Hiv 3

ReVIeWs
CD8+ T cells in HIV control, cure and

prevention
David R. Collins1,2, Gaurav D. Gaiha1,3 and Bruce D. Walker 1,2,4 ✉
Abstract | HIV infection can be effectively treated by lifelong administration of combination

antiretroviral therapy, but an effective vaccine will likely be required to end the HIV epidemic.
Although the majority of current vaccine strategies focus on the induction of neutralizing
antibodies, there is substantial evidence that cellular immunity mediated by CD8+ T cells can
sustain long-term disease-free and transmission-free HIV control and may be harnessed to induce
both therapeutic and preventive antiviral effects. In this Review, we discuss the increasing
evidence derived from individuals who spontaneously control infection without antiretroviral
therapy as well as preclinical immunization studies that provide a clear rationale for renewed
efforts to develop a CD8+ T cell-based HIV vaccine in conjunction with B cell vaccine efforts.
Further, we outline the remaining challenges in translating these findings into viable HIV
prevention, treatment and cure strategies.
Combination antiretroviral therapy (ART) has dramati- infection, which, in addition to combating viral diver-
cally transformed HIV infection from a death sentence to sity, would also need to eradicate persistent viral reser-
a clinically manageable chronic disease. Strict adherence voirs. Indeed, the only two examples of apparent HIV
to ART effectively suppresses viraemia, halts progres- reservoir clearance have been mediated not by immuno-
sion to acquired immune deficiency syndrome (AIDS), logical or pharmacological interventions but rather by
thwarts HIV acquisition when used as pre-exposure or HIV-resistant haematopoietic stem cell transplantation8,9.
post-exposure prophylaxis, and prevents transmission1. In contrast to these cases of transplant-induced elim-
However, limitations in medication access and adher- ination of infection, approximately 1 in 300 infected
ence, together with emerging drug resistance, remain individuals is able to maintain viraemia below thresh-
major obstacles to ending the epidemic with ART alone2. olds associated with transmission and disease progres-
Moreover, the risks of disease progression and virus sion without the need for ART10. An extensive body of
transmission rapidly re-emerge in the vast majority of evidence indicates that this durable control is mediated
individuals upon cessation of ART due to rebound from not by antibodies but by effective HIV-specific CD8+
viral reservoirs that persist during treatment3, necessita T cells. Given documented cases of spontaneous viral
ting lifelong ART administration. These key limitations control for decades, such untreated HIV controllers
compel refocused efforts towards understanding the represent a viable model for an effective vaccine and
determinants of HIV immune control, and the failure durable immune-mediated HIV remission. In this
Ragon Institute of MGH, MIT of such control, in order to inform the development of Review, we synthesize evidence that supports a translat-
1
and Harvard, Cambridge,

MA, USA.
preventive and therapeutic vaccine strategies. able CD8+ T cell-mediated mechanism of durable HIV
A central challenge to immune containment and vac- control, highlighting preclinical evidence suggesting that
2
Howard Hughes Medical
Institute, Chevy Chase,
cine development is that HIV is among the most diverse vaccine-induced HIV-specific CD8+ T cells are able to
MD, USA. and rapidly evolving human pathogens ever encountered. limit both the transmission and establishment of persis-
3
Gastrointestinal Unit, For perspective, a snapshot of HIV sequence diversity tent viral reservoirs. Finally, we outline the remaining
Department of Medicine, within a single individual is comparable to the global hurdles for T cell-based HIV prevention and cure strat-
MGH, Boston, MA, USA. diversity of influenza virus over an entire year4. Perhaps egies to complement and synergize with ongoing B cell
4
Institute for Medical unsurprisingly in light of such variation, vaccine strate- vaccine approaches.
Engineering and Sciences gies to date have failed to provide adequate protection
and Department of Biology,
MIT, Cambridge, MA, USA.
from HIV infection5–7, and the path forwards to an Spontaneous control of HIV infection
✉e-mail: bwalker@ effective neutralizing antibody-based vaccine remains Whereas most infectious agents are effectively contained
mgh.harvard.edu uncertain. Considering the formidable challenges asso- or eliminated by pathogen-specific immune responses,
https://doi.org/10.1038/ ciated with a preventive vaccine, it is perhaps even more immune failure is a hallmark of HIV pathogenesis. In the
s41577-020-0274-9 difficult to imagine immune-based elimination of HIV early stages of HIV infection, the window of opportunity
NAtuRe RevIews | Immunology volume 20 | August 2020 | 471

