TRENDS
I M M U N O L O G Y TO D AY
Immune correlates of protection from HIV and AIDS –
more answers but yet more questions
Jonathan L. Heeney, Peter Beverley, Andrew McMichael, Gene Shearer,
Jack Strominger, Britta Wahren, Jonathan Weber and Frances Gotch
At an international symposium*,
specific clinical and preclinical
I
mmunity to human immuno- settings were examined in order to (SIVs) that are closely related to HIV-1 and
deficiency virus (HIV) infection is HIV-2. Some of these infected animals do not
increase our understanding of
apparent in certain clinical settings readily develop AIDS and appear to have
and is likely to be naturally ac- immunity to HIV. This data might evolved mechanisms of disease resistance4
quired rather than genetically determined in help the design of more effective and successfully coexist with viruses that
the majority of instances (Table 1). In labora- cause AIDS when transmitted to other pri-
tory settings a limited number of candidate
vaccine strategies for protection mate species. African Sooty Mangabeys are
vaccines have protected non-human pri- from HIV or the treatment of AIDS. commonly infected with SIVsm without
mates from infection with HIV or simian im- pathologic consequences, whereas the same
munodeficiency virus (SIV). In the unfortu- virus is pathologic when transmitted to
nate event of infection, cases are also HIV2 individuals were susceptible to infec- Asian Rhesus Macaques. F. Villinger
emerging in which the host appears to de- tion by SF-2 or the partner’s virus, or both. A (Atlanta) reported that these two species
velop specific immune responses to certain wide range in CTLp to gag, env and pol was were similar with respect to the levels of
viral epitopes that appear to protect from observed with no distinct pattern except that b-chemokines secreted and their receptor
disease progression. It is the underlying na- CTLp to gag may have been relatively (CCR5, CCR2b, CXCR4) homologies,
ture of these protective immune responses to greater in exposed uninfected (EU) individ- although constitutive expression of CCR5
infection or disease progression that are of uals. CTL responses were sometimes tran- was higher in rhesus PBMC (Ref. 5). An
importance and need to be further defined. sient and weak proliferative responses were important difference appeared to be an
present. There was no correlation between undefined soluble CD81 T cell suppressor
lack of transmission and viral load in the factor of SIV that is produced by Sooty
‘Has nature done the experiment HIV1 partner. Mangabeys before infection, but is only
for us?’ – mechanisms of natural M. Clerici (Milan) summarized an analy- found in Rhesus macaques at similar levels
immunity in exposed but sis of mucosal and cellular immunity in after infection.
uninfected individuals peripheral blood mononuclear cells (PBMC) Evidence has accumulated suggesting a
The meeting opened with discussions of and IgA and IgG antibodies to HIV in tolerance-like phenomenon with a lack of
work in this field. F. Plummer (Nairobi) and serum, urine and vaginal washes in a cohort antibodies to non-denatured gag protein in
S. Rowland-Jones (Oxford) summarized epi- of 16 discordant (HIV2) EU females (Table 2) both African Green monkeys (another natu-
demiological, immunological and virologi- Controls included HIV1 females and low ral SIV host) and Sooty Mangabeys
cal analyses of Kenyan and Gambian sex- risk HIV2 females. (S. Norley, Langen)6. This lack of gag re-
workers, followed longitudinally for several There was no correlation of resistance sponse is attributed to a possible lack of
years1,2. Approximately 40% of uninfected with the D32 mutation in CCR5, nor with antigen–antibody complexing and lack of
entrees into the Kenyan cohort became in- increased b-chemokine production3. These virus trapping in lymph nodes. Infected
fected in the first year, with a decreasing per- findings suggested compartmentalized chimpanzees in most cases also maintained
centage of infection during the next two mucosal immunity and raised the possibility low virus loads, which correlates with a lack
years. By the fourth year 5–15% of women that both systemic cellular and mucosal of trapping of virus in lymph nodes and
remained uninfected (Box 1). humoral immunity could contribute to pro- relative resistance to AIDS (Ref. 7).
