July 25, 2017
The 9th International AIDS Society Conference on HIV Science (IAS 2017) began on Sunday in Paris, and the topic of HIV remission has been the focus of several high profile presentations.
One of the first major news stories to emerge from the meeting involves a newly described example of prolonged HIV remission in a nine-year-old South African (see the conference abstract and poster discussion slides presented today by Avy Violari). The case was identified because the child was a participant in the Children with HIV Early Antiretroviral Therapy (CHER) trial, which took place from 2005-2011 in South Africa and evaluated immediate, time-limited (40- or 96-week) courses of antiretroviral therapy (ART) in perinatally infected infants compared to the strategy of deferring initiation until clinical or immunological signs of disease progression were evident (preliminary results from the study, demonstrating the benefits of immediate ART, were published in the New England Journal of Medicine in 2008).
The child was diagnosed by HIV DNA PCR 32 days after birth, and displayed pre-treatment viral load levels of over 750,000 copies/ml and 151,000 copies/ml on days 39 and 60, respectively. ART was initiated after 61 days, with viral load declining to below 50 copies/ml at week 24 of on-treatment follow up. ART was subsequently stopped at week 40. The CHER protocol mandated restarting ART if certain immunological and/or clinical criteria were met, but the child has remained healthy and maintained a high CD4 count throughout follow up.
The researchers have conducted multiple analyses to try and gain insight into the factors that may have contributed to the outcome. Measurement of the HIV reservoir using a sensitive test for total HIV DNA revealed similar levels after one year and at 9.5 years of age: around 5 copies per million peripheral blood mononuclear cells (PBMC). However, no replication-competent virus could be detected using two different culture methods. Virus sequencing showed that the child was infected with HIV-1 from clade C, the most prevalent strain in South Africa.
The ELISA HIV antibody test was negative but weak reactivity to Gag p40 and p24 was detectable by Western blot. One exception to the generally weak HIV-specific antibody responses was a high IgA2 (a type of mucosal antibody) response to the gp41 protein. In studies of cellular immunity, a low-level CD4 T cell response to the HIV Gag protein was discernible with a whole blood intracellular cytokine assay, but no HIV-specific CD8 T cells could be detected.
Additional parameters that were investigated included the density of CCR5 molecules on CD4 T cells, which was found to be lower than HIV-negative controls -- it is perhaps possible that lower CCR5 density contributed to the maintenance of an HIV-specific CD4 T cell response by reducing the susceptibility of these cells to HIV infection. Encouragingly, levels of immune activation were similar to HIV-negative individuals and lower than those observed in elite controllers (in the latter group, elevated immune activation has been associated with disease progression despite persistently low viral loads).
PD-1 expression was found to be high on both CD4 and CD8 cells compared to HIV- individuals and elite controllers; the significance of this finding remains to be elucidated. None of the beneficial HLA alleles that have been associated with elite control were present, although the child was heterozygous at all HLA loci and this has been linked to a better prognosis compared to homozygosity.
The researchers note that other factors beyond the temporary course of ART likely contributed to the salutary outcome -- the majority of participants in both the 40- and 96-week immediate ART arms of the CHER trial had met the criteria for restarting treatment by the time the study ended, and no other cases of HIV remission have yet been identified.
The hope is that additional analyses will uncover novel correlates of immune control and aid the design of interventions aiming to induce HIV remission in larger numbers of HIV-positive individuals.
The news coverage of the case -- which has been extensive -- appears to have generally been accurate, although the BBC erred by describing the child as "virtually cured" in their headline -- it is not known if viral load might rebound at some point in the future, as has occurred in some other examples of HIV remission. There are articles describing the child as either a girl or a boy, but Amy Green from the South African Health News Service interviewed Avy Violari and reports that gender is not being disclosed in order to protect the individual's privacy.
The New York Times article, authored by Donald McNeil Jr., has some poor mistakes: the opening paragraph erroneously states that the ART was given at "high doses" when the CHER trial employed normal pediatric dosing. Later in the piece, individuals who are homozygous for the CCR5delta32 mutation, which confers a high degree of resistance to HIV infection, are mistakenly referred to as elite controllers (elite controllers are HIV-positive individuals who naturally contain HIV viral load to low levels in the absence of ART). Timothy Brown, the one individual considered cured of HIV infection, is said to have received a bone marrow transplant from an elite controller, which is not the case - his bone marrow donor was HIV-negative and homozygous for the CCR5delta32 mutation. One of these errors has since been corrected, but two remain at the time of writing.
The first mention of the South African HIV remission case at the IAS conference came yesterday in a presentation by Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) during the "Challenges and Opportunities in HIV Science" session -- this appears to explain the timing of the NIAID news release about the study. Fauci's talk was titled: "Sustained ART-free HIV remission: opportunities and obstacles" and he offered some additional nuggets of news, as well as discussing issues to be considered when evaluating the remission cases that have been reported to date (slides are available for download, and video was posted to the IAS conference youtube channel on July 26).
In particular, he outlined two potential contributors to HIV remission: in some cases, the size of the HIV reservoir may be so small that after an ART interruption the few latently infected CD4 T cells that are present remain dormant for an extended period, before one or more cells is activated and starts producing HIV (triggering viral load rebound). Fauci referred to this phenomenon as "stochastic reactivation," and evidence suggests it may explain the period of remission documented in the Mississippi baby who was started on ART prior to developing detectable immune responses to HIV (it has also been posited to explain the adult examples of the Boston patients and an individual treated within days of infection at UCSF -- see below).
In other instances -- such as the South African child, the French teenager and the VISCONTI cohort participants -- evidence suggests immunological control of HIV replication is contributing, although the exact mechanisms are unclear.
Fauci noted that both of these phenomena could also be operational simultaneously, but presently the short answer as to precisely what explains a given case of HIV remission is: "we don't know."
On the topic of interventions aiming to induce HIV remission, Fauci offered a glimpse of unpublished data from two studies. The first was a clinical trial conducted at the National Institutes of Health (NIH) Clinical Center that evaluated the effect of therapeutic vaccination in HIV-positive individuals started on ART within 12 weeks of a diagnosis of acute or early infection, who had maintained undetectable viral loads for over a year.
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