Reviews
to mount an effective immune response is limited by in individuals with protective alleles. The HLA associ-
profound CD4+ T cell depletion in blood and tissues11, ations indicate a critical role for CD8+ T cell-mediated
mutational escape from early HIV-specific immune immunity in spontaneous HIV control, an inference
responses12 and immune exhaustion13–15. Consequently, that is most strongly supported by CD8+ T cell deple-
most immune responses ultimately fail to contain HIV tion studies leading to loss of simian immunodeficiency
infection, resulting in progression to AIDS. virus (SIV) control in a non-human primate (NHP)
By contrast, a small subset of infected individuals, model27–30. The characteristics that define effective
known as HIV controllers, can suppress viral replica- CD8+ T cell responses in infected persons are coming
tion without antiretroviral medications. These unique into ever greater focus, as are outlined below.
persons have been broadly defined by sustained levels
of viraemia below 2,000 RNA copies per ml of plasma, CD8+ T cell function in spontaneous HIV control. Nearly
a level at which disease progression and sexual transmis- all individuals infected by HIV mount high-magnitude,
sion are markedly reduced16–18, and can be subdivided virus-specific CD8+ T cell responses, including the vast
into elite controllers (often defined as those with a viral majority who fail to control infection31–33. Interferon-γ
load <50 RNA copies per ml) and viraemic controllers (IFNγ) secretion by CD8+ T cells exposed to HIV anti
(viral load 50–2,000 RNA copies per ml). An additional gens, a widely used metric for identifying antigen-specific
category has been termed long-term non-progressors, responses, does not correlate with HIV control33–35.
usually defined by the ability to maintain stable CD4+ Additionally, the limitations of IFNγ assays are under-
T cell counts above 500 cells per µl for 10 or more years scored by a study showing that HIV-specific CD8+ T cells
in the absence of ART19. Despite considerable clinical, that secrete IFNγ are rarely the same cells that kill
genetic and phenotypical heterogeneity among these infected target cells36. The ability of antigen-stimulated
groups, common features have emerged indicating that cells to secrete combinations of cytokines and effec-
HIV-specific CD8+ T cells mediate durable HIV control, tor molecules, termed polyfunctionality, is greater in
offering critical insight for the design and implemen- controllers than progressors37–39. However, whether
tation of approaches to induce similar immunity on a this enhanced functionality is a cause or consequence
broader scale for HIV prevention and cure. of lower viral load has been difficult to discern.
Importantly, polyfunctionality is lowest in those with the
CD8+ T cells and HIV control: clues from host genetics. lowest viral loads by ultrasensitive assays, the smallest
One of the early links implicating CD8+ T cells in modu viral reservoirs and the least culturable virus40,41.
lating HIV control came not from studies of immune In contrast to assays measuring IFNγ secretion or
function but rather from cohort studies of host HLA polyfunctionality, assays measuring in vitro expansion
class I alleles20, which present viral peptides on the sur- of HIV-specific CD8+ T cells following stimulation with
face of infected cells for recognition by HIV-specific HIV antigens revealed properties of these cells that con-
CD8+ T cells. Unlike many features assessed in com- sistently distinguished controllers from progressors42.
parative studies between HIV controllers and chronic HIV-specific CD8+ T cells from controllers, compared
progressors, genetic polymorphisms are not influ- with those from progressors, have greater capacity to
enced by HIV infection. Initial studies in long-term proliferate and develop cytolytic potential upon in vitro
non-progressors identified a dramatic enrichment in antigenic stimulation42,43; this is also the case for HIV-
HLA-B*57 (ref.21), and subsequent genome-wide asso- specific CD8+ T cells from elite controllers with unde-
ciation studies encompassing over 6,000 infected indi- tectable responses following ex vivo antigen stimulation,
viduals across multiple large international cohorts as described above44. By contrast, CD8+ T cells from pro-
have confirmed that the major genetic polymorphisms gressors often exhibit strong ex vivo activation but fail to
modulating HIV control reside almost entirely within proliferate or acquire cytolytic capacity due to exhaus-
the HLA-B and HLA-C loci on chromosome six22–26. tion and necroptotic cell death42,45, and these deficiencies
In particular, these studies identified strong associations are not restored despite prolonged ART46,47. Moreover,
between HIV control and polymorphic amino acids the ability of in vitro-expanded CD8+ T cell populations
lining the HLA class I peptide-binding groove, which to suppress HIV replication38,48 also distinguishes elite
likely influence the viral peptides that are presented for controllers from progressors, further implicating the role
CD8+ T cell recognition of virally infected cells22. Variation of CD8+ T cell function in HIV control.
at these amino acid positions define specific class I Given that the functional ability of CD8+ T cells to
HLA alleles that previous studies have repeatedly proliferate differentiates controllers from progressors,
shown to be associated with increased likelihood of the lack of detectable IFNγ responses or CD8+ T cell
control (for example, HLA-B*57, HLA-B*27, HLA-B*52 polyfunctionality by direct ex vivo assays in some elite
and HLA-B*14) and others with risk of progression controllers likely reflects differential in vivo antigen
(for example, HLA-B*07, HLA-B*08 and HLA-B*35). exposure rather than being evidence for alternative
However, genetic associations offer an incomplete CD8+ T cell-independent mechanisms of control. Thus,
explanation, as no HLA class I allele is necessary or suf- combined analysis of both ex vivo and expanded CD8+
ficient for viral control and genetic associations defined T cell responses in the context of antigen exposure pro-
by genome-wide association studies account for less vides a more accurate perspective on which qualities
than 25% of observed variance in host control22. Thus, of CD8+ T cells are associated with spontaneous viral
additional non-genetic factors must influence control in control (Fig. 1). In comparison with progressors, CD8+
individuals without protective alleles and progression T cell responses in HIV controllers show an overall
472 | August 2020 | volume 20 www.nature.com/nri

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increased ability to maintain long-term memory and EC VC CP

effector potential, with the ability to kill infected cells
before progeny virions are produced49–51, providing a Mutational escape and/or T cell exhaustion
clear rationale for exploiting these features for treatment,
prevention and cure. Ex vivo IFNγ ELISPOT
CD8+ T cell function