J. McElrath (Seattle) summarized unpub- tection against heterosexual transmission of With respect to possible important im-
lished results in which genetic, virologic and HIV. munogenetic factors in non-human pri-
immunologic parameters were assessed in mates, R. Bontrop (Rijswijk) presented data
HIV discordant couples. PCR, Western blot, that implicated particular chimpanzee MHC
viral co-culture in the absence of CD8 cells, The ‘long-term survivors’ class I alleles and effective CTL responses to
cytotoxic T lymphocyte (CTL) assays and Non-human primate host genetics and highly conserved HIV-1 epitopes4 in the
proliferative responses to HIV antigens were progression to disease chimpanzee’s response to lentiviruses. It was
performed. With the exception of one D32 A number of African non-human primates also reported by D. Watkins (Wisconsin) that
deletion homozygote individual, cells from are naturally infected with lentiviruses some Asian rhesus macaques with particular
PII: S0167-5699(98)01437-6 0167-5699/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.
J U N E 1 9 9 9
*The Second International Workshop on ‘Immunological Correlates of Protection
from HIV Infection and Disease’ was held at Oxford, UK, on 17–20 April 1998. Vo l . 2 0 No.6 247
, TRENDS
I M M U N O L O G Y TO D AY
Table 1. Cohorts and their types of responses
Cohorts of exposed uninfected Types of responses that might be protective
individuals from infection chemokine RANTES by CD41 cells was ob-
served, which correlated with the reduced
Homosexual men Th1 responses as a result of Immunologic?
ability of macrophage-tropic viruses to repli-
Female sex-workers previous primary responses
cate in vitro and to lower viral loads in vivo9.
Discordant sexual partners to HIV antigens
G. Ogg (Oxford) used novel HLA-peptide
Newborn infants of HIV1 Polymorphisms in HIV Genetic?
tetrameric complexes to demonstrate an in-
mothers coreceptors
verse relationship between plasma viral
Healthcare workers HIV-1-specific factors? Virologic?
Other cohorts? (hemophiliacs) RNA and CTL frequencies. No correlation
was seen between CTL and the clearance of
infected cells10. Individuals who maintain a
strong CTL response to an HLA-B27 re-
Box 1. Epidemiological, immunological and virological analyses stricted epitope tend to survive, whereas
of Kenyan and Gambian sex-workers CTL efficacy is lost and these patients
Resistance was not due to: progress to AIDS if viral mutation results in
• a difference in lifestyle or sexual behaviour from those who became changes in the epitope.
infected; CD81 CTL in HIV-infected progressors
• natural killer (NK) cells;
are highly activated expressing both
• viral-suppressive factor in the plasma;
• an unusually high incidence of D32 CCR5 polymorphisms; HLA-DR and CD38 antigens11. J. Giorgi (Los
• a generalized greater Th1-like response; Angeles) reported that in an activated-state
• an increase in resistance to in vitro infection by diverse HIV-1 isolates. effector, CTL were recruited from the
CD45RA2 CD62L2 subset. However in
Factors that could account for resistance included:
donors with less activation (low CD38 ex-
• HIV specific CTL activity (demonstrable in 66% women), which was often specific
for HIV-1 epitopes conserved across clades; pression) and lower virus loads, memory
• IL-2 produced in response to HIV antigens; cells were also found in the CD45RA1
• IgA but not IgG antibodies to HIV found in the genital tracts of >50% women; CD62L1 subset. In individuals with high
• Genetic factors – HLA A6802 individuals had a twofold risk reduction; viral loads data suggested that CTL were
– HLA B18 might be associated with resistance to infection;
being actively recruited from the CD281 and
– There was a significant MHC class II rarity score;
– Resistance appeared to cluster in families. CD282 subsets, while those with low viral
loads had memory CTL predominantly
recruited from the CD282 population12.
