nature reviews microbiology https://doi.org/10.

1038/s41579-023-00914-1

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Prevention, treatment
and cure of HIV infection
Raphael J. Landovitz    1, Hyman Scott    2,3 & Steven G. Deeks    3 
Abstract Sections

The development of antiretroviral therapy for the prevention and Introduction

treatment of HIV infection has been marked by a series of remarkable HIV prevention and treatment:
successes. However, the efforts to develop a vaccine have largely failed, current state of the art

and efforts to discover a cure are only now beginning to gain traction. Emerging strategies: PrEP,
treatment, vaccines and cure
In this Review, we describe recent progress on all fronts — pre-exposure
prophylaxis, vaccines, treatment and cure — and we discuss the unmet Cross-cutting themes and
opportunities
needs, both current and in the coming years. We describe the emerging
Conclusions
arsenal of drugs, biologics and strategies that will hopefully address
these needs. Although HIV research has largely been siloed in the past,
this is changing, as the emerging research agenda is marked by multiple
cross-discipline synergies and collaborations. As the limitations of
antiretroviral drugs as a means to truly end the epidemic are becoming
more apparent, there is a great need for continued efforts to develop an
effective preventative vaccine and a scalable cure, both of which remain
formidable challenges.

Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California,
1

Los Angeles, CA, USA. 2Bridge HIV, San Francisco Department of Public Health, San Francisco, CA, USA. 3Division
of HIV, Infectious Diseases & Global Medicine, Department of Medicine, University of California, San Francisco,
CA, USA.  e-mail: Steven.Deeks@ucsf.edu