CD8+ T cell specificity in spontaneous HIV control. In
addition to the importance of functional features of
HIV-specific CD8+ T cells in viral control, evidence also Ex vivo killing
points to the importance of the specificity of these
responses. Antigenic specificity of CD8+ T cell res
ponses is influenced by the unique binding properties
of expressed HLA class I alleles, each of which presents Proliferation and
expanded killing
a restricted set of HIV-derived peptides 8–11 amino
acids in length52. Polymorphic positions within the HIV antigen exposure, HIV reservoir size
HLA peptide-binding groove determine differential
Fig. 1 | Ex vivo CD8+ T cell function and phenotype are
peptide binding constraints among HLA alleles, includ- modulated by the magnitude and duration of in vivo
ing anchor residue preference and orientation of pep- HIV antigen exposure. The graph illustrates correlations
tide presentation to T cell receptors (TCRs). Despite between in vivo antigen exposure and HIV reservoir size
the strong association between certain HLA alleles and (x-axis), increasing levels of mutational escape and T cell
disease outcome, specific alleles are neither necessary exhaustion in elite controllers (EC), viraemic controllers
nor sufficient for durable HIV control. The majority of (VC) and chronic progressors (CP), and HIV-specific CD8+
infected individuals with protective HLA alleles are pro- T cell function following ex vivo antigenic stimulation
gressors and a significant proportion of HIV controllers (y-axis) by different measurements, including interferon-γ
lack protective HLA alleles22. (IFNγ) production in ELISPOT assays (solid blue line),
immediate cytolytic capacity (dashed blue line) and
Comprehensive assessment of CD8+ T cell specificity
proliferative capacity and cytolytic capacity of expanded
in viral control is complicated by HIV diversity, as assays T cells (red line).
are typically confined to recognition of a single reference
strain of the virus and longitudinal samples spanning
from acute to chronic phases of infection are limited. Consistent with this, robust CD8+ T cell targeting of
The magnitude and breadth of CD8+ T cell responses highly networked epitopes in controllers was associated
measured by IFNγ ELISPOT targeting the relatively with fewer mutations, especially at HLA anchor and
conserved HIV structural protein Gag but not the highly TCR contact sites61. Perhaps most importantly, elite con-
variable surface protein Env are associated with a trollers lacking protective HLA alleles were also found
lower viral load and preserved CD4+ T cell counts irre- to target epitopes containing highly networked amino
spective of HLA allele and epitope sequence conserv acids that are not commonly targeted, suggesting that
ation53–55. Moreover, comparative analysis of sequence what has been considered a genetic barrier to control
conservation of targeted epitopes does not distin- can be overcome.
guish HLA-B*57/HLA-B*27-negative controllers and TCR usage may also influence differences in CD8+
progressors56. T cell-mediated HIV control. Viral control has been
Although sequence conservation is a reasonable associated with more cross-reactive public TCR clono
proxy for mutational constraint, immune targeting of types62–64. HLA alleles associated with HIV control
conserved regions may be insufficient as only a sub- impart thymic selection for TCR repertoires with
set of conserved regions exhibits fitness defects when increased HIV recognition and variant cross-reactivity65.
mutated57. Computational modelling of HIV sequence Although differential TCR usage alone is insufficient to
diversity has revealed that Gag regions targeted by explain spontaneous control or confer functional differ-
controller responses have a lower mutational tolerance ences in CD8+ T cells66–68, cross-reactive TCRs have been
than those targeted by progressors, implying a structural shown to limit viral escape pathways in controllers, con-
basis for the observed mutational constraints58–60. The sistent with the findings that mutations within epitopes
importance of CD8+ T cell epitope specificity is further targeted predominantly by controllers are poorly toler-
supported by application of network theory to HIV pro- ated due to impaired viral replication69,70 and that their
tein structure. Network analysis of crystallographic HIV recognition is maintained in controllers by cross-reactive
protein structures using a novel algorithm to quantify TCRs and de novo responses71–73.
the contribution of non-covalent amino acid side chain Taken together, the combination of functional CD8+
interactions to overall protein structure revealed that T cell responses and targeting of mutationally con-
proliferative CD8+ T cell responses in HIV controllers, strained epitopes offers a compelling mechanism to
irrespective of expressed HLA alleles, preferentially explain the observed genetic association between HIV
target HIV epitopes containing amino acids derived control and expression of certain class I HLA alleles,
from highly interconnected (‘networked’) regions of and how individuals without protective HLA alleles can
viral protein structure61. Mutation of these highly net- mediate effective immune control. The data indicate
worked amino acids was also highly disruptive to viral that specificity and function of CD8+ T cells are neces-
fitness, making them ideal targets for immune pressure. sary for durable control, yet neither alone is sufficient,

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as mutational escape from functional responses and T cells are present in high concentrations75. Consistent
dysfunctional responses against non-mutated epitopes with this, increased frequencies of functional CD8+
represent parallel pathways of immune evasion (Fig. 2). T cells have been observed in the rectal mucosa of HIV
Induction of functional CD8+ T cell responses against controllers76. HIV-infected follicular helper CD4+ T cells,
highly networked epitopes restricted by common which reside within B cell follicles in lymphoid tissue
HLA alleles offers an opportunity for broad transla- and direct humoral immune responses, constitute a
tion of these findings towards preventive and curative significant fraction of the persistent viral reservoir
interventions74. during chronic infection77,78. Importantly, CD8+ T cells
are largely excluded from B cell follicles, representing a
CD8+ T cell localization in spontaneous HIV control. In significant obstacle to CD8+ T cell-mediated clearance
order to control chronic infection, HIV-specific CD8+ of infected follicular helper T cell reservoirs79. Recent
T cells must be able to traffic to and function at ana- evidence demonstrates that a population of follicular
tomical sites where HIV persists, especially mucosal and CD8+ T cells that express the follicle-homing receptor
gastrointestinal lymphoid tissues where infected CD4+ CXCR5 can traffic to or reside in lymphoid tissues under
certain circumstances80–82. Viral control is associated
with a higher proportion and functionality of follicu-
Proliferation Cytolysis HIV controller lar CD8+ T cells83–86, but viral replication within follicles
can persist even during elite control of HIV87,88, under-
Perforin/ scoring the need to develop strategies that promote the
granzyme trafficking and function of HIV-specific follicular CD8+
T cells. Tissue-resident memory T (TRM) cells represent
an additional subset of CD8+ T cells that control viral
CD8
pMHC-I infection in various tissue sites89. Relative to peripheral
TCR blood CD8+ T cells, follicular CD8+ T cells and TRM cells
Structurally
in lymphoid tissues have a lower expression of per-
constrained forin and granzymes, potentially due to tissue-specific
HIV peptide microenvironmental regulation of T cell function as
CD8+ T cell Infected cell
a means to limit tissue inflammation and damage90,91.
However, their precise functional profiles and roles in
HIV control remain unclear. Suppression of viral repli-
cation by lymphoid CD8+ T cells from elite controllers
HIV progressor has been observed in the absence of detectable cytol-
Mutated ytic activity, suggesting that non-cytolytic CD8+ T cell
CD8 HIV peptide
Escape functions may also be important for ongoing control of
TCR HIV in lymphoid tissues92. Although, as with peripheral
blood responses, ex vivo function of HIV-specific folli-
pMHC-I cular CD8+ T cells and TRM cells in lymphoid tissue must
IFNγ be carefully interpreted in the context of recent local
pMHC-I antigen exposure, epitope specificity and viral escape
Inhibitory from recognition. Additional studies aimed at under-
ligand standing the precise role and mechanisms of action of
HIV-specific follicular CD8+ T cells and TRM cells in
Inhibitory Exhaustion spontaneous control will be crucial to the development
receptor
HIV of strategies that harness these cells for the cure and
prevention of HIV infection.
Additional host and viral contributions to CD8+ T cell-

