Paediatric HIV infection: the potential for cure

Abstract

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.

Fig. 1. Changes in viral load following HIV infection in paediatric and adult cases

Typical, progressing adult and paediatric infection (upper panels), and non-progressing adult and paediatric infection (lower panels)^,,,. Typically, in HIV infection of ART-naïve adults, a viral setpoint is reached after 6 weeks and the median time to AIDS is 10 years. In typical, ART-naïve paediatric HIV infection, a viral setpoint is reached after 5 years and the median time to AIDS is 1 year. Non-progressing adult infection is characterised by low/undetectable viral loads and low levels of immune activation. The prevalence of non-progressing paediatric infection is 5–10% [ref 7,158,159], and of adult elite control ~0.3% [ref 146]. Non-progressing paediatric infection also features low levels of immune activation, but in the setting of high viral loads (~30,000 copies/ml).

Fig. 2. Risk of Mother-to-child HIV transmission in utero and in early life

Mother-to-child transmission (MTCT) risk of HIV in the absence of prophylactic measures is approximately 7% from in utero infection, 18% from intra-partum infection, and 15% from post-partum transmission (through breast-milk; breast-feeding for 18–24 months)^–. In utero-infected infants are viraemic and HIV DNA positive at birth, whereas transmission arising at the time of delivery (intra-partum) results in viraemia only some 4 weeks later. Treatment with ART of all mothers testing HIV-positive in pregnancy has reduced combined in utero and intra-partum MTCT from 25% to 1–2% [ref 102], and prevention of breast-milk transmission via ART also has reduced post-partum MTCT rates to 1–2% [ref 164]. The remaining 1–2% MTCT rate results either from ART non-adherence or from acute infection during pregnancy or after birth (in utero MTCT risk of ~20% [refs 163,165,166] or post-partum MTCT risk of 20–25% [ref 167]), since tests to detect HIV antibody are negative during acute maternal infection when peak viraemia is ~10⁷ copies/ml and transmission risk is high.

Fig. 3. Paediatric factors affecting immune activation and therefore size of the HIV reservoir

The vicious cycle of HIV infection — resulting in intestinal mucosal damage, microbial translocation across the intestinal barrier and increased immune activation, leading to increased CD4⁺ T-cell decline, which predisposes to further co-infections, increased immune activation, HIV replication and CD4+ T cell loss — can be prevented by the initiation of antiretroviral therapy sufficiently early in adult and paediatric infection. There are factors specific to paediatric infection that tend to interfere with this vicious cycle, and others that contribute to it, the balance of which may vary between individuals and also may depend crucially on the timing of ART initiation. Aspects of immune ontogeny that favour decreased immune activation include the tolerogenic immune environment in utero and in early life and the high proportion of naïve CD4⁺ T-cells. Aspects of immune ontogeny that tend to decrease paediatric cure potential include the large number of T_H17 cells in the intestinal mucosa. Maternal factors favouring paediatric cure potential include maternal health, exclusive breast-feeding, lack of co-infections, and expression of HLA class I molecules that bind LILRB2 with high avidity.

Fig. 4. Principal opportunities for immunotherapeutic interventions to maximise the potential for HIV cure or remission in paediatric HIV infection

In utero paediatric infection provides particular opportunities for ART to be initiated with or without additional interventions (such as broadly neutralising antibodies) very early in the course of infection. As cell-mediated immunity is likely to have a key role in eradication of the viral reservoir, and T_H1 cell responses take some years to develop fully, a period of time on ART alone may be useful to minimise the size of the viral reservoir prior to further interventions designed to eradicate infection. In late childhood, approximately between the ages of 3 and 9 yrs, immune ontogeny favours the generation of effective CD8+ T-cell immunity, which provides a window of opportunity for therapeutic intervention before the onset of puberty with associated behavioural changes including loss of ART adherence and onset of sexual activity.