Nature Reviews Microbiology

Review article
Introduction
The development of antiretroviral therapy (ART) for the prevention
and treatment of HIV infection is one of the greatest achievements of
modern medicine. A person who is at high risk for HIV and has access
to preventative services can now take either a daily pill or an injec-
tion every 2 months and be highly protected from acquiring HIV1,2.
A person with HIV (PWH) who has access to treatment services can
now take a daily pill or a once-monthly injection and control their
infection indefinitely. These approaches continue to be optimized, and
we will probably soon have very long-acting (greater than 6 months
after a single injection) options for prevention and treatment that
are highly effective, safe and scalable. This raises the question of
whether we should declare victory, work on ensuring global access
and equity to prevention and treatment, and shift attention to other
urgent matters.
Despite our unquestioned success, there remain many unmet
needs, and the HIV pandemic continues to spread. Approximately
1.5 million people acquire HIV infection annually, and approximately
650,000 die from HIV-related complications3. Despite a massive and
unprecedented global public health investment, approximately one-
third of those who have HIV are undiagnosed, not in care or not on
effective therapy3. A large proportion of these individuals, if not the
majority, are unable to access and remain on effective therapy for
decades4,5, with periodic breaks in treatment common, leading to an
increased risk of disease progression in the individual and an increase
risk of transmission of the virus to their partners. Improvements in
care delivery will be needed to support expanded access to long-acting
options, but this cannot be assured. Importantly, our progress to date
is vulnerable to changes in public health funding3. The commitment of
global funding agencies to continue providing the resources needed
to prevent and treat HIV is waning, and many countries may lack the
resources needed to fill in the gaps.
The global public health community remains galvanized to end the
epidemic. Within the USA, the federal government initiative ‘Ending
the HIV Epidemic (EHE)’ seeks to reduce the number of new HIV infec-
tions by 90% by 2030. Globally, the Joint United Nations Programme on
HIV/AIDS (UNAIDS) ‘Fast-Track’ initiative seeks to reduce the number
of new infections annually to less than 200,000 and eliminate stigma.
This goal should be achievable if, by 2030, 95% of people living with
HIV know their status, 95% of those who know their status are in care
and on therapy, and 95% of those individuals have an undetectable viral
load. These are ambitious goals, but some countries such as Botswana
have achieved them, providing a road map for others. Both the EHE and
Fast-Track initiatives recognize that the most marginalized populations
are being left behind.
What will be needed to ensure that everyone has access to pre-
vention and treatment, so that we can end this pandemic for good?
Further refinements in our current antiretroviral drugs will certainly
help. Implementation science is a growing field, and one assumes that
more cost-effective means of disseminating current options globally
will emerge. Indeed, three landmark community-randomized studies
involving hundreds of thousands of individuals demonstrated that
universal testing and treatment can increase the level of community-
wide viral suppression and that higher levels of viral suppression were
associated with lower rates of HIV transmission6–8. Given the challenges
of accessing those now left behind — the most marginalized in our
societies — these programmes may be difficult to resource indefinitely
or may fail to end the pandemic even if well resourced. As we argue
here, the next frontier of HIV medicine will focus on developing single
Nature Reviews Microbiology
one-time prevention or cure interventions that will provide the tools
necessary to truly end the epidemic.
In this Review, we summarize the current state of the art for HIV
prevention and treatment, focusing on the unmet needs. We then
discuss the emerging arsenal of tools that address these unmet needs.
Finally, we discuss how these tools are being studied and describe
how the various approaches — prevention, treatment and cure — are
­beginning to leverage emerging cross-cutting synergies.
HIV prevention and treatment: current state
of the art
HIV prevention: pre-exposure prophylaxis
Biomedical strategies have revolutionized HIV prevention during the
past 15 years. Importantly, the demonstration of complete preven-
tion of sexual HIV transmission from PWHs who are on effective ART
counts as one of the greatest achievements in HIV medicine9. The fact
that ‘undetectable equals untransmissible’ (U = U) is great not only for
public health (less transmission) but also for the individual (protec-
tion of sexual partners, more sexual freedom and less stigma). ART
as prevention has limits, however, as many people remain untreated
(about one-third of the global population)3. Also, with delays in HIV
diagnoses, transmissions occur during acute infection and before
people get diagnosed and treated10.
Remarkable progress has been made using ART in the uninfected
at-risk person to prevent infection (‘pre-exposure prophylaxis’ (PrEP)).
Tenofovir disoproxil fumarate (TDF)-based oral PrEP reduces popu-
lation-level HIV incidence when made widely available and barriers
to access are minimized, as has been demonstrated in multiple urban
centres11–13. When used as prescribed, daily TDF-based PrEP is effective
(99% protective against rectal exposures to HIV and 92–94% protective
against vaginal exposures) and well tolerated2, but rare signature tox-
icities of renal injury and loss of bone mineral density led to develop-
ment of tenofovir alafenamide (TAF) as PrEP (for sexual transmission
except receptive vaginal sex)14. Studies of daily TAF combined with
emtricitabine (FTC) for vaginal exposures and parenteral exposures
(intravenous drug use) are ongoing.
In an effort to be more congruent with sexual practices, ‘on-
demand’ peri-coital TDF–FTC in a four-dose daily sequence of two
tablets taken 2–24 h before planned sexual activity, one tablet taken
24 h after the first dose and one final tablet taken 24 h after the second
dose is now an option for men who have sex with men (MSM)15, with
some guidelines generalizing this for all at-risk men and transgender
women16,17.
Unfortunately, oral TDF–FTC PrEP has not performed consistently
well in cisgender women18,19, probably owing to low adherence and
acceptability. A tenofovir-based topical vaginal gel did not achieve
regulatory approvals owing to limited success in a daily gel-application
strategy trial19–21. Given these failures, there is interest in developing
more HIV prevention options for cisgender women. Inspired by the
use of vaginal rings used for contraception, a monthly vaginal ring con-
taining the non-nucleoside reverse transcriptase inhibitor dapivirine
has advanced through efficacy testing. Although the dapivirine ring
underperformed in randomized placebo-controlled trials (~30% reduc-
tion in HIV incidence)18,22, this approach has great appeal for women
who prefer not to take oral or injectable medications and who want the
privacy, discretion and control that a vaginal ring provides. Owing to
limited efficacy, the product was withdrawn from consideration for reg-
ulatory approval in the USA, but has been recommended as an option
for use in low-income and middle-income settings, in which women at
Review article
risk for HIV want and need multiple options from which to choose23.
Longer-duration rings (3 months or more) containing dapivirine or
tenofovir, as well as ‘multi-purpose technology’ rings that contain an
antiretroviral drug and a hormonal contraceptive, are being explored.
The vaginal ring has crystallized arguments in support of the need for
a more diverse ‘menu’ of HIV prevention options, allowing individuals
to select the most suitable product for their specific circumstances at
a given time in their sexual life cycle24.
The next generation of PrEP drugs will focus largely on the use of
long-acting injectables or extended-use preparations. Long-acting
cabotegravir, a novel integrase strand transfer inhibitor, is adminis-
tered as a single gluteal injection every 8 weeks. As compared to daily
oral TDT–FTC, cabotegravir reduced incident HIV by 66% in MSM and
transgender women and by 89% in cisgender women1,25; given that
daily oral TDF–FTC is highly effective for HIV prevention when taken
as prescribed, this is a staggering result. Estimates of the effective-
ness of cabotegravir compared to a counterfactual placebo are in
the 92–95% range. Scale-up has been hampered in the USA by high
medication costs, the need for novel clinic operational pathways for
injection provision, and an FDA and CDC requirement for RNA-based
testing as part of HIV screening for PrEP failure. Further complicating
decision-making around implementation, particularly in low-income
and middle-income settings, is the observation that cabotegravir PrEP
failures, although rare, are often characterized by integrase inhibitor
resistance, with the potential to compromise the activity of global
first-line ART regimens26. The WHO recently included recommenda-
tions and guidance for use in low-income and middle-income settings
in updated PrEP guidance16. Cabotegravir is also in early-stage inves-
tigation as a subdermal implant, in a new preparation with even more
extended pharmacokinetics and potentially as a topically applied
microneedle patch.