Fig. 2 | CD8+ T cell function and specificity differentiate
HIV controllers and progressors. Diagram representing mediated HIV control. Factors that modulate the mag-
CD8+ T cell interactions with infected cells in HIV controllers nitude and duration of initial viraemia influence the
(top) and progressors (bottom). HIV controller CD8+ T cells ability of CD8+ T cells to control infection. Consistent
recognize structurally constrained HIV peptides presented with this, a role for natural killer cells in modulating
via MHC class I (pMHC-I) on infected cells via T cell HIV control through modest reductions in viral load
receptors (TCRs), inducing proliferation and perforin/ has been well established by a large body of literature,
granzyme-mediated cytolysis of infected cells. Mutation including robust genetic associations93–97. Viral factors
of HIV epitopes presented via MHC-I in HIV progressors have also been implicated in modulating HIV control;
promotes escape from recognition by functional CD8+ however, it is difficult to distinguish causal from conse-
T cells, and dysfunctional CD8+ T cells recognize non-
quential associations due to CD8+ T cell-associated muta-
escaped viral epitopes through TCR–pMHC-I interactions
and secrete interferon-γ (IFNγ) but fail to proliferate or kill tions that impair viral replication capacity98. Although it
infected cells due to inhibitory receptor–ligand interactions, is clear that fully replication-competent viruses can be
such as PD1 and PDL1. Infected cells that evade killing via isolated from controllers99, control has also been associ-
escape and/or exhaustion spread infection and promote ated with viruses harbouring mutations that impair viral
further immune dysregulation in progressors. replication fitness100–102. Studies of HIV transmission

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events between controllers and progressors demonstrate In addition to spontaneous HIV control, some
that viral properties are neither necessary nor sufficient individuals also control viraemia after ART interrup-
to mediate spontaneous HIV control103,104. Nonetheless, tion125,126. These persons, termed post-treatment control-
many transmitted viruses are pre-adapted to immune lers (PTCs), have smaller HIV reservoirs and are often
responses in their prior hosts, which may impair fit- treated early after acute infection125–130. Interestingly,
ness and/or blunt the ability of CD8+ T cells to achieve although protective HLA alleles have been associated
spontaneous control in recipients expressing the same with delayed viral rebound following ART interrup-
HLA allele105,106. tion131, such alleles were not enriched in PTCs125, raising
In contrast to cellular immunity, there is little evi- the possibility of distinct mechanisms of viral control in
dence to support a role for humoral immunity in these individuals, which warrant further investigation.
maintaining spontaneous HIV control. Antibody neu- The translation of findings from both spontaneous
tralization breadth, which requires affinity maturation controllers and PTCs to the broader population for the
against continually evolving Env antigenic variants, is development of effective HIV immunization and cure
associated with the duration of uncontrolled chronic strategies remains an important goal.
viraemia and is negatively correlated with spontane-
ous HIV control107–110. Moreover, broadly neutralizing Prospects for T cell-based HIV vaccines
monoclonal antibodies from HIV controllers rarely Vaccines seeking to elicit sterilizing humoral immunity
target autologous virus111. Studies of non-neutralizing have a strong historical precedent. However, the induc-
antibody function in HIV controllers have not reported tion of broadly neutralizing antibodies (bNAbs) against
strong correlations with HIV control112,113. Although HIV has thus far proved challenging and will likely
HIV-specific CD4+ T cells are required for effective require serial immunization with a succession of vari-
adaptive immunity in HIV controllers and are affected ant Env immunogens to mobilize germline precursors
by chronic infection, depletion of either CD4+ T cells or and guide subsequent somatic hypermutation to achieve
B cells in a NHP model of SIV control had no impact on neutralization breadth132–134. Moreover, humoral immu-
viraemia114,115, suggesting that neither cell type is directly nity alone may be insufficient for protection against the
involved in durable spontaneous HIV control. transmission of cell-associated HIV135–137. By contrast,
T cell-based vaccines enable targeting of viral anti-
Spontaneous HIV control as a model for functional gens less permissive to viral escape than Env, do not
cure and vaccine development. The demonstrated anti- require additional somatic hypermutation and may
viral efficacy of CD8+ T cells in mediating long-term be able to augment humoral vaccine efforts. Although
spontaneous control of infection in many individuals cellular immunity-based vaccines lack historical pre
offers a clear rationale for harnessing cellular immu- cedent from other infectious diseases and cells must
nity to combat HIV; however, there remains a lack of become infected before CD8+ T cells can recognize and
consensus as to whether this represents a viable model induce cytolysis, in vitro studies clearly show that HIV-
for the development of preventive and therapeutic HIV specific CD8+ T cells can kill both activated and resting
vaccines. On the one hand, a small fraction (1.2% per CD4+ T cells before progeny virus is produced49–51,138.
year) of HIV controllers ultimately lose control, expe- This suggests the possibility that these responses may
riencing rebound viraemia and CD4+ T cell depletion10. not only serve to control established infection but
Furthermore, some controllers experience significant may also, in sufficient numbers, be able to clear the first
immune activation in the absence of detectable virae- infected cells rapidly before persistent reservoirs are
mia due to persistent viral replication in tissue sites and established.
expression of antigen from defective proviruses88,116–118, Human trials of T cell-based HIV vaccines to date
which can be reduced by ART119. On the other hand, have been disappointing. However, accumulating pre-
a subset of elite controllers is able to maintain a sta- clinical evidence demonstrates that emerging approaches
ble state of undetectable viraemia with no appreciable for vaccine-induced CD8+ T cell-mediated immunity can
immune activation. Indeed, many elite controllers provide sterilizing protection from retroviral infection
have extremely small replication-competent proviral and establish durable remission upon therapeutic vacci-
reservoirs with low sequence diversity, suggesting func- nation (Fig. 3). Moreover, clear evidence in some persons
tional reservoir suppression120–123. In some elite con- of the ability of HLA class I-restricted HIV-specific CD8+
trollers, viral reservoirs are suppressed so profoundly T cells to provide durable control following infection
that replication-competent virus cannot be detected or represents an important means to potentially enhance
recovered102,124. Such cases of exceptional control, albeit the impact of vaccine-induced humoral immunity that is
rare, represent a natural model for immune-mediated not fully protective. Although efforts to induce protective
functional cure approaches with the goal of durable T cell responses in clinical trials have not been success-
remission, providing optimism that immune-mediated ful, they have revealed the need for the rational design
eradication of infection may be possible. Further and selection of immunogens and vectors for improved
research is warranted to determine whether individ- next-generation T cell-based immunogens (Box 1).
uals with the best reservoir containment represent an
extreme on a continuum of spontaneous HIV control CD8+ T cells in prophylactic immunization: moving
mediated by a common mechanism or whether addi- beyond STEP and HVTN505. Much of the scepticism
tional mechanistic features distinguish this subset from of CD8+ T cell-b ased vaccines for HIV prevention
other HIV controllers. emerged from the disappointing results of the STEP