A. Dalgleish (London) expanded on re-
MHC class I alleles are relatively resistant to Genetically determined causes include mu- cent observations of HLA-like sequences in
AIDS when infected with SIVsm (Ref. 8). It tations in important HIV-1 coreceptors such the envelope of HIV-1. Data point to pan-
seems that MHC class I molecules, and pep- as CCR5. B. Paxton (Amsterdam) discussed activation of the immune system being a
tides restricted through them, greatly influ- HIV-1-infected individuals heterozygous for pivotal event in AIDS pathogenesis, which
ence the course of disease. Unequivocal evi- the D32 CCR5 allele. Lower levels of cell sur- he suggested could be attributed to
dence of correlations between virus escape face expression of CCR5 were seen, and in ‘allo-like’ activation induced by gp120
from CTL epitopes and disease progression some cases increased production of the b- binding of allo-reactive peptides13.
was demonstrated, underscoring the point
that effective CTL responses, if specific for
highly conserved invariant epitopes, might Table 2. Differences in immune responses in exposed uninfected (EU)
be effective mediators of disease resistance. individuals
HIV2 EU HIV1 HIV2/low risk
What differences are observed between HIV-specific serum IgA 9/11 All 1/50
human long-term non-progressors and rapid HIV-specific urine IgA All None None
progressors? HIV-specific serum IgG None All None
It is now apparent that the human long-term IL-2 by env peptides 9/16 5/16 1/50
survivors (LTS) and long-term non-progres- PHA stimulated IL-2 High Low ND
IL-10 production Low High ND
sors (LTNP) can be placed in several
MHC class I-restricted CTLs 4/7 – –
categories depending on the underlying
cause for their lack of disease progression. Abbreviations: CTL, cytotoxic T lymphocytes; IL-2, interleukin 2; MHC, major histocompatibility
Again we must consider immunological, complex; ND, not done; PHA, phytohemagglutinin.
virological and genetic factors (Table 1).
J U N E 1 9 9 9
248 Vo l . 2 0 No.6
I M M U N O L O G Y TO D AY
Immune correlates of protection from HIV and AIDS –
more answers but yet more questions
Jonathan L. Heeney, Peter Beverley, Andrew McMichael, Gene Shearer,
Jack Strominger, Britta Wahren, Jonathan Weber and Frances Gotch
At an international symposium*,
specific clinical and preclinical
I
mmunity to human immuno- settings were examined in order to (SIVs) that are closely related to HIV-1 and
deficiency virus (HIV) infection is HIV-2. Some of these infected animals do not
increase our understanding of
apparent in certain clinical settings readily develop AIDS and appear to have
and is likely to be naturally ac- immunity to HIV. This data might evolved mechanisms of disease resistance4
quired rather than genetically determined in help the design of more effective and successfully coexist with viruses that
the majority of instances (Table 1). In labora- cause AIDS when transmitted to other pri-
tory settings a limited number of candidate
vaccine strategies for protection mate species. African Sooty Mangabeys are
vaccines have protected non-human pri- from HIV or the treatment of AIDS. commonly infected with SIVsm without
mates from infection with HIV or simian im- pathologic consequences, whereas the same
munodeficiency virus (SIV). In the unfortu- virus is pathologic when transmitted to
nate event of infection, cases are also HIV2 individuals were susceptible to infec- Asian Rhesus Macaques. F. Villinger
emerging in which the host appears to de- tion by SF-2 or the partner’s virus, or both. A (Atlanta) reported that these two species
velop specific immune responses to certain wide range in CTLp to gag, env and pol was were similar with respect to the levels of
viral epitopes that appear to protect from observed with no distinct pattern except that b-chemokines secreted and their receptor
disease progression. It is the underlying na- CTLp to gag may have been relatively (CCR5, CCR2b, CXCR4) homologies,
ture of these protective immune responses to greater in exposed uninfected (EU) individ- although constitutive expression of CCR5
infection or disease progression that are of uals. CTL responses were sometimes tran- was higher in rhesus PBMC (Ref. 5). An
importance and need to be further defined. sient and weak proliferative responses were important difference appeared to be an
present. There was no correlation between undefined soluble CD81 T cell suppressor
lack of transmission and viral load in the factor of SIV that is produced by Sooty
‘Has nature done the experiment HIV1 partner. Mangabeys before infection, but is only
for us?’ – mechanisms of natural M. Clerici (Milan) summarized an analy- found in Rhesus macaques at similar levels
immunity in exposed but sis of mucosal and cellular immunity in after infection.