Additional delivery systems including a subdermal implant of
TAF or cabotegravir and a rectal douche of tenofovir are in the earliest
stages of clinical development. A novel tablet-based ‘insert’ for either
vaginal or rectal use, containing a combination of TAF and the integrase
inhibitor elvitegravir, is in more advanced stages of development. This
approach has the potential to block both HIV and herpes simplex virus
acquisition.
Antiretroviral therapy
The first fully suppressive combination regimens emerged in the
1990s27. Since then, treatment has gone through multiple iterations,
with regimens becoming increasingly safer, better tolerated, easier to
administer and more effective. Today, a single once-daily tablet contain-
ing two or three drugs results in sustained viral suppression in nearly all
individuals who can access and adhere to daily regimens28. ART is not
curative, however. Treatment can block new infection events but does
not eradicate long-lived populations of cells harbouring integrated
replication-competent proviruses (the ‘reservoir’). Once treatment is
interrupted, active replication begins, with the virus typically detectable
in days to weeks. Treatment hence must be administered consistently
and indefinitely. Many individuals are unable to adhere in a consistent
manner owing to side effects, mental health issues and/or substance
use, or numerous other social and structural issues including stigma.
Non-adherence can lead the development of drug-resistant variants.
Long-term toxicities of both living with HIV and current treatments —
including weight gain and related metabolic complications — remain a
concern29,30. Resource limitations and access to therapy pose the largest
threat on a global level, however. Resources for large, highly effective
Nature Reviews Microbiology
implementation programmes such as PEPFAR (the (US) President’s
Emergency Plan for AIDS Relief) are becoming more constrained owing
to competing public health needs31.
Given the challenges associated with adherence to daily therapy,
current efforts are focused on developing longer-acting or extended-
release approaches. Recently, a two-drug combination of cabotegravir
and rilpivirine given as intramuscular injections every 1 to 2 months
was approved for maintenance of virological suppression32. This com-
bination is well tolerated but carries a small but clinically important
risk of virological failure and the emergence of drug resistance even
when taken as prescribed. However, a recent report suggests that this
combination may be able to be deployed even for individuals who are
not virologically suppressed33; rigorous data informing the risks and
benefits of such a strategy are still unavailable. Potent agents with even
longer intervals of administration are currently in clinical development,
as described below.
Emerging strategies: PrEP, treatment, vaccines
and cure
Long-acting antiretroviral agents for PrEP and treatment
Lenacapavir is a novel parentally administered HIV-1 capsid inhibitor
now in development for both PrEP and treatment (Fig. 1). Lenacapavir
has a remarkably long half-life and needs to only be administered as a
subcutaneous injection every 24 weeks. It appears to be safe and highly
effective, working against both wild-type and multidrug-resistant HIV34.
It is particularly attractive as an agent for PrEP, as it lacks the potential
liability of PrEP failure leading to resistant virus with reduced suscep-
tibility to first-line ART — a concern with the integrase strand transfer
inhibitor cabotegravir. The prolonged administration interval would
be a substantial advantage for both PrEP and treatment, although the
subcutaneous route of injection may result in some limitations (injec-
tion site reactions). Still, lenacapavir administered subcutaneously
at home will probably prove to be more acceptable and scalable than
those l­ ong-acting options that require intravenous infusion in a c­ linical
setting.
Islatravir, a remarkably potent first-in-class nucleoside reverse
transcriptase translocation inhibitor, was being actively developed
for HIV prevention as a once-monthly oral tablet and as treatment in
combination with other drugs, including lenacapavir. Development was
placed on hold in December 2021 owing to dose-dependent decreases
in lymphocytes. An investigational islatravir subdermal implant with
the potential for once-yearly dosing was also put on hold. Development
has now been resumed for treatment but not prevention, with lower
doses being used (daily in combination with doravirine and weekly in
combination with lenacapavir).
Early work is now being pursued to develop and evaluate implants
for a variety of agents including dolutegravir, which could work for a
year or longer35,36.
Broadly neutralizing antibodies
Antibodies that directly target the envelope protein on the surface of
circulating virus can effectively prevent virus spread. Over the past
decade, numerous broadly neutralizing antibodies (bNAbs) that target
accessible parts of the envelope protein (for instance, the CD4-binding
site and variable loops) have been isolated from untreated PWHs and are
now being developed for prevention, treatment and cure strategies37,38.
Although these antibodies were discovered based on the abil-
ity of the variable regions (antigen-binding fragment (Fab) regions)
to neutralize free virus, they have the ability through their constant
Review article
bNAbs
gp120–gp41 interface
Envelope
MPER
Capsid core
Attachment Attachment
CCR5
inhibitors
Viral RNA
CCR5 antagonists
Reverse
Nucleoside reverse transcription
transcriptase inhibitors
and nucleoside reverse
transcriptase translocation
inhibitors
DNA
Non-nucleoside reverse
transcriptase inhibitors
Integrase strand transfer inhibitors
Fig. 1 | Mechanism of action for current and emerging antiretroviral
therapies. The HIV replication cycle provides multiple opportunities for
therapeutic disruption of virus-specific replicative activities. Currently
available approaches include entry inhibitors, reverse transcriptase inhibitors,
integrase inhibitors and protease inhibitors. Emerging therapies including
broadly neutralizing antibodies (bNAbs) that target the envelope V1–V2 loop
(PDGM1400, CAP256), the V3 loop (10-1074, PGT121), the CD4-binding site
domains (crystallizable fragment (Fc) regions) to induce the death of
cells expressing the envelope protein on their surface. This dual capac-
ity (neutralization and cytotoxicity) suggests that they might eventu-
ally prove to be superior to ART for both prevention and treatment, as
ART lacks the ability to clear an infected cell. Pharmacologically, a single
infusion of unmodified antibodies can result in therapeutic levels for
weeks. However, small modifications to the Fc domain of the antibody
(the ‘LS mutation’) increase antibody binding to the neonatal Fc recep-
tor, reducing the rate of antibody clearance. A single administration
of an LS-modified antibody can result in therapeutic levels for many
months39,40. Given their unique ability to clear infected cells and their
favourable pharmacokinetic properties, bNAbs are now being actively
developed for prevention (as PrEP), treatment (as part of a long-acting
regimen) and cure.
There are several studies of bNAbs in various stages of devel-
opment. The first bNAb evaluated for prevention in an efficacy trial
was VRC01. Targeting the CD4-binding site, VRC01 was evaluated in
MSM in the Americas and heterosexual women in sub-Saharan Afri-
can (collectively referred to as the Antibody Mediated Prevention
(AMP) studies). Among the 4,623 participants across these two trials,
there was no difference in HIV incidence (prevention efficacy 8%; 95%
Nature Reviews Microbiology
High-mannose V3 loop
Protease inhibitor
V1–V2 loop
CD4 binding site
Maturation
CD4
Host cell
Virus assembly
Nucleus and budding
Gag-Pol
Gag
Integration
(VRC07-523LS, 3BNC117, N6), the gp120–gp41 interface and the membrane
proximal external region (MPER; 10E8V), all obstructing viral entry. Lenacapavir
is a first-in-class capsid inhibitor, believed to inhibit multiple critical life
cycle processes including cytoplasmic capsid dissolution and formation
of functional new capsid for viral progeny. Islatravir is a first-in-class
nucleoside reverse transcriptase translocation inhibitor. CCR5, CC-chemokine
receptor 5.
confidence interval (CI) −45.1 to 42.6). However, a pre-specified analy-
sis found a higher efficacy (75.4%; 95% CI 45.5–88.9) for strains that
were sensitive to VCR01 — these strains were only 30% of the isolates
from the trial41. This study provided proof of concept that antibod-
ies can prevent HIV infection, an important advance for the vaccine
field, as discussed below. This study also provided strong rationale
for the continued development of bNAbs for both prevention and
treatment.
There are numerous bNAbs now being developed for prevention,
treatment and cure, and more are being discovered regularly. The lead-
ing candidates now in development include antibodies that target the
CD4-binding site (VRC07-523LS, 3BNC117 and N6), the variable loops
V1 and V2 (PDGM1400 and CAP256), the variable loop V3 (10-1074 and
PGT121) and the membrane proximal external region (10E8V)38.
As with ART, bNAbs work best when used in combination42,43. It
is unlikely that any single bNAb will prove so broadly neutralizing
as to prevent or treat all possible variants of interest. To be effective
for prevention and treatment, more potent agents or combinations
that target different regions of the envelope protein will probably be
needed. Towards this end, bi-specific and tri-specific antibodies that
target non-overlapping regions are being developed44.
Review article