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antigens. These immunogens largely give rise to CD8+
Natural HIV infection

VL nCD8 T cell responses specific for immunodominant viral
CD4 epitopes that are similar to those targeted in natural
infection, where the majority of individuals fail to con-
trol infection due to the emergence of viral variants that
evade immune recognition. Consistent with this, viral
Progression sequence analysis from STEP trial participants revealed
a ‘sieving’ effect, whereby vaccine-induced CD8+ T cell
responses led to an enrichment of viral species with
Vaccination
mutations at common HLA class I restricted T cell
Therapeutic vaccination
VL nCD8 vCD8
epitope sites140. This also occurred in HVTN505, where
CD4 CD8+ T cell responses were primarily directed against
Env141, which is among the most variable viral proteins
and whose targeting by CD8+ T cells is associated with
higher viral loads53.
Control/clearance To induce immune responses that resemble those
found in spontaneous HIV controllers, next-generation
prophylactic T cell vaccines may benefit from the use of
Memory immunogens limited to mutationally intolerant regions
Preventive vaccination
recall within the HIV proteome. Preclinical studies of vaccine-

vCD8
induced CD8+ T cells targeting three epitopes presented
CD4 by the protective Mamu-B*08 allele were able to sup-
press viral loads to less than 1,000 RNA copies per ml in
Reservoir prevention/ six of eight vaccinated Mamu-B*08+ rhesus macaques
VL control/clearance compared with only one of eight in a Mamu-B*08+ con-
trol arm142, suggesting that narrowly targeted, vaccine-
Fig. 3 | HIV-specific CD8+ T cell responses in natural induced, virus-specific CD8+ T cell responses against
infection as well as following therapeutic and specific epitopes can effectively control replication fol-
preventive vaccination. Diagram representing relative lowing SIV challenge to below the transmission thresh-
HIV viral load (VL, green), relative total CD4+ T cell count old. Thus, new immunogens composed specifically of
(CD4, violet), and relative natural (nCD8) or vaccine-
sequence-conserved regions of the viral proteome143,144,
induced (vCD8) HIV-specific CD8+ T cell responses over
time. In natural HIV infection (top panel), incomplete
regions with a relative association with viral control in
natural CD8+ T cell-mediated control of VL eventually leads large patient cohorts (HIVACAT T cell immunogen)145
to disease progression, marked by CD4+ T cell decline and or structurally constrained ‘networked’ epitopes that are
uncontrolled VLs. Therapeutic vaccines that elicit effective mutationally intolerant61 may portend a higher proba-
vaccine-induced CD8+ T cell-mediated control of viraemia bility of success in future studies. Moreover, directing
aim to protect against disease progression, lower VLs to T cell responses to a limited number of epitopes may
below the transmission threshold and contain and reduce reduce antigenic interference of vaccine components146
the residual HIV reservoir in the absence of antiretroviral and limit the induction of strong T helper 1-biased CD4+
therapy. Preventive CD8+ T cell-mediated vaccines aim to T cell responses, which have been shown to diminish
induce a rapid memory-recall, vaccine-induced CD8+ T cell
vaccine efficacy in NHPs147.
response and clear the first infected cells to prevent
reservoir establishment as well as to control and ideally
While immune focusing is likely to be crucial for
clear residual infected cells. prophylactic vaccine development, additional efforts
have been dedicated to improving the breadth of T cell-
based antigens in order to address possible vaccine–virus
and HVTN505 trials6,139. In STEP, a recombinant adeno sequence mismatch between immunogen and circulat-
virus serotype 5 (Ad5) vector encoding HIV Gag, Pol ing virus species. One promising strategy involves using
and Nef induced HIV-specific CD8+ T cells and showed a ‘mosaic’ of viral sequences, which are comprised of
evidence of T cell selection pressure, although responses naturally occurring epitope sequences and common
were of low magnitude, targeted few epitopes, and did variants148,149. Correlates of protection in NHPs include
not improve the prevention of HIV acquisition or con- Env-specific antibody responses measured by ELISA and
trol of subsequent HIV infection6. Moreover, there was T cell responses measured by IFNγ149. These antigens
an increased risk of HIV acquisition in males lacking have been tested in human subjects and have demon-
circumcision and with pre-existing anti-Ad5 antibodies. strated safety and tolerability as part of the APPROACH
In HVTN505, these at-risk groups were excluded and study150, with clinical efficacy assessment already under-
a DNA prime/Ad5 boost was used to elicit antiviral way. As part of a complementary strategy, immuno-
T cell responses but, again, no protection from HIV gen designs have also aimed to induce broad cellular
infection was afforded139. Consequently, major concerns immune responses solely against sequence-conserved
about the viability of CD8+ T cell-based vaccines for HIV regions of the virus (tHIVConsvX)151, which integrates
prevention have persisted. the concepts of protective specificity and breadth into a
Upon further examination of both trials, an impor- single immunogen and may afford even greater coverage
tant consideration may be the use of full-length HIV of incoming viruses.

