Child cured of HIV: can this be repeated?

Abstract

Eradication of HIV infection is the most challenging research area in the HIV/AIDS field. Treatment of HIV infection with antiretrovirals halts viral replication but fails to eradicate infection because it does not eliminate latent viruses. Eradication has only been achieved in one exceptional case after bone marrow transplantation. For this reason, researchers were surprised by a report describing the first cure of an HIV-infected individual using antiretrovirals. It was an in utero HIV-infected newborn treated immediately after birth with a potent antiretroviral combination. After treatment interruption, the child showed no evidence for active HIV infection; she was apparently cured. The case is particular and can be seen as an extreme case of postexposure prophylaxis. Moreover, due to strong immunological differences between newborns and adults, the case does not provide new hope for adult HIV-infected individuals, although it may open new treatment standards for functional cure of HIV-infected newborns. However, new studies to proof the benefit of immediate treatment of HIV-exposed newborns will require the definition of point of care diagnostic tools, drug regimens and the minimal time from birth to therapy introduction, and also importantly, when and under what settings should treatment be interrupted to test for functional cure.

Keywords::

• antiretrovirals
• cART
• HIV cure
• prophylaxis
• reservoir

1. Introduction

In March 4, 2013, the headlines of most newspapers in the world displayed a good news – an infant had been cured of HIV infection. The news was released concomitantly to the presentation of the case by Dr. Deborah Persaud of Johns Hopkins Children's Medical Center in Baltimore, at the annual Conference on Retroviruses and Opportunistic Infections held in Atlanta [1].

2. A cure for HIV infection

The possibility of eradicating HIV from infected individuals or curing them from HIV infection has been a major area of research in retrovirology over the last years. The discovery of several families of antiretrovirals in the 1990s allowed for the introduction of combination treatments defined as highly active antiretroviral therapy (HAART) or combined antiretroviral therapy (cART). cART combinations included three drugs and achieved a durable blockade of HIV replication in HIV-infected patients, leading to a sharp reduction in AIDS-related deaths and opening a new era in HIV treatment. The great success of cART stimulated the idea that the infection could be eradicated easily; however, interruption of cART in treated HIV-infected individuals led to an inexorable rebound of viral replication. This was due to the existence of a viral reservoir that encompasses a series of transcriptionally inactive (silent and invisible to the immune system) proviral DNA sequences integrated in the cell host genome, mainly in resting memory CD4 T cells [2].

Although our knowledge of the dynamics of HIV reservoir in HIV-infected newborns is limited [3], it is well known that in adults the HIV reservoir is established shortly after primoinfection [2]. This latent reservoir is reduced but not eliminated by cART. Indeed, long-term follow-up of treated patients showed that that eradication of the HIV reservoir by cART could take longer than the life span of infected individuals [2,4]. For this reason, the most recent approaches to HIV cure are focused to the definition of new drug families that do not target the replication of HIV but the transcription of proviruses in CD4 T cells. In combination with cART, these drugs would make the virus visible and harmless to the immune system. Unfortunately, no clear clinical data are available yet for these approaches [5].

In fact, only one HIV-infected individual, the Berlin patient, has been cured and the reasons for that are still controversial. The patient developed acute myelogenous leukemia (AML) and underwent a complex clinical process that included in 2007 an allogeneic hematopoietic stem cell transplant from a donor who was homozygous for the CCR5-Δ32 deletion, which confers resistance to HIV infection. After 4 years without antiretroviral treatment, the patient has no detectable signs of HIV infection [6]. More recently, two additional HIV-infected individuals that have undergone allogeneic hematopoietic stem cell transplant from CCR5 wild-type donors seem to be also cured, suggesting that graft- versus host-mediated destruction of potentially remaining HIV infected cells could be a determinant cause of HIV eradication [7]. In addition to complete viral eradication, a functional cure of HIV infection has also been reported in some HIV-infected individuals. In this case, patients do not show active viral replication after stopping cART, although the viral reservoir is still present, suggesting that immune control is the key factor for functional cure [8]. In any case, cART alone is able to eradicate HIV infection in adults.