Preventative vaccines was demonstrated in the AMP studies, but the bar will be high for this
The decades-long effort to develop a vaccine for HIV paid off when approach to be effective41. The critical task at hand is coming up with
COVID-19 emerged as a public health threat. These investments in labo- an immunogen that can induce B cells to durably produce antibodies
ratory science (for instance, mRNA platforms and viral vectors such that can neutralize all circulating viruses (Table 1). This will not be easy,
as adenovirus 26 (Ad26)) and clinical trial and laboratory infrastruc- as the bNAbs that have been isolated from PWHs were highly mutated
tures directly led to both the rapid development of several candidate and took years to develop. Also, based on the AMP studies, any effective
COVID-19 vaccines and their clinical development45. However, despite vaccine will have to induce the production of relatively high levels of
major scientific advances and the successful completion of several antibodies in a sustained manner.
phase III studies, no vaccine for HIV is available, and the most promising One approach that is now in the proof-of-concept stage is to use a
approaches are still in the earliest stages of clinical development. series of immunogens to prime and then ‘shepherd’ B cells to mature
Vaccines that used adenovirus 5 as a platform failed to protect from the unmutated state (germ line) to the point at which they produce
and even increased susceptibility to infection46. A vaccine strategy potent bNAbs (‘germline targeting’)56,57 (Fig. 2). In a recent study, an
involving a recombinant canarypox vector boosted with an envelope adjuvanted protein-based priming immunogen (eOD-GT8) induced the
protein provided modest but transient protection in Thailand (RV144 first step in the predicted evolution of a VRC01-like bNAb58. A follow-up
Thai Study)47. Subsequent studies suggested that protection was pre- study has been initiated in which the priming immunogen (eOD-GT8)
dicted by the level of non-neutralizing antibodies to the V1–V2 loop and will be followed weeks later by a boosting immunogen. Theoretically,
identified several other promising responses48. Although a modified several serial vaccinations will be needed to fully mature (shepherd)
version of this vaccine strategy specific for clade C induced the desired B cells. As more than one bNAb will probably be needed to fully protect
immune response in an African population49, the approach failed in a against all circulating viruses, a combination of strategies will probably
recent phase IIb/III clinical trial (Uhambo, HIV Vaccine Trials Network need to be administered.
(HVTN) 702)50,51. Other closely related antibody-inducing vaccine strategies are
Given the failure of these largely T cell-focused and non-neutraliz- in development. In the epitope-focused strategy, a series of immuno­
ing antibody-focused vaccines, the field shifted towards the develop- gens are used to induce responses to the fusion peptide, a critical
ment of a vaccine that would produce a protective antibody response. part of the envelope protein. These responses are then boosted with a
The most advanced approach employs an Ad26 vector containing a soluble native envelope protein59. If this works, several unique antibod-
mosaic immunogen optimized to induce responses across multiple ies targeting the fusion peptide would be produced, thus providing
clades (Ad26.Mos4.HIV)52. In a recent phase IIb study of young women protection against infection. Another strategy uses a self-assembling
in sub-Saharan Africa (Imbokodo, HVTN 705/HPX2008), Ad26.Mos4. nanoparticle form of the immunogen 426c.Mod.Core in a prime–boost
HIV was administered at four vaccination visits over a year, with an adju- strategy to engage germinal centres to induce VRC01-like bNAbs60.
vanted soluble protein component (clade C gp140) given at the third and These bNAb-inducing strategies will require time to develop.
fourth vaccination visits (a ‘prime–boost’ strategy). The study showed Fortunately, the recent validation of mRNA technology as a safe and
a vaccine efficacy of 25.2% (95% CI −10.5% to 49.3%), and the study was effective way to induce protective immunity provides a viable road
halted. Notably, the incidence of HIV infection among the young women
in the study was high, providing continued rationale for the develop- Table 1 | Novel vaccine strategies for HIV prevention and cure
ment of an effective and scalable HIV vaccine in the region. A parallel
phase III study of a similar vaccine in MSM and transgender persons in Strategy Definition Examples
the Americas (Mosaico study, HVTN 706/HPX3002) enrolled 3,900 par-
Germline-targeting Immunogens are designed eOD-GT8 multimer
ticipants. Enrolment was completed in September 2021 and, in January vaccine design to activate naive (‘germline’) 426c Core gp120
2023, the trial was discontinued after a planned interim data and safety precursor B cells; serial CH505TF SOSIP
monitoring board meeting found that the vaccine was generally safe immunogens are used to trimer
induce multiple mutations
and well tolerated, but that there was no HIV prevention efficacy. HIV needed to produce a mature
incidence was high (4.1/100 person-years in both placebo and v ­ accine bNAb
arms), demonstrating the ongoing need for a preventative vaccine.
Lineage-based This strategy also uses serial CH103 lineage
The rhesus cytomegalovirus (RhCMV) vector induces potent T cell vaccine design immunogens to induce bNAb CH235 lineage
responses in macaques: although the vaccine does not prevent infec- maturation down a specific
tion, 50% of infected animals completely eradicate pathogenic SIV53. lineage; envelope proteins
from PWHs followed over time
First-in-human studies of a candidate CMV vector are ongoing. Even if as they develop bNAbs are
this approach fails to progress for prevention, the striking and unique used to design immunogens
observation that administering the RhCMV simian immunodeficiency
Immunofocusing Immunogens are designed to MPER
virus (SIV) vaccine before infection can induce an immune response vaccine design focus responses on particular Fusion peptide
that later prevents the establishment of a permanent reservoir provides epitopes (for example, fusion
a potential road map for curing HIV. Recent examples in which such a peptides) but may be agnostic
to germ line or lineage
cure was achieved naturally in people have been described54,55, with
T cells presumably the mechanism for this outcome. Polishing trimers Mature trimers having a near- BG505.664 SOSIP
A consensus has emerged that that to prevent transmission, anti- native conformation are used trimer
in the final step(s) of sequential VRC-HIVRGP096-
bodies that neutralize the virus will be necessary. These bNAbs would protocols to increase bnAb 00-VP (trimer 4571)
need to target the diverse population of circulating viruses, accumulate potency and breadth Con M SOSIP
at high levels in relevant tissues (vaginal and rectal mucosa) and per- bNAb, broadly neutralizing antibody; MPER, membrane proximal external region;
sist for years. Proof of concept that such a bANb would be protective PWH, person with HIV.

