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HIV Remission News From IAS 2017

July 25, 2017

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A total of 30 participants enrolled, with 15 randomized to receive a prime-boost HIV vaccine regimen developed by Profectus Biosciences (comprising DNA and vesicular stomatitis virus vectors) and 15 randomized to receive placebo immunizations. The final vaccination was administered at week 48 of the study and, eight weeks later, all participants underwent a 16-week analytical ART interruption.

The results demonstrated that there were no significant differences in time to viral load rebound to over 40 copies/ml (or to over 400 copies/ml) between the vaccine and placebo groups. Fauci emphasized the importance of the placebo group by showing that at the end of the ATI period, 20% of controls had viral loads less than 20 copies/ml, 27% were below 400 copies/ml, and 40% were below 2,000 copies/ml.

This finding may temper excitement about the single-arm study of therapeutic vaccination plus romidepsin that drew so much attention at CROI earlier this year -- in that trial, the fact that 38% of participants maintained viral loads below 2,000 copies/ml at 4-6 months after an ATI was presented as evidence that the interventions had enhanced control of HIV replication, compared to historical studies of ART alone. Fauci suggested that preliminary clinical trials and animal studies using broadly neutralizing antibodies (bNAbs) offer evidence that they may have more potential for enhancing post-treatment control of viral load than therapeutic vaccines.

Fauci's own laboratory has reported that administering an antibody against the α4β7 integrin to SIV-infected macaques led to surprisingly robust control of SIV replication after an ART interruption, and in his presentation he showed the unpublished results of recent experiments aiming to shed light on the mechanisms involved. The approach that the researchers took was to deplete different types of immune cells in the animals controlling SIV viral load, then assess whether this led to an increase in viral replication. The experiments compared:

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  • Antibodies to the CD8 receptor alpha chain, which deplete CD8 T cells, natural killer T cells (NKTs) and natural killer (NK) cells
  • Antibodies to the CD8 receptor beta chain, which deplete CD8 T cells
  • Antibodies to CD20, which deplete B cells

A transient rebound in viral load was only seen in recipients of antibodies to the CD8 receptor alpha chain, indicating that NKTs and NK cells are making an important contribution to the observed control of SIV replication. A clinical trial investigating the anti-HIV effects of the anti-α4β7 integrin antibody vedolizumab, which is FDA-approved for the treatment of ulcerative colitis and Crohn's disease, is ongoing at the NIH Clinical Center, and another is due to start soon at the Ottawa Hospital Research Institute in Canada.

Timothy Henrich from UCSF gave another presentation involving HIV remission today, in the same poster discussion session during which Avy Violari described the South African case (video of most of the session is posted on the IAS youtube channel, but Violari's talk is not included). Henrich reported details relating to an individual who was mentioned several times during CROI earlier this year (see the BSVC blog conference report). Both Henrich's abstract and slide presentation are available on the IAS conference website.

The individual in question was diagnosed within an estimated 10 days after acquiring HIV infection, because the exposure occurred in a short window between screening for a pre-exposure prophylaxis (PrEP) program and the baseline visit at which Truvada PrEP was first administered. When the baseline test results came back showing the presence of HIV, Truvada was quickly switched to a four-drug ART regimen including Truvada, darunavir and raltegravir. No HIV could be detected in blood or tissue samples during ART, although a low level of viremia was briefly detected in one out of 10 humanized mice administered a large volume of cells sampled from the individual (this novel test is known as the murine viral outgrowth assay).

After 34 months of continuous ART, an analytical treatment interruption was undertaken, and no viral load rebound occurred for 224 days, during which time no HIV DNA or RNA was detectable in plasma or sampled CD4 T cells. After this prolonged period of HIV remission, viral load rebounded and was initially detected at a level of 36 copies/ml. Six days later viral load had increased to 59,805 copies/ml and ART was immediately restarted. Sequencing of the HIV genome demonstrated that the rebounding virus was identical to that sampled at the time of acute infection.

In a collaboration with Alison Hill, mathematical modeling studies estimated the size of the HIV reservoir to have been approximately 200 latently infected cells prior to the ART interruption. Based on Hill's prior work, a latent HIV reservoir of this size confers only a small (~1%) chance of achieving a lifelong cure, due to the risk of stochastic reactivation of one or more of the latently infected cells.

Henrich and colleagues continue to evaluate enrollees in PrEP projects for evidence of recent HIV infection, and he showed a slide documenting that another individual has been started on ART very early as a result of the effort. Follow up of this second individual is ongoing.

In addition to several sessions and presentations related to HIV cure research at the main conference (see here for a roadmap), IAS hosted a pre-conference HIV Cure & Cancer Forum at the Institut Curie. The abstracts and many of the presentations have already been made available online, and a brief report from the meeting will follow in a separate blog post.

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This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Cure Project.
 

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