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Beyond immunogen design, developments in vac- in humans (with only two known alleles)158, inducing
cine delivery vectors have also yielded promising new such responses may be particularly advantageous for
directions for prophylactic T cell-based HIV vaccines. a prophylactic T cell-based HIV vaccine to broadly
The reliance of many existing vaccine modalities on the achieve both global coverage and sterilizing immu-
induction of central memory CD8+ T cell responses nity. In conjunction with vector modification efforts
has raised concern over whether immune recall will to achieve these same kinds of responses in humans,
be sufficiently rapid to prevent the early phases of viral additional studies to determine the immune para
dissemination. Circumventing this issue are novel rhe- meters that differentiate protected from non-protected
sus cytomegalovirus (RhCMV) vectors that are able to animals may also elucidate further improvements to
elicit persistently active effector memory CD8+ T cell this innovative vector system in order to achieve pro-
responses in rhesus macaques due to the constitutive tection from infection in a larger percentage of those
expression of SIV Gag antigen and CMV-induced mem- vaccinated. Nonetheless, an emerging spectrum of
ory inflation152,153. Remarkably, in numerous studies, immunogens, vectors and delivery routes to improve the
these vectors have been able to consistently protect ~50% specificity, function and location of vaccine-induced
of animals from viral challenge154–157. Moreover, detailed CD8+ T cell responses highlights the promise of prophy-
evaluation at necropsy revealed that vaccinated animals lactic T cell-based HIV vaccine approaches currently in
lacked any detectable virus, indicating that continuous development (Table 1), which are being actively pursued
effector memory T cell responses were able to clear alongside humoral vaccines.
tissue-associated viral reservoirs and thus achieve ster-
ilizing immunity155. This protection was also afforded CD8+ T cells in therapeutic immunization: translating
by attenuated RhCMV, even when challenged 3 years HIV control to the population at-large. In addition to
post-vaccination156. their utility for HIV prevention, CD8+ T cells that can
Follow-up studies of these animals have revealed durably suppress viral replication as demonstrated by
that CD8+ T cell responses elicited by RhCMV vectors spontaneous HIV controllers represent a promising
are exceptionally broad and restricted non-classically therapeutic modality towards the development of a
by HLA class II and the simian HLA-E orthologue functional HIV cure or remission. Reversal of immune
Mamu-E157. Due to the limited polymorphism of HLA-E exhaustion alone is unlikely to have durable clinical ben-
efit as many of the epitopes targeted in chronic infection
have mutated to escape recognition159. Indeed, although
Box 1 | Comparison of humoral and cellular HIV vaccine approaches additional studies are warranted to test immunothera-
Humoral pies and other strategies being developed for immune
• Advantages:
oncology160, preclinical trials of immune checkpoint
-- Strong historical precedent for prevention of other infections blockade during ART suppression did not significantly
-- May provide sterilizing immunity via prevention of cellular infection by non-escaped delay or reduce rebound viraemia upon treatment inter-
HIV variants ruption161–163. Likewise, attempts to mobilize the latent
-- Not restricted by HLA type reservoir with pharmacological interventions, such as
-- May also provide non-neutralizing benefits via vaccinal effect and/or histone deacetylase inhibitors, will require CD8+ T cell
antibody-recruited immune cells elimination of these cells, where again issues of pre-
• Disadvantages: existing immune escape are prominent159. Together,
-- Can only target highly variable and heavily glycosylated HIV Env these considerations suggest that vaccine-mediated
-- Broadly neutralizing antibody (bNAb) induction requires somatic hypermutation induction of new HIV-specific CD8+ T cell responses
and serial immunizations to mutationally constrained epitopes will be required.
-- Escape from bNAbs often requires only single mutation with compensable fitness
Early therapeutic immunization studies using antigen-
defects
pulsed dendritic cells have shown modest augmenta
-- May be ineffective against cell-associated viral transmission
tion of immune responses and viral load reduction164–168,
Cellular whereas other therapeutic vaccination strategies aimed
• Advantages: at eliciting CD8+ T cell responses have yielded promising
-- Strong basis for protection derived from spontaneous HIV controllers preclinical results. Delivery of rAd26 and modified vac-
-- Ability to target broad, mutationally constrained epitopes across entire viral cinia Ankara expressing full-length SIV Gag–Pol–Env
proteome via many HLAs
along with Toll-like receptor 7 agonist GS-986 to ART-
-- Do not require somatic hypermutation; therefore, standard prime–boost vaccine
regimens may be possible suppressed, SIV-infected rhesus macaques led to the
-- Mucosal responses may protect against cell-associated HIV transmission and clear induction of broad de novo cellular immune responses,
infection before reservoir establishment which were strongly correlated with a reduction in
-- May facilitate long-term control of established infection median set point viral load to 1,000 SIV RNA copies
• Disadvantages: per ml and a delay in viral rebound following ART
-- Limited historical precedent for the prevention of other infections cessation169. The impressive cellular immune breadth
-- Previous HIV trials unsuccessful achieved by animals with more effective viral suppres-
-- Requires cellular HIV infection; cannot neutralize cell-free virus sion is consistent with observations in HIV-infected
-- Distinct immunogen design may be required to avoid mutationally tolerant humans, where broad and functional cellular immune
immunodominant epitopes responses to non-escaped CD8+ T cell epitopes have
-- Epitope-focused approaches must contend with HLA diversity, perhaps via been implicated in a reduction of the latent HIV-1
targeting constrained epitopes presented by major HLA supertypes
reservoir159.