Nature Reviews Microbiology

Review article
Germline-targeting vaccine bNAb maturation vaccine
Precursor bNAb Intermediate bNAb
Germinal centre
Fig. 2 | bNAbs vaccine strategies. Broadly neutralizing antibodies (bNAbs) with
sufficient potency and breadth will likely be needed to prevent HIV acquisition.
Inducing the development of these bNAbs has been elusive as the precursor
B cells are rare and require specific mutational evolution to achieve the desired
high potency and breadth. Emerging vaccine strategies use non-native trimer
immunogens to induce the precursors (germline targeting), followed by a
map. A key attribute of mRNA technology is its ‘plug and play’ capac-
ity: once the immunogen is designed, a viable vaccine ready for human
testing can be produced in weeks. A long-term strategy to conduct
experimental-medicine studies of novel and evolving immunogens
in an iterative manner has been implemented, with a goal of identify-
ing and developing a testable strategy in a few years. For example,
the HVTN 301 trial (NCT05471076) is evaluating a germline-targeting
immunogen, 426c.Mod.Core-C4b, designed to induce VRC01-like
bNAbs through prime–boost immunization. This vaccine study is also
evaluating the use of a fractionated, escalating-dose priming strategy
to achieve the induction of VRC01-like precursor B cells. These studies
are in an early clinical trial phase and are primarily focused on estab-
lishing proof of concept rather than product development, although a
promising candidate could potentially move forward. Passive immuni-
zation with combination bNAbs, however, is moving forward through
clinical trials with a combination bNAbs regimen being evaluated in a
phase IIb/III efficacy trial.
Although the field has sharply shifted towards antibody-inducing
vaccines, there is a growing awareness that inducing an effective T cell
response may also be necessary and that a more holistic approach to
vaccine development is needed61,62.
HIV cure
Given the challenges of delivering lifelong ART to a global population,
interventions that eradicate all replication-competent virus from a
person (a ‘cure’) may be needed63. Should such a cure prove to be impos-
sible, interventions that induce host-mediated control of a persistent
reservoir (a ‘remission’) could still go a long way in addressing many of
the current limitations associated with lifelong therapy64,65.
ART is not curative. During the life cycle of HIV, the proviral
genome becomes integrated into host chromosomes. Most integrated
genomes are defective66; however, a small proportion of infected
cells harbouring an intact genome adopt a state in which the provi-
rus is silenced (latency). Cells harbouring these latent proviruses are
maintained for decades through the usual mechanisms of CD4+ T cell
Nature Reviews Microbiology
bNAb-polishing vaccine
Mature bNAb Mature bNAb memory B cells
series of immunogens designed to induce more potent and broader bNAbs
(shepherding). Final boost vaccination with native-like trimers may provide
additional affinity maturation for the bNAbs (polishing). An effective strategy
will presumably require the induction of at least two lineages targeting distinct
parts of the envelope protein.
biology, particularly homeostatic proliferation67–69. Should a latently
infected cell become activated for any reason, the provirus might be
transcribed, leading to the release of new virions. This can happen after
years to decades of latency.
Although the reservoir has long been assumed to be stable,
recent data suggest that it evolves over time, with proviruses that are
integrated in the more transcriptionally active areas of the genome
decaying more rapidly than those in less active areas, presumably as
these cells are more likely to produce virus, making them suscepti-
ble to clearance70,71. With time, much of the reservoir is in relatively
silent areas of the genome and may hence not be readily transcribed.
Some people who naturally control HIV in the absence of therapy (‘elite
controllers’) have a similar phenotype, with much of the provirus in
the transcriptionally silent ex-genic regions54. Rare cases in which all
replication-competent virus may have been cleared (‘natural cures’)
have recently been described54,55.
There is a rapidly expanding series of studies aimed at achiev-
ing a cure or remission. These strategies can be divided into those
that seek to reduce the size of the replication-competent reser-
voir, enhance immune control of the reservoir, or make target cells
­resistant to i­ nfection. Combinations of these approaches may be
necessary.
Multiple reservoir-reduction strategies are in clinical develop-
ment. The first series of cure studies in the modern era sought to induce
HIV provirus transcription (latency reversal) so that the infected cell
could be targeted, either by virus-induced cell death or by the host
immune response (‘shock and kill’). Recent studies suggest that latency
can be reversed therapeutically in people, although the effect is modest
at best and insufficient to result in any measurable reductions in the
reservoir size. More potent latency reversal has been recently achieved
in non-human primates72, but again the approach failed to reduce
the reservoir, perhaps because the cells that harbour the virus are
relatively resilient73 or because the immune response to the virus was
dysfunctional74,75. A far more radical approach to clear the reservoir
involves directly disrupting the provirus in vivo using gene editing
Review article
technologies. Some success has been achieved in animal models using
adeno-associated virus (AAV) to deliver a CRISPR–Cas-based enzyme
designed to excise large regions of the integrated provirus76. Human
studies are in development. Although genome editing has several
potential toxicities, in theory this approach has the chance to deliver
a one-time curative intervention, a goal that now may be aspirational
but one that the field is aiming to achieve. Yet another approach to
reduce the effective reservoir size involves permanently silencing the
integrated provirus (‘block and lock’). A few promising candidates have
been identified in preclinical studies77, but this field is in a nascent stage,
with dedicated funding only now emerging.
Multiple immune system-focused strategies are also in clinical
development. Most of these strategies aim to enhance the ability of
T cells to recognize HIV and control its replication in the absence
of ART (Fig. 3). Post-ART control of SIV has been achieved in the non-
human primate model using vaccines developed for prevention and
then repurposed for treatment78. Progress in identifying therapeutic
vaccine strategies that enhance HIV control in the absence of ART is
finally being made79, after decades of failure. Post-ART control has also
been achieved in non-human primates and perhaps some people with
bNAbs80–82; mechanistically, bNAbs in this context are hypothesized to
clear infected cells during ART (cytotoxicity)43 and/or to form highly
immunogenic antigen–antibody immune complexes, resulting in the
induction of an adaptive immune response (the ‘vaccinal effect’)83,84
(Figs. 3,4).
Immune control may also be achieved with gene-based and cell-
based therapies. Leveraging advances made in the development of CAR
T cells for cancer treatment, promising approaches are now emerging
in which T cells are modified ex vivo so that they recognize HIV envelope
proteins on the cell surface85. Novel delivery mechanisms (AAV and
others) are being developed to deliver genes for broadly neutralizing
antibodies in vivo86. A combination of genes for three bNAbs resulted
in durable control of simian–human immunodeficiency virus in a non-
human primate87. In a small phase I clinical trial, AAV-mediated delivery
of the gene for VRC07 through a single injection was safe and resulted
in sustained production of a fully active antibody88.
ART
Viral load
CD4+ T cell
Months to years
Fig. 3 | Immunotherapy for HIV. HIV cure research has entered an era of proof-
of-concept testing, with multiple groups seeking to use immunotherapy to
control the virus post-antiretroviral therapy (ART). A popular approach is
to enhance the innate and adaptive immune responses in the immediate post-
ART period, with a goal of blunting the initial rebound, thus allowing an effective
adaptive immune response to emerge. Therapeutic vaccines, T cell therapies
(CAR T cells and others), broadly neutralizing antibodies, vaccine adjuvants
Nature Reviews Microbiology
Finally, efforts are underway to make T cells resistant to HIV infec-
tion. This work is largely inspired by the Berlin Patient and at least four
other cases89,90 (Table 2). Most HIV variants enter their target cells by
binding to CD4 and then CCR5. Approximately 1% of people of Euro-
pean descent are homozygous for a 32-bp deletion within the CCR5
gene. Allogenic stem cell transplantation in people with HIV and either
leukaemia or lymphoma from a donor homozygous for this deletion is
curative, providing proof of concept that genetically modifying cells to
make them resistant to new infections is a viable cure strategy. Using
ex vivo and eventually in vivo methods to genetically modify CD4+
T cells such that they resist HIV infection is a growing part of the HIV
cure agenda.
Cross-cutting themes and opportunities
The HIV research agenda is becoming less siloed, with multiple themes
that cross prevention, treatment and cure emerging.
The PrEP–PEP–cure continuum
There is a continuum in terms of level of virus exposure and infec-
tion as one considers the poorly defined boundaries between PrEP,
post-exposure prophylaxis (PEP) and early ART, which at least in non-
human primates can be curative91 (Fig. 5). The study of those who
become infected during PrEP is one example of how the study of this
continuum can be informative. One well-characterized individual
initiated PrEP soon after unknowingly becoming infected, when he
had a barely detectable viral load92; once the infection was detected,
his treatment regimen was intensified. He later was found to have no
detectable virus in blood or tissues through a variety of sensitive assays,
suggesting that early ART may have acted as PEP. To interrogate a pos-
sible cure, he underwent a highly monitored treatment interruption and
rebounded after 8 months, a remarkably long time. This case provided
some key insights: (1) even a very small reservoir is sufficient to support
a systemic spread of the virus post-ART; (2) methods to detect very
low levels of replication-competent HIV may be needed to evaluate
reservoir-reduction interventions; and (3) monitoring for rebound
required an intensive visit schedule, whereas a sensitive home-based
Coordinated response involving
innate and adaptive immunity
Antigen-presenting cell
CD8+ T cell
Long-term control
Natural killer cell
Monocyte
B cell
Antibody
Weeks
(TLR agonists and others), immune modulators (immune checkpoint inhibitors
and others) and cytokines (IL-15 and others) are being studied in the clinic in
various combinations to achieve these goals. A coordinated response involving
the innate and adaptive immune responses needs to be present at the time of the
initial rebound. Long-term control will presumably be mediated via T cells, as it
is in states of natural (or ‘elite’) control.
Review article
ART
bNAb levels
• bNAb infusion Antibody- • Low-level viral replication
• ART interruption mediated • Vaccinal effect
reservoir • T cell production
clearance • Slow rebound
Fig. 4 | Multiple roles of bNAbs in treatment and cure. All broadly neutralizing
antibodies (bNAbs) were selected for their ability to neutralize free virus. When
present in combination and at high levels, bNAbs can suppress HIV replication
in a manner similar to that with antiretroviral therapy (ART). Owing to their
ability to mediate cytotoxicity (through the activities of the crystallizable
fragment (Fc) region), bNAbs may be able to clear the reservoir during periods
of viral suppression. When virus begins to rebound in the presence of bNAbs,
assay would render such treatment interruptions much more easily
­monitored.
Intensive investigation of host–virus interactions during the earli-
est stages of infection can be informative. People destined to control
HIV exhibit potent responses early, although to date no study has fully
defined why in rare cases the immune system responds effectively and
durably to the acute infection (Fig. 5). As ART essentially ‘freezes’ the
virus and host, careful investigation of these interactions might be pos-
sible when ART is subsequently interrupted, assuming that the inter-
ruption is done carefully and in an intensively monitored study. Early
signals suggest an important role of interferons and innate immunity
during this period93–95.
Occult HIV infection during PrEP
The new generation of long-acting or extended-release antiretroviral
drugs, including long-acting broadly neutralizing monoclonal anti-
bodies, has great promise for advancing biomedical HIV prevention
options; however, infection in the presence of antiretroviral drugs
can occur, albeit rarely. These infection events are typically present
as a potential ‘smouldering’ incident HIV infection, with very low-level
viraemia and a limited immunological response. This clinically protean
presentation is often characterized by negative HIV RNA and antibody
tests, making it hard to make the diagnosis26,96. Novel assays that detect
HIV DNA (or HIV DNA and RNA) may increase the sensitivity97, thus
allowing for confirmation of HIV infection.
This ‘long-acting early viral inhibition’ syndrome is rare but might
become more common as these PrEP strategies are implemented. HIV
testing assays, including RNA-based assays, can often have a ‘flickering’
pattern that may be confusing or misleading; therefore, a high degree
of suspicion is required when reactive HIV diagnostics are encountered
in the care of patients taking long-acting PrEP agents. Resistance to the
PrEP agent is often present, but again hard to confirm, given the low
levels of viraemia. It is unknown whether this syndrome will be gen-
eralizable to other long-acting PrEP agents in development. It is clear
Nature Reviews Microbiology
Viral load
• T cell expansion
• Virus control
immunogenic antibody–antigen complexes form; these in turn may have the
capacity to induce potent HIV-specific T cells. As bNAbs slowly wane, they may
blunt the rate of virus rebound, providing the adaptive immune system with time
to expand. This delay may allow for a more effective host response to the rapidly
expanding virus population. The collective impact of these activities (reservoir
reduction, induction of potent T cell responses and delay in rebound) can result
in post-treatment control.
that as we make progress in developing novel strategies for prevention,
treatment and cure, novel diagnostics will be needed.
PrEP after a cure
The Berlin Patient (Timothy Brown) and now at least four other people
were cured with an allogenic stem cell transplant using cells from a
donor whose immune system did not express CCR5, a key receptor used
by HIV to enter cells. Although uncommon, people can become infected
with viruses that utilize CXCR4 rather than CCR5 for cell entry. T. Brown,
who had become a well-respected cure advocate and shared his experi-
ences widely, became concerned about this possibility and hence used
a two-drug PrEP post-cure. This raises the question of whether having
gone from a standard three-drug regimen (treatment) to a two-drug
regimen (PrEP) was really a cure. For any intervention that does not
result in complete protection from new infections, this dilemma will
remain. On a public health level, any cure strategy that does not protect
against reinfection poses problems. Indeed, some have argued that
for a cure to be truly impactful in terms of ending the epidemic, such
protection will be required98.
Another complex issue pertains to the concern that a person with
a near-cured state (and low-level virus replication) might develop drug
resistance if they choose to go on PrEP. These are challenging issues
that the field will need to resolve as the pros and cons of any viable
cure strategy are debated.
Universal need for point-of-care or at-home HIV testing
For each of the major indications outlined here — prevention, treatment
and cure — the development and implementation of an inexpensive,
highly sensitive point-of-care (and perhaps even self-administered)
assay to detect low levels of HIV RNA would be transformative. Among
those starting PrEP, such an assay would reduce the risk that an antiret-
roviral drug was initiated during recent infection, which can lead to
emergence of drug resistance26,99. Acquisition of HIV during PrEP can
occur1,4,26,97, particularly if drug levels are low. For treatment, such an
Review article