uninfected individuals peripheral blood mononuclear cells (PBMC) Evidence has accumulated suggesting a
The meeting opened with discussions of and IgA and IgG antibodies to HIV in tolerance-like phenomenon with a lack of
work in this field. F. Plummer (Nairobi) and serum, urine and vaginal washes in a cohort antibodies to non-denatured gag protein in
S. Rowland-Jones (Oxford) summarized epi- of 16 discordant (HIV2) EU females (Table 2) both African Green monkeys (another natu-
demiological, immunological and virologi- Controls included HIV1 females and low ral SIV host) and Sooty Mangabeys
cal analyses of Kenyan and Gambian sex- risk HIV2 females. (S. Norley, Langen)6. This lack of gag re-
workers, followed longitudinally for several There was no correlation of resistance sponse is attributed to a possible lack of
years1,2. Approximately 40% of uninfected with the D32 mutation in CCR5, nor with antigen–antibody complexing and lack of
entrees into the Kenyan cohort became in- increased b-chemokine production3. These virus trapping in lymph nodes. Infected
fected in the first year, with a decreasing per- findings suggested compartmentalized chimpanzees in most cases also maintained
centage of infection during the next two mucosal immunity and raised the possibility low virus loads, which correlates with a lack
years. By the fourth year 5–15% of women that both systemic cellular and mucosal of trapping of virus in lymph nodes and
remained uninfected (Box 1). humoral immunity could contribute to pro- relative resistance to AIDS (Ref. 7).
J. McElrath (Seattle) summarized unpub- tection against heterosexual transmission of With respect to possible important im-
lished results in which genetic, virologic and HIV. munogenetic factors in non-human pri-
immunologic parameters were assessed in mates, R. Bontrop (Rijswijk) presented data
HIV discordant couples. PCR, Western blot, that implicated particular chimpanzee MHC
viral co-culture in the absence of CD8 cells, The ‘long-term survivors’ class I alleles and effective CTL responses to
cytotoxic T lymphocyte (CTL) assays and Non-human primate host genetics and highly conserved HIV-1 epitopes4 in the
proliferative responses to HIV antigens were progression to disease chimpanzee’s response to lentiviruses. It was
performed. With the exception of one D32 A number of African non-human primates also reported by D. Watkins (Wisconsin) that
deletion homozygote individual, cells from are naturally infected with lentiviruses some Asian rhesus macaques with particular
PII: S0167-5699(98)01437-6 0167-5699/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.
J U N E 1 9 9 9
*The Second International Workshop on ‘Immunological Correlates of Protection
from HIV Infection and Disease’ was held at Oxford, UK, on 17–20 April 1998. Vo l . 2 0 No.6 247
, TRENDS
I M M U N O L O G Y TO D AY
Table 1. Cohorts and their types of responses
Cohorts of exposed uninfected Types of responses that might be protective
individuals from infection chemokine RANTES by CD41 cells was ob-
served, which correlated with the reduced
Homosexual men Th1 responses as a result of Immunologic?
ability of macrophage-tropic viruses to repli-
Female sex-workers previous primary responses
cate in vitro and to lower viral loads in vivo9.
Discordant sexual partners to HIV antigens
G. Ogg (Oxford) used novel HLA-peptide
Newborn infants of HIV1 Polymorphisms in HIV Genetic?
tetrameric complexes to demonstrate an in-
mothers coreceptors
verse relationship between plasma viral
Healthcare workers HIV-1-specific factors? Virologic?
