Recent anecdotal reports of HIV remission in children following a discrete period of antiretroviral therapy (ART) have prompted the suggestion that HIV cure might be more readily achieved in children than in adults. This Review examines the evidence for such a claim and discusses the unique opportunities for immunotherapeutic interventions in children to maximize HIV cure potential.
ART can be initiated within minutes of birth following in utero infection with HIV. Early initiation of ART results in a substantially smaller viral reservoir. The decay half-life of the viral reservoir is shorter following ART initiation in children compared with adults, and the decrease in size of the reservoir seems to continue for longer in children.
The tolerogenic immune environment in utero and in early life increases the potential for HIV cure in infants. Other aspects of immune ontogeny, including the strong T helper 17 cell bias at birth, decrease cure potential in children. The overall balance between these opposing influences may depend crucially on the timing of initiation of ART.
Maternal factors — including maternal health (which influences child feeding, general care and ART provision), maternally transmitted infections (such as cytomegalovirus and tuberculosis) and genetic factors (such as the effect of HLA class I alleles on dendritic cell function through leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) binding avidity) — could all markedly affect the potential for HIV cure in children.
Paediatric infection presents particular opportunities for HIV cure through early interventions in addition to ART. Certain challenges are also posed by paediatric infection and the effects of immune ontogeny. The onset of puberty may limit the optimal window of opportunity for immunotherapeutic interventions in children to the ages of ∼3–9 years.
Recent anecdotal reports of HIV-infected children who received early antiretroviral therapy (ART) and showed sustained control of viral replication even after ART discontinuation have raised the question of whether there is greater intrinsic potential for HIV remission, or even eradication ('cure'), in paediatric infection than in adult infection. This Review describes the influence of early initiation of ART, of immune ontogeny and of maternal factors on the potential for HIV cure in children and discusses the unique immunotherapeutic opportunities and obstacles that paediatric infection may present.
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P.J.G. is funded by the Wellcome Trust (WT104748 MA). S.R.L. is supported by the National Institutes of Health Delaney AIDS Research Enterprise (Grant U19 AI096109) and a National Health and Medical Research Council (NHMRC) of Australia Practitioner Fellowship. E.M.L. is supported by the Clarendon Foundation.
The authors declare no competing financial interests.
- Antiretroviral therapy
(ART). The combination of usually a minimum of three anti-HIV drugs that aim to suppress viral replication, slow disease progression and minimize the risk of transmission. Pre-exposure prophylactic ART has also been shown to protect against HIV infection.
- CD4+ T cell counts
The number of T cells expressing the CD4 receptor on their surface in a microlitre of blood. These white blood cells 'help' the immune system to mount a response against pathogens and are the main target cells of HIV infection.
- Elite controllers
A rare subset (less than 1%) of antiretroviral therapy (ART)-naive, HIV-infected individuals who have undetectable plasma viral load (by standard assays) and remain clinically healthy in the long term. HIV controllers is sometimes used synonymously with elite controllers.
- VISCONTI cohort
(Viro-Immunologic Sustained Control after Treatment Interruption cohort). A French cohort of 14 adults in whom antiretroviral therapy (ART) was initiated during primary HIV infection and interrupted after a median of 36.5 months. For a median of 7.4 years after treatment interruption, the viral load remained at less than 400 copies per ml; these 14 individuals are therefore referred to as post-treatment controllers.
- CHER study
(Children with HIV Early Antiretroviral Therapy study). A randomized Phase III study that enrolled 6–12-week-old HIV-positive infants in South Africa with a percentage of CD4+ lymphocytes of more than 25%, who were assigned either to receive immediate antiretroviral therapy (ART) for 40 or 96 weeks or to defer treatment until clinical criteria were met.
- PEHSS study
(Paediatric Early HAART and Strategic Treatment Interruption study). A feasibility study of 63 perinatally infected infants in KwaZulu-Natal, South Africa, who were randomized to receive either immediate 12-month uninterrupted antiretroviral therapy (ART), immediate 18-month treatment with structured interruptions or deferred treatment.
- Viral reservoir
Virus that persists in patients on antiretroviral therapy (ART) in the form of latent or productively infected cells. Latency is established in long-lived resting memory T cells as integrated virus that is replication competent but transcriptionally silent. Latently infected cells persist for decades and are more frequent in tissue compared with blood. Reactivation of virus in these cells (for example, upon ART interruption) is the major obstacle to HIV eradication.
- Fiebig stages I–VI
Categorization of primary HIV infection in six stages based on the detection of different HIV markers. Staging begins with viral detection by PCR (stage I), then ELISA detection of Gag p24 (stage II) or HIV-specific antibody (stage III), and then sequential stages of HIV-specific antibody detection by western blot (stages IV–VI).
- Cell-associated unspliced HIV RNA
Unspliced HIV RNA is detected in cells of individuals on antiretroviral therapy (ART) from the initial first step of long-terminal repeat-mediated HIV transcription before splicing, host promoter-initiated HIV transcription (or read-through transcription) or virus production. By contrast, plasma HIV RNA measures RNA in mature virus particles.
- 2-LTR circles
(2-long-terminal repeat circles). Circularized forms of unintegrated viral DNA that are by-products of HIV DNA integration into the host genome and exist only in the nucleus. The stability of 2-LTR circles is controversial, but they are generally thought to be short-lived.
- Miliary tuberculosis
(Miliary TB). Dissemination of Mycobacterium tuberculosis most often throughout the body, including the brain.
- Phambili trial
A trial that tested the efficacy of the MRKAd5 subtype B HIV-1 Gag/Pol/Nef vaccine in South Africa, where subtype C virus is dominant. The vaccine increased the risk of HIV acquisition and did not reduce early viraemia.
- Escape mutants
Viral variants that reduce recognition by the immune system, typically arising in epitopes that are targeted by HIV-specific CD8+ T cells or neutralizing antibodies.
- Broadly neutralizing antibodies
HIV-specific antibodies that arise during natural infection in 10–30% of individuals and can effectively neutralize diverse viral isolates.
- Step trial
A trial that tested the efficacy of the MRKAd5 subtype B HIV-1 Gag/Pol/Nef vaccine in North and South Americas, Australia and the Caribbean, where subtype B virus is dominant. The vaccine increased the risk of HIV acquisition.
- Treatment intensification
Introduction of additional antiretroviral drugs to a standard three-drug suppressive regimen.
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Goulder, P., Lewin, S. & Leitman, E. Paediatric HIV infection: the potential for cure. Nat Rev Immunol 16, 259–271 (2016). https://doi.org/10.1038/nri.2016.19
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