assay can provide a quick yes/no answer in the clinic as to whether a
treatment is working or might need to be optimized. Failure to promptly
detect the presence of virus while on ART can lead to emergence of
higher levels of resistance. Point-of-care measurements of drug levels
might also prove useful for monitoring adherence during PrEP and
treatment. For a cure strategy in which the post-ART outcome is uncer-
tain and the risk of rebound is always present92, an at-home test will be
essential100. Owing to the limited volume of plasma that can be easily
collected at home, these assays may ultimately provide only qualitative
results. However, they still may be useful, with sensitivities ranging from
200 to 1,000 copies RNA per millilitre, which may be more copies than
needed for detection by standard assays. Other possible biomarkers
of an active infection are being pursued.
Vaccine-induced seropositivity and the need for ultrasensitive
nucleic acid assays
New, highly sensitive ways to detect for the presence of HIV nucleic
acid will also be needed to diagnose the infection in people who have
received a preventative vaccine. Most HIV vaccines are designed to
induce HIV antibodies. As many standard HIV diagnostic tests target
antibodies, vaccinated people might have a positive HIV test even in the
absence of any infection. Theoretically, those who receive an effective
vaccine might be more likely to maintain very low levels of HIV should
they become infected. Novel, scalable assays that can detect HIV nucleic
acid (or perhaps protein) at low levels is now a major research priority.
Ubiquitous role of bNAbs across the care continuum
bNAbs are now being widely developed for prevention, treatment
and cure. The rapidly evolving evidence indicates that bNAbs can (1)
prevent infection in people exposed to viruses highly susceptible to
the bNAb41; (2) delay the rate of rebound post-ART42,81; (3) reduce the
reservoir size during viral suppression43; and (4) bind with antigen
and, through the production of immune complexes, induce a virus-
specific T cell response (the vaccinal effect)83. Also, when bNAbs are
used during a treatment interruption, their antiviral activities — which
may wane slowly as the antibody levels decline — might blunt the acute
rebound, allowing the immune system time to respond. This dynamic
was postulated to explain why some people who slowly develop drug
resistance were able to mount and maintain a strong T cell response101
(Fig. 4). Multiple bridges across the largely siloed areas of HIV preven-
tion, treatment and cure are being built in large part because of the
cross-disciplinary appeal of bNAbs.
The potential for bNAbs to prevent HIV infection with sensitive
viruses was demonstrated in the AMP studies41. A vaccine strategy that
induces the sustained production of high titres of bNAbs that neutral-
ize the diverse population of circulating viruses would go a long way
towards ending the pandemic. Might such a bNAb-inducing vaccine
also have a role in treatment and cure? In a recent ex vivo study, viruses
induced to replicate in vitro were partially neutralized by autologous
antibodies in plasma obtained at the same time point, raising the pos-
sibility that antibodies in vivo might delay virus rebound post-ART102.
In rare cases, the presence of potent antibodies directed against autolo-
gous virus has been associated with stringent control of the virus in the
absence of ART103. When used therapeutically, combinations of at least
two bNAbs have routinely been associated with virus control42,43. Finally,
when gene editing technologies are used to induce the sustained pro-
duction of bNAbs in vivo, virus control is possible, at least in non-human
primates87. These data collectively argue that if a vaccine strategy can be
used to induce the right types of antibodies at the right concentrations
in a sustained manner, then a long-term remission might be possible.
Efforts to leverage the emerging neutralizing antibody-inducing vaccine
strategies58 in a treatment or cure setting are in development.
Ubiquitous role of vaccines and vaccine adjuvants across the
care continuum
Although the massive investment in vaccine development for preven-
tion helped to build the nascent HIV cure clinical trials agenda, repurpos-
ing vaccines developed to prevent HIV acquisition for a cure indication
has limitations104,105. For prevention, the goal is to either avoid the estab-
lishment of a permanent systemic reservoir or induce sustained immune