Reviews
Table 1 | Vaccine strategies for inducing antiviral CD8+ T cells Challenges facing prophylactic and therapeutic vaccine
development. Given the advantages and disadvantages
Vaccine CD8+ T cell quality Vaccine strategy Refs of each approach, cellular and humoral HIV vaccine
component
methods will likely be complementary in providing full
Immunogen Specificity Broad Mosaic whole viral proteins 150,169
protection from HIV infection (Box 1). However, elic-
↕
Whole viral proteins 6,7,139,154 iting each response will require different immunogens
and optimization of distinct parameters, warranting
Mosaic conserved elements 151
separate but parallel development efforts171. In addi-
Conserved elements 143,170
tion, the selection of vaccine immunogens, vectors and
Focused delivery routes will have important impacts on CD8+
Networked/beneficial epitopes 61,145
T cell function, specificity and localization (Table 1).

Vector Function Transient Nucleic acids 183
Optimal immunogen design may require an improved
↕
Dendritic cell priming 166,168
understanding of the effects of immunodominance and
Poxvirus 7 original antigenic sin on immunogenicity and protective
efficacy. The selection of vectors and adjuvants to elicit
Adenovirus 6
the appropriate targeting of functional responses in the
Persistent
Cytomegalovirus 154
appropriate tissues against protective antigenic epitopes
Delivery route Localization Systemic Intramuscular/subcutaneous 6,7,150,154 will require significant development and empirical test-
ing, which should be derived by iterative, small-scale
↕
Intranodal 184
human immunogenicity studies before moving forwards
Intranasal 185 to larger efficacy trials. The induction of CD4+ T cell
Oral/gastrointestinal 186 help to assist the development of effective CD8+ T cell
Mucosal immunity will also be required, but activation of these
Intravaginal/prime–pull 187,188
CD4+ T cells will need to be carefully regulated given
that this may cause increased susceptibility to HIV infec-
Similar to T cell-based preventive vaccines, such tion, diminished vaccine efficacy and more rapid disease
insights emphasize the need for therapeutic immuno- progression147,172,173. The widespread availability and use
gens that are able to direct cellular immune responses of pre-exposure prophylactic ART poses unique chal-
to specific invariant sites within the HIV proteome. lenges to the design of and recruitment for prophylactic
Initial efforts to accomplish this in HIV-infected indi- vaccine efficacy trials, and the anticipated introduction
viduals have primarily focused on sequence-conserved of long-acting injectable ART may further complicate
viral regions, with one of these immunogens (tHIV- future studies174.
Consv) having been administered in a therapeutic vac- The development of therapeutic vaccines involves
cine setting to evaluate its safety and immunogenicity many unique challenges. Efficacy trials require moni
(BCN01)170. Vaccination with a chimpanzee adeno tored interruption of ART, including for individuals
virus vector (ChAdOx) prime and a modified vac- not receiving vaccination in controlled studies, which
cinia Ankara boost of tHIVConsv led to a clear shift has raised important medical and ethical concerns175.
in CD8+ T cell immunodominance patterns towards Recent evidence that brief treatment interruption has
conserved segments170. These data provide optimism no significant long-term impact on immune activation,
that augmentation of cellular antiviral immunity drug resistance, reservoir size or composition indi-
and redirection towards protective epitopes is pos- cates that such studies are safe176–178. Another challenge
sible via therapeutic vaccination with focused HIV is that preventive vaccines may be ineffective in a thera
immunogens. peutic setting. For example, therapeutic immunization
Because sequence conservation of targeted epitopes with the same RhCMV vector that afforded substan-
does not clearly differentiate HIV controllers from tial protection and early clearance of SIV infection in a
progressors56, alternative approaches to therapeutic prophylactic setting was ineffective in reducing the SIV
immunogen design are warranted and being pursued. reservoir after therapeutic immunization despite early
Higher order HIV sequence analysis of couplings initiation of ART179. Pre-existing immune escape and
between viral mutations within the conserved Gag dysfunctional immune responses in chronically infected
protein using random matrix theory58 and quantita- individuals represent added challenges for therapeutic
tive fitness landscapes59 has revealed multidimensional immunization approaches as immunization may pre
constraints on viral evolution that predict regions of ferentially expand these responses. Nonetheless, much of
vulnerability. These mutationally intolerant amino the preliminary clinical testing for cellular immune HIV
acids are likely related to structural interdependencies vaccines will likely occur in a therapeutic setting owing
that are important for viral fitness, and thus represent to practical considerations in evaluating efficacy and
promising targets for CD8+ T cell pressure. Recent iden- managing risk, and where shifts in CD8+ T cell immuno
tification of structurally constrained epitopes restricted dominance to specific regions of the viral proteome
by common HLA alleles and strongly associated with have been previously demonstrated165,170. The develop-
spontaneous HIV control provides an additional ave- ment of optimal adjuvants, immunomodulatory agents
nue for re-directing CD8+ T cell responses, which may and latency-reversing agents for coadministration with
further increase the probability of inducing protective immunogens will also be important for the success of
immunity61. therapeutic HIV vaccines180. Intriguingly, the infusion

