnitude similar to
that seen with B*5703 and B*8101 carriers.
B58s alleles and HIV disease progression in Rwandans. Of
202 seropositive women whose specimens were typed at the
HLA-B locus, 73 (36.1%) carried at least one B58s allele.
Frequencies of individual B58s alleles in this population (2N ?
404) ranged from 2% for B*1516-*1517 to 3.7% for B*5801,
7.4% for B*5703, and 8.2% for B*5802. The proportions of
each HIV-1 disease progression group who carried B58s alleles
did not differ (P ? 0.81). B*5703 was associated with a rela-
tively favorable disease course (POR ? 0.47; 95% CI ? 0.21 to
1.07; P ? 0.06), whereas B*5802 was strongly associated with
accelerated HIV-1 progression (POR ? 3.46; 95% CI ? 1.6 to
7.7; P ? 0.003) (Fig. 2b). No trends were apparent for B*5801
(P ? 0.46) or B*1516-*1517 (P ? 0.25).
Our observations for two populations of Africans infected
with different HIV-1 subtypes demonstrate functional hetero-
geneity for individual alleles within the B58 supertype. We
found no appreciable advantage of the B58 supertype as a
whole on HIV/AIDS, in contrast to several previous studies (3,
16, 23, 31). Different HIV-1 subtypes or HLA class I supertype
frequencies could have accounted for the observed population-
specific effects of supertypes on viral control and immune es-
cape (31). The more likely reason, however, is that contribu-
tions of the individual component alleles of the B58s were not
examined (3, 16) or that their analysis was limited by the rarity
of certain B58s alleles (23, 31). In particular, the very low
frequency of B*5802 among Caucasians (5) precluded assess-
ment of its contribution to the protection by B58s seen in the
Multicenter AIDS Cohort Study.
Our results confirm the favorable effect of B*5703 and un-
favorable effect of B*5802 on VL previously reported for
HIV-1 subtype C in South Africa (14). Additionally, our find-
ings extend the evidence to include the acceleration by B*5802
of the disease progression among Rwandans with the HIV-1
clade A. An earlier report on the failure of B*5802 to prsent
immunodominant HIV-1 subtype C Gag peptides in subjects
from Botswana (19) accords with poor control of viremia in
Zambians and disease progression in Rwandans with B*5802.
The available experimental and epidemiologic data point to
structural and functional features of B*5802 that set it apart
from the other members of the B58 supertype with regard to its
capacity to respond to HIV-1 subtype C peptides. Specifically,
it has been suggested that changes in amino acid side chains
(94I3T, 95I3L, and 97R3W) in the ?-2 helix of HLA class
I molecules affect the key structures of the antigen binding
groove such as the tyrosine bed and the F-pocket (2, 12, 21,
26), thereby impairing the presentation of immunodominant
While B*5802 has structurally been predicted to function
inadequately, B*5801 would be expected to resemble B*57
alleles in controlling HIV-1 infection. However, we did not
detect a uniform advantage for all Zambian B*5801 carriers.
The protective effect of B*5801 was particularly apparent
among seroprevalent subjects in conjunction with a closely
linked Cw*03 allele. The absence of a B*5801 benefit among
seroconverters may imply a later effect of B*5801 as distinct
from the early protection well established for B*57 in a study
of recent seroconverters (1) and in our own. Thus, despite their
similarity in both predicted and reported binding motifs,
B*5801 differed somewhat from B*5703 in its associations with
HIV-1 outcomes in our study. Together, our data from Afri-
cans suggest important functional differences between B*58
and B*57 in the context of HIV/AIDS.
Although the preeminence of HLA-B alleles in HIV/AIDS
has been demonstrated experimentally and epidemiologically
(7, 14), in our Zambian cohort certain HLA-C alleles in link-
age disequilibrium with their corresponding HLA-B alleles
appeared to be contributing to their effect on VL. In particular,
Cw*18 showed significant associations with low VL both in the
presence and in the absence of B*5703, with which it is in
linkage disequilibrium; conversely, VL was higher in subjects
carrying B*5703 who lacked Cw*18. Compared with the effect
of B*5703 overall, the magnitude of the VL association with
the B*5703-Cw*18 haplotype was greater. In Rwandan sub-
jects, neither the number of patients with the B*5703-Cw*18
haplotype nor the strength of linkage disequilibrium between
the two alleles of the haplotype was sufficient to assess the
effects of the two alleles with appropriate stratification.
The advantage of B*5801 likewise appeared dependent on
the presence of the Cw*03 allele in Zambians. For B*5802 and
Cw*0602, the linkage disequilibrium was so uniform that an
independent deleterious effect of B*5802 could not be estab-
lished. For reasons that are unclear, in Zambians these HLA-
B–HLA-C haplotype combinations may have exerted particu-
larly strong joint effects on the usual class I-mediated CTL
pathway. It is also possible that HLA-C-restricted CTL re-
sponses may influence the epitopes targeted by relevant
HLA-B alleles. A third possibility is that HLA-C alleles are
involved through their additional role as ligands for killer im-
munoglobulin-like receptors (KIRs). However, HLA-KIR in-
teractions are complex; they can drive both activating and
inhibiting KIR effects (16, 17). Similar contributions of HLA-C
alleles were not observed in Rwandans, probably due to dif-
ferences in HLA-B–HLA-C haplotype frequencies and the
prevalent HIV-1 subtype.
Our study had several strengths and limitations. We were
able to examine the effects of B58s alleles in two African
populations with distinct circulating viral subtypes. The capa-
bility of assessing the effects of B58s alleles among both sero-
prevalent and recently seroconverted individuals was also ad-
vantageous. Our longitudinal study design enabled us to detect
the protective effect of B*5801 among the seroprevalent but
not the recently seroconverted Zambians. This effect had been
predicted in seroprevalent South Africans (14) but may not be
generalizable to subjects in earlier stages of infection. The
relatively high prevalence of several B*58s alleles among Af-
ricans provided sufficient power to evaluate the associations of
HIV-1 outcomes with individual B58s alleles, except for
B*1516-*1517, which has also been shown to be protective
VOL. 80, 2006HLA-B*58 SUPERTYPE ALLELES AND HIV-16059
(10). The assessment of this pair of alleles was limited by small Download full-text
numbers in both cohorts. An absence of virologic data for
Rwandans further limited our assessment, which was confined
to categorical analysis of clinical outcomes.
In summary, B58s alleles or their haplotypes exert effects
distinct enough from each other that the properties of all
alleles of the B58 supertype should not be considered the
same. Because HLA alleles interact with products of other
genes inside and outside of the major histocompatibility com-
plex as well as products of the virus itself, it is rather unlikely
that their supertype classification based solely on CTL function
can entirely capture their pluripotential effects. Further sys-
tematic investigation of individual alleles within other known
HLA supertypes could prove equally informative for studies of
infection and immunity.
This work was supported by several grants (AI40591, AI42454,
AI41530, and AI41951) from the National Institute of Allergy and
Infectious Diseases (NIAID), with additional funding from the Center
for AIDS Research at the University of Alabama at Birmingham.
We are grateful to investigators, staff, and participants of the Zam-
bia-Emory HIV-1 Research Project (ZEHRP) and Project San Fran-
cisco for their valuable contributions to this work. We also thank I.
Brill, G. Cloud, and A. Moore for their help in data management.
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