Table 2 | HIV cures

Case HIV outcome Comments

Berlin patient (Timothy Brown)
London patient (Adam Castillejo)
Dusseldorf patient (Marc Franke)
New York patient
City of Hope patient (Paul Edmonds)
San Francisco patient (Loreen
Willenberg)
Esperanza patient
AML, acute myeloid leukaemia; ART, antiretroviral therapy; PBMC, peripheral blood mononuclear cell.
Cured (>10 years)
Cured (>30 months)
Cured (>2 years)
Possible cure (>14 months)
Possible cure (>17 months)
Spontaneous cure (>25 years)
Spontaneous cure (>8 years)
Allogenic stem cell transplant for AML in 2007; male sex; donor homozygous for
CCR5 Δ32 deletion; two transplants required, first in 2007 (ref. 89); stopped ART in
2007; residual HIV fragments detected years later132
Allogenic stem cell transplant for Hodgkin lymphoma in 2016 (ref. 90); male sex; donor
homozygous for CCR5 Δ32 deletion; stopped ART in 2017; HIV fragments detected
28 months later
Allogenic stem cell transplant for AML in 2013; male sex; donor homozygous for
CCR5 Δ32 deletion; stopped ART in 2018 (ref. 133)
Allogenic dual (haplo-cord) stem cell transplant for AML in 2017; umbilical cord blood
stem cell donor homozygous for CCR5 Δ32 deletion; stopped ART 37 months after
transplant; first mixed-race person and first female with possible cure134
Allogenic stem cell transplant for AML in 2019; male sex; donor homozygous for
CCR5 Δ32 deletion; low intensity pre-transplant chemotherapy; stopped ART in 2021;
oldest person with possible cure (63 years of age at transplant)
Diagnosed in 1992; no ART used; female sex; no intact HIV proviruses in >1.5 billion
PBMCs studied; low HIV antibody levels; mechanism unknown, presumed to be
immunological54,135
Diagnosed in 2013; brief ART during two pregnancies; female sex; no intact HIV
proviruses in >1.1 billion PBMCs; mechanism unknown, presumed to be immunological55