Reviews
of two potent bNAbs (3BNC117 and 10-1074) early efforts. Persons with durable spontaneous control of
during SHIV infection led to sustainable viral sup- HIV demonstrate that CD8+ T cells hold substantial
pression that was lost upon subsequent delivery of a promise to combat the HIV epidemic. Mechanistic
CD8β-depleting antibody, suggesting a possible vacci- studies in spontaneous HIV controllers highlight the
nal effect of these bNAbs that can improve the induc- function, specificity and localization of CD8+ T cells as
tion of antiviral CD8+ T cells181. Although NHP models important determinants of protection, and the ability to
have provided clear benefits for preclinical vaccine test- uncouple protection from specific HLA alleles represents
ing182, differences in viral diversity, duration of therapy, a key step towards broad clinical translation. Preclinical
anti-vector immunity and pathogenesis may contribute and clinical vaccine trials have provided additional
towards the limited translation of efficacy from such insights towards the development of improved T cell-
models to humans. based prevention and cure modalities. Further rational
design of immunogens and careful selection of appro-
Conclusions priate vectors to elicit functional effector-memory CD8+
Several remaining hurdles will need to be overcome to T cell responses against protective epitopes in vulnerable
successfully harness T cells for prevention, treatment viral regions represents a promising path forwards for
and cure. However, the above data provide ample sup- preventive and therapeutic T cell-based HIV vaccines.
port for renewed efforts to develop CD8+ T cell-based
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Reviews
macaques due to a proposed vaccinal effect of responses in a randomized controlled trial. PLoS One Author contributions
antibody–antigen complexes that may facilitate 9, e112556 (2014). All listed authors contributed to the writing, editing and
induction of de novo antiviral CD8+ T cell 186. Stephenson, K. E. et al. First-in-human randomized preparation of this review article.
responses. controlled trial of an oral, replicating adenovirus 26
182. Rahman, M. A. & Robert-Guroff, M. Accelerating vector vaccine for HIV-1. PLoS One 13, e0205139 Competing interests
HIV vaccine development using non-human primate (2018). G.D.G. and B.D.W. have filed a provisional patent application
models. Expert. Rev. Vaccines 18, 61–73 (2019). 187. Tan, H. X. et al. Induction of vaginal-resident HIV-specific (62/817,094) related to HIV vaccine design. D.R.C. declares
183. Kalams, S. A. et al. Safety and comparative CD8 T cells with mucosal prime-boost immunization. no competing interests.
immunogenicity of an HIV-1 DNA vaccine in Mucosal Immunol. 11, 994–1007 (2018).
combination with plasmid interleukin 12 and impact 188. Shin, H. & Iwasaki, A. A vaccine strategy that protects Peer review information
of intramuscular electroporation for delivery. J. Infect. against genital herpes by establishing local memory Nature Reviews Immunology thanks P. Goulder, S. Lewin and
Dis. 208, 818–829 (2013). T cells. Nature 491, 463–467 (2012). the other, anonymous, reviewer(s) for their contribution to the
184. Leal, L. et al. Phase I clinical trial of an intranodally peer review of this work.
administered mRNA-based therapeutic vaccine Acknowledgements
against HIV-1 infection. AIDS 32, 2533–2545 We are grateful to the participants of all cited studies. We Publisher’s note
(2018). apologize to the many authors whose work was not cited in Springer Nature remains neutral with regard to jurisdictional
185. Brekke, K. et al. Intranasal administration this review owing to space limitations. This work was sup- claims in published maps and institutional affiliations.
of a therapeutic HIV vaccine (Vacc-4×) induces ported by the US National Institutes of Health (NIH) grant
dose-dependent systemic and mucosal immune UM1AI100663 and R37AI067073. © Springer Nature Limited 2020

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CD8+ T cells in HIV control, cure and

Abstract | HIV infection can be effectively treated by lifelong administration of combination

and Harvard, Cambridge,

NAtuRe RevIews | Immunology volume 20 | August 2020 | 471

472 | August 2020 | volume 20 www.nature.com/nri

increased ability to maintain long-​term memory and EC VC CP

CD8+ T cell function

NAtuRe RevIews | Immunology volume 20 | August 2020 | 473

Additional host and viral contributions to CD8+ T cell-​

474 | August 2020 | volume 20 www.nature.com/nri

NAtuRe RevIews | Immunology volume 20 | August 2020 | 475

antigens. These immunogens largely give rise to CD8+

Natural HIV infection

recall within the HIV proteome. Preclinical studies of vaccine-​

476 | August 2020 | volume 20 www.nature.com/nri

NAtuRe RevIews | Immunology volume 20 | August 2020 | 477

T cell function, specificity and localization (Table 1).

478 | August 2020 | volume 20 www.nature.com/nri

NAtuRe RevIews | Immunology volume 20 | August 2020 | 479

480 | August 2020 | volume 20 www.nature.com/nri

NAtuRe RevIews | Immunology volume 20 | August 2020 | 481

482 | August 2020 | volume 20 www.nature.com/nri

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increased ability to maintain long-term memory and EC VC CP

Additional host and viral contributions to CD8+ T cell-

recall within the HIV proteome. Preclinical studies of vaccine-