Other cohorts? (hemophiliacs) RNA and CTL frequencies. No correlation
was seen between CTL and the clearance of
infected cells10. Individuals who maintain a
strong CTL response to an HLA-B27 re-
Box 1. Epidemiological, immunological and virological analyses stricted epitope tend to survive, whereas
of Kenyan and Gambian sex-workers CTL efficacy is lost and these patients
Resistance was not due to: progress to AIDS if viral mutation results in
• a difference in lifestyle or sexual behaviour from those who became changes in the epitope.
infected; CD81 CTL in HIV-infected progressors
• natural killer (NK) cells;
are highly activated expressing both
• viral-suppressive factor in the plasma;
• an unusually high incidence of D32 CCR5 polymorphisms; HLA-DR and CD38 antigens11. J. Giorgi (Los
• a generalized greater Th1-like response; Angeles) reported that in an activated-state
• an increase in resistance to in vitro infection by diverse HIV-1 isolates. effector, CTL were recruited from the
CD45RA2 CD62L2 subset. However in
Factors that could account for resistance included:
donors with less activation (low CD38 ex-
• HIV specific CTL activity (demonstrable in 66% women), which was often specific
for HIV-1 epitopes conserved across clades; pression) and lower virus loads, memory
• IL-2 produced in response to HIV antigens; cells were also found in the CD45RA1
• IgA but not IgG antibodies to HIV found in the genital tracts of >50% women; CD62L1 subset. In individuals with high
• Genetic factors – HLA A6802 individuals had a twofold risk reduction; viral loads data suggested that CTL were
– HLA B18 might be associated with resistance to infection;
being actively recruited from the CD281 and
– There was a significant MHC class II rarity score;
– Resistance appeared to cluster in families. CD282 subsets, while those with low viral
loads had memory CTL predominantly
recruited from the CD282 population12.
A. Dalgleish (London) expanded on re-
MHC class I alleles are relatively resistant to Genetically determined causes include mu- cent observations of HLA-like sequences in
AIDS when infected with SIVsm (Ref. 8). It tations in important HIV-1 coreceptors such the envelope of HIV-1. Data point to pan-
seems that MHC class I molecules, and pep- as CCR5. B. Paxton (Amsterdam) discussed activation of the immune system being a
tides restricted through them, greatly influ- HIV-1-infected individuals heterozygous for pivotal event in AIDS pathogenesis, which
ence the course of disease. Unequivocal evi- the D32 CCR5 allele. Lower levels of cell sur- he suggested could be attributed to
dence of correlations between virus escape face expression of CCR5 were seen, and in ‘allo-like’ activation induced by gp120
from CTL epitopes and disease progression some cases increased production of the b- binding of allo-reactive peptides13.
was demonstrated, underscoring the point
that effective CTL responses, if specific for
highly conserved invariant epitopes, might Table 2. Differences in immune responses in exposed uninfected (EU)
be effective mediators of disease resistance. individuals
HIV2 EU HIV1 HIV2/low risk
What differences are observed between HIV-specific serum IgA 9/11 All 1/50
human long-term non-progressors and rapid HIV-specific urine IgA All None None
progressors? HIV-specific serum IgG None All None
It is now apparent that the human long-term IL-2 by env peptides 9/16 5/16 1/50
survivors (LTS) and long-term non-progres- PHA stimulated IL-2 High Low ND
IL-10 production Low High ND
sors (LTNP) can be placed in several
MHC class I-restricted CTLs 4/7 – –
categories depending on the underlying
cause for their lack of disease progression. Abbreviations: CTL, cytotoxic T lymphocytes; IL-2, interleukin 2; MHC, major histocompatibility
Again we must consider immunological, complex; ND, not done; PHA, phytohemagglutinin.
virological and genetic factors (Table 1).
J U N E 1 9 9 9
248 Vo l . 2 0 No.6