Nature Reviews Microbiology

Review article
Exposure Reservoir
transmission transmission
Days
Prevention Post-exposure Early ART:
PrEP: ART, bNAbs, prophylaxis cure?
vaccines ART ART
Fig. 5 | HIV exposure and infection. The host–virus interactions during
exposure and transmission are complex and dynamic. If antiretroviral drugs
or neutralizing antibodies are present in the mucosal tissues at the time of
exposure, transmission can be effectively prevented. If the virus is transmitted,
immediate antiretroviral therapy (ART) within 72 h of exposure can prevent an
established infection (post-exposure prophylaxis). In non-human primates and
humans, ART administered during the ‘hyperacute’ phase and administered for
control of a very small reservoir. For a cure, the goal is to clear or control
an established reservoir that is much larger, more diverse and more
widely distributed, with some of the virus residing in immune-privileged
sanctuaries106. In prevention, the immune system presumably has not
been exposed to HIV. In a therapeutic setting, however, the immune
system has been primed, with T cells induced to recognize immuno-
dominant epitopes, which in most cases results in poor control. An ideal
curative vaccine would need to overcome ‘original antigenic sin’ and
induce a response to novel subdominant epitopes. Also, cure strategies
will need to work against a viral landscape dominated by the presence
of defective genomes, which can produce immunogenic proteins that
might act as decoys107,108, constantly inducing novel responses to HIV
that are irrelevant. For these reasons and others, the ideal vaccine for
a cure may prove to be very different from that for prevention.
Based on current conceptual models, the ideal cure vaccine would
result in a sustained T cell response that targets the most vulnerable
(often conserved) regions of the HIV genome109–111. As the most con-
served areas of the virus are in gag and pol, most T cell vaccine immuno-
gens contain these regions. Early evidence suggests that such vaccines
may prove effective79. Inducing a response to those proteins produced
immediately after the provirus is activated (Nef, Tat and Rev) might
also prove effective112.
The virus has developed a number of strategies to avoid T cell
recognition. The Nef protein is produced early and induces down-
regulation of major histocompatibility complex I, which in turn allows
the cell to evade clearance by circulating HIV-specific CD8+ T cells112.
Theoretically, a vaccine that induces an effective T cell response to Nef
might be able to clear the infected cell before this defence mechanism
is induced113. An alternative approach recently suggested is the use
of Nef inhibitors as a possible adjuvant to therapeutic vaccination114.
The quality of the T cell response will also be important, and these
cells will need to be primed and located in the right place. Recent
research on elite controllers shows that HIV-specific memory T cells
with high proliferative potential are necessary during steady state
(when the virus is under control), presumably because such cells have
the capacity to rapidly expand in response to any isolated bursts of rep-
lication75,115. Although many vaccine strategies were advanced based on
the CD8+ T cell response, the CD4+ T cell response has in many studies
been a stronger correlate of virus control.
Only the RhCMV vaccine, now in early human testing for pre-
vention, has the proven capacity to clear established infection, but
Nature Reviews Microbiology
Weeks Months to years
Early ART: Late ART
post-treatment ART
control?
ART
an extended period reduces the reservoir by multiple orders of magnitude92
and may be curative91. Once a permanent reservoir is established, a cure is no
longer possible, but the reservoir size may be limited and immune function
preserved, setting up the potential for ‘post-treatment control’136. Within
months of infection, however, an established, difficult-to-control reservoir
becomes permanently established. bNAb, broadly neutralizing antibody;
PrEP, pre-exposure prophylaxis.
it should be noted that early non-human primate studies of the CMV
vector in a model of treated, established SIV infection failed to show
any effect91.
Effective PrEP strategies: implications for vaccine
development
The effectiveness of long-acting PrEP poses challenges for the develop-
ment of new prevention strategies, including an HIV vaccine. The expec-
tation is that many future vaccine clinical trial participants will take PrEP
if it is accessible. If uptake and adherence is indeed high, the incidence
of new infections — the primary outcome — will be exceedingly low, mak-
ing efficacy studies nearly impossible. The most recent vaccine efficacy
trial (HVTN 706, Mosaico) only enrolled participants who chose not to
use PrEP at the time of enrolment; any participants who desired PrEP
after enrolment were navigated to PrEP services and remained on the
study. PrEP uptake was low in this study as only daily oral medications
were available for most of the study. In the future, more desirable and
effective options will need to be offered, and as a consequence, inno-
vative efficacy trial designs will be needed. As an example, in ongoing
studies assessing the efficacy of lenacapavir, which is given as a twice-
yearly injectable medicine, the overall incidence of HIV will first be
defined in a lead-in ‘incidence cohort’. The HIV incidence rate among
at-risk individuals administered lenacapavir will then be defined and
compared to that observed in the incidence cohort. Future HIV vaccine
candidates might be studied using a similar study design.
Long-acting ART: implications for HIV cure studies
Advances in long-acting ART may complicate evaluation of cure inter-
ventions, as the ability to rapidly begin a treatment interruption, obliga-
tory to evaluation of many cure strategies, becomes challenging when
long-acting antiretroviral drugs are being used. Long-acting antiviral
agents cannot be easily removed from the body once administered:
when a dose is missed, drug levels will slowly decay through a range in
which the virus is able to replicate in the presence of drug — a perfect
environment for the selection of a drug-resistant variant96. Hence, if
a long-acting drug is interrupted in a cure study, its terminal decay
period would need to be ‘covered’ by a more conventional short-acting
ART regimen. For example, long-acting rilpivirine–cabotegravir will
probably require at least a year of transition to daily oral ART before
an analytical treatment interruption is considered; this period may
need to be even more prolonged for female patients, as the terminal
Review article
pharmacokinetics of cabotegravir are highly impacted by sex assigned
at birth and, to a lesser extent, body mass index. Similarly, therapeutic
drug monitoring to assure washout of the long-acting or sustained
release agent may be required to demonstrate that any sustained remis-
sion after a cure intervention is not due to ongoing antiretroviral drug
exposure.
Long-acting ART versus a remission: is there a difference?
The ideal outcome from any curative intervention would be complete
eradication of the reservoir and protection against reinfection116, a goal
many consider aspirational. Achieving durable control of a persis-
tent reservoir seems more likely, but this will require a sustained host
response that persists for decades, with frequent boosters to support
waning immunity. As these strategies move forward, the capacity to
deliver very long-acting ART with injectables and implants is expected
to mature, resulting in options in which ART is administered very infre-
quently. Whether these longer-acting treatment regimens might be
considered a form of a remission largely becomes semantic.
A major driving force for the development of a remission or cure
strategy is that sustained viral suppression (over years) can be chal-
lenging, at least in some settings4,5. Periodic breaks in treatment are
common117 and might pose problems for individuals on these long-
acting agents as compared to those treated with an effective remission
or cure strategy.
Advancing emerging strategies to prevent vertical
transmission and manage paediatric HIV
In this Review, we have focused entirely on advances being made in
the general adult population. Although ART can eliminate mother-
to-child vertical transmission, there are still approximately 161,000
children who acquire HIV each year. According to recent estimates
from UNAIDS, only about 50% of children with HIV are receiving ART,
a far lower frequency than in adults118. Clearly, there are multiple unmet
needs in the management of pregnancy, breastfeeding and children.
Much of the prevention and treatment or cure progress outlined here
could address many of these unmet needs.
There is great interest and potential in leveraging long-acting
and extended-release preparations to (1) prevent HIV acquisition dur-
ing pregnancy and breastfeeding, (2) provide PEP to newborn babies
exposed in utero and during breastfeeding, and (3) provide more con-
venient and effective therapeutic options for mothers and children.
The safety, pharmacokinetics and efficacy of each agent being devel-
oped must be carefully evaluated for each of these outcomes to fully
­understand the risks and benefits.
In pregnant people with HIV, cabotegravir–rilpivirine, although
attractive for maintenance of virological suppression, has not been rig-
orously evaluated in this setting119 and is therefore not recommended
in current guidelines for prevention of mother-to-child transmission
of HIV. For prevention among HIV-negative pregnant people, limited
experience suggests that long-acting cabotegravir is safe and effec-
tive during pregnancy25; studies are ongoing to establish safety in
pregnancy and breastfeeding. Long-acting cabotegravir for the infant
as postnatal prophylaxis is of particular interest to the global commu-
nity, but again it has not yet been studied120. Administration of bNAbs
to the infant to prevent HIV acquisition during breastfeeding is being
studied: a very low dose of a single long-acting bNAb has the potential
to be fully protective for weeks to months. Agents being studied in this
context include long-acting antiviral agents, monoclonal antibodies
and combinations of both.
Nature Reviews Microbiology
Children, adolescents and young adults represent populations
challenged by adherence to ART and at high risk for HIV acquisition
after sexual debut. In particular, young cisgender men, transgender
women and non-binary individuals who have sex with men are dispro-
portionately affected by HIV in the USA and Europe, as are adolescent
girls and young women in southern and eastern Africa. Long-acting and
extended-release preparations that provide adherence advantages
and are increasingly discreet are of great potential benefit in these
settings. Unfortunately, antiretroviral drug development has not
usually been done synchronously for both non-pregnant and pregnant
adults, as well as minors, with initial regulatory pathways, but accel-
erating the development of long-acting options for adolescents and
young adults is now a priority. Novel delivery mechanisms — microarray
patches, injectable agents and implants — have unique advantages in
the young adult and adolescent population120.
There is a robust HIV paediatric cure programme64. The first
potential cure related to ART was reported in a child121, and two of the
best-characterized post-treatment ‘remissions’ are in the paediatric
population122,123. Given the unique nature of the infant immune system,
the rate of decay in the reservoir during early life might prove to be
more rapid than that observed in adults124. Many children who have
been on ART for years have exceedingly small reservoirs125. Many of the
leading curative agents in adults are now being studied in children126.
Addressing disparities in access to prevention and treatment
Observing the population-level reductions in HIV incidence and treat-
ment responses, it is clear that some US communities are disproportion-
ately affected by incident HIV, including children and adolescents, Black
and Latinx MSM, and transgender individuals, and that these groups
are not uniformly benefitting from the current generation of preven-
tion and treatment options127–130. Globally, remarkable success has
been achieved in expanding access to treatment, with the most notable
successes in western and central Africa and in the Caribbean. Still, pro-
gress has slowed, with the growth in those going on ART lower in 2021
than in the past 10 years, and the declines in HIV incidence lower in
2021 than in the past 5 years131. These concerning trends are driving the
development of ‘next’-generation prevention and treatment strategies
described here, all with a goal of improving adherence, persistence
and self-efficacy of use in those most-affected populations for whom
existing modalities have not worked successfully.
Efforts to streamline services, ensure equity in access and address
co-occurring conditions of mental health, substance use disorder and
social and structural barriers to health-care access will be essential to
closing these gaps. It is assumed that the lessons learned in the ongoing
efforts to expand access to treatment globally will inform the imple-
mentation of PrEP strategies and of vaccines and cures, should they
become available.
Conclusions
Despite the development and global implementation of highly effec-
tive prevention and treatment strategies, the HIV epidemic continues.
With people living much longer and the virus continuing to spread, the
number of those living with HIV is now growing, putting great pressure
on overtaxed health-care systems around the world. To end the growth
of the epidemic and free up resources for other public health needs,
we will probably need an effective preventative vaccine that is safe,
affordable and scalable. To address the ongoing needs of those who
are infected, very long-acting antiretroviral drugs will probably prove
to be helpful but may be insufficient. A truly transformative advance
Review article
will be the development of a safe and effective cure, particularly one
that provides protection against future infections.
Several cross-cutting areas of synergy are emerging within the
HIV research agenda. Long-acting ART will revolutionize prevention
and treatment, and some might argue as we develop annual dosing
regimens that these might be perceived as no different than a curative
strategy that requires occasional boosting. bNAbs are being actively
developed for prevention, treatment and cure, and bNAb-inducing
vaccines are being developed for prevention and cure. A scalable point-
of-care or at-home diagnostic that can detect the virus directly is one of
the most important unmet needs in the field. These assays will probably
be required to implement all of the strategies now in development. It
is hoped that the prevention, treatment and cure fields will find ways
to collaborate and share resources more directly as advancements are
made in these largely cross-cutting areas of research.
Published online: xx xx xxxx
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Author contributions
S.G.D. researched data for the article. All authors contributed substantially to discussion of
the content. All authors wrote the article. All authors reviewed and/or edited the manuscript
before submission.
Competing interests
The authors declare no competing interests.
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