3. The Mississippi case

For the above-mentioned reasons, the expectation in the Retrovirus Conference was maximal when the new case of HIV cure was presented. The case was a baby girl, born in Mississippi to a woman, which was diagnosed for HIV infection shortly before delivery. The newborn blood was tested for HIV after birth and was found to be positive for viral RNA, and a posteriori also for viral DNA, suggesting the presence of HIV-infected cells. The medical team decided to immediately treat the newborn with a combination of azidothymidine (AZT), lamivudine (3TC) and nevirapine rather than to wait for a full diagnosis or to treat with a short course of one or two drugs, following current guidelines to prevent infection in HIV-exposed babies [1,9]. Treatment was initiated 30 hours after birth and was continued with a switch of nevirapine to lopinavir for 18 months. At that moment, the clinical team lost contact with the mother and the child. When they came back to the clinic after a 5-month period off-treatment, researchers rapidly analyzed the child for the expected viral rebound. Surprisingly, there was no evidence of active HIV infection in the child, although some level of a latent viral reservoir could be detected by the most sensitive and accurate techniques available. The Mississippi girl, as the Berlin patient, seemed to be cured.

3.1 Exceptionality and implications

The Berlin patient and the Mississippi case are exceptional and of exceptional interest. However, the cases are completely opposite, the former eradicated HIV infection, while the Mississippi baby seems to maintain a low level of inactive latent virus, although it is only detectable using sensitive droplet digital PCR [1]. Moreover, eradication in the Berlin case was achieved after a complex medical process, while the child is the first case of a potential HIV cure achieved using a simple pharmacological combination of antiretrovirals. The reason for explaining the success of this approach, which is known to be ineffective in adults, could rely in the particularities of the immune system that HIV encounters in a fetus or a newborn.

HIV infects CD4 T cells and requires some level of immune activation to replicate. For this reason, the virus infects mostly memory cells, in particular cells from the gut-associated lymphoid tissue (GALT) that concentrates most of activated CCR5-expressing memory CD4 T cells. GALT depletion is a major pathogenic event in HIV infection and is associated with the establishment of a long-lived viral reservoir and disease progression in adults [10]. In contrast, the immunological setting of a fetus shows a CD4 T-cell compartment in which memory cells are virtually absent [11] and a GALT tissue that is anatomically immature, since it requires commensal bacteria for full development [12]. In the absence of optimal setting for replication, the virus may hardly establish a long-lived latent reservoir and therefore, under this particular situation, very early treatment could have an additional beneficial effect that cannot be seen in chronically infected adults.

A major concern in the Mississippi case is whether the infant was actually infected or was only exposed to HIV. Some researchers were skeptical about a real infection and suggested that the child could be naturally resistant to HIV infection. However, the authors argued that the presence of detectable but low levels of circulating virus and proviral DNA in blood samples indicates that some level of infection occurred. This possibility is consistent with the low level of HIV replication expected in a fetal setting. An alternative possibility is that the cells from the child were not infected and that viral RNA and DNA detected in her blood come from cells having migrated from the mother to the fetus. Against this possibility, the authors presented comparative data on viral load (the concentration of circulating viruses) in the mother and the infant that suggested that this situation could only be explained by a massive and unlikely viral transfer from the mother to the infant. Both scenarios are possible and difficult to discriminate due to sample availability. However, the difference is relevant, because only in the first scenario the word ‘cure' is correct; in the second one, cART exclusively acts as prophylactic treatment. Nonetheless, in both cases, the outcome is that the treatment efficiently protected the baby from HIV infection.

4. Expert opinion

The seemingly cure of a newborn infected by HIV and immediately treated with cART after birth is an excellent new for the definition of strategies to reduce mother-to-child HIV transmission, specifically for those occurring in utero, which represent a 7% of the reported cases [13]. However, the modification of current protocols of antiretroviral regimens to prevent vertical transmission will require an optimal study design to proof the benefit of immediate potent antiretroviral treatment. This design faces technical, logistical and ethically pertinent questions. Among current limitations, accurate and fast point-of-care diagnostic tools for rapid detection of infection, the optimal treatment regimen for newborns and the window of opportunity for the intervention need to be defined. Finally, when and under what settings should treatment be interrupted to test for functional cure remain also as open questions.

Unfortunately, the lessons that we can learn from the Mississippi case cannot be translated to adult HIV infection. The strong differences between the fetal and the adult immune system, in particular those affecting CD4 T cells, account for this. In adult settings, we know that cART is unable to eradicate HIV, and only functional cure has been reported in exceptional cases. These cases include patients enrolled in very early treatment after infection, which is known to have long-term beneficial effects in disease progression. Moreover, we also know that prophylactic cART treatment (24 – 48 hours after HIV exposure) is efficient in avoiding HIV transmission and the well-defined standard protocols have been already implemented. Thus, besides reinforcing the notion that early treatment could help to control HIV infection, no major changes in treatment of chronic infection or prophylactic interventions are expected after this case.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.