Capsules From CROI 2017
March 10, 2017
Another Case of Temporary HIV Remission in a Stem Cell Transplant Recipient
To date, Timothy Ray Brown remains the only individual considered to have been cured of HIV infection, an outcome achieved as a result of a complex series of treatments for a life-threatening cancer that included stem cell transplants from a donor homozygous for the CCR5δ32 mutation (which renders immune cells resistant to most HIV strains). Brown was in attendance at CROI, celebrating reaching a milestone of ten years since those transplants were performed. But it has also been learned -- as a result of the experience of two individuals known as "the Boston patients" -- that HIV-positive people who receive stem cell transplants for cancer treatment can experience dramatic reductions in the HIV reservoir even when the stem cell donors lack the CCR5δ32 mutation. In the case of the Boston patients, this shrinking of the reservoir ultimately allowed for a temporary period of remission after ART interruption; the individuals were able to go for three and eight months without any signs of HIV activity, respectively, before viral load rebounded (Boston patient Gary Steinkohl has since gone public to discuss the experience of participating in this research).
A poster at CROI 2017 from Nathan Cummins at the Mayo Clinic in Rochester reported another case of HIV remission with broad similarities to the Boston patients. The individual received a stem cell transplant from a donor without the CCR5δ32 mutation as part of his treatments for acute lymphoblastic leukemia. By day 56 post-transplant, HIV DNA was no longer detectable in blood and subsequent sampling of large numbers of cells by leukapheresis showed significant declines in measures of the HIV reservoir. An occurrence of graft-versus host disease (GVHD) was associated with apparent elimination of most of the individual's original CD4 T cells, which were present at a frequency of around 1 in 10 cells at day 142 but had diminished to ~13 per every million cells by day 265. HIV-specific antibody responses also waned.
Approval was obtained to interrupt ART on day 784 post-transplant. HIV viral load rebound occurred after a period of remission lasting 288 days (a little over nine months), with levels rising relatively slowly from 60 copies/ml initially to 1640 copies/ml five days later, at which point ART was restarted. No symptoms were associated with the reappearance of viral load, contrasting with the Boston patients who both experienced sharp increases in viral load and symptoms of acute retroviral syndrome at the time they rebounded.
A colleague of Nathan Cummins, Stacey Rizza, presented the poster, and in discussing the case revealed that the individual had the misfortune to experience a car accident shortly before viral load rebounded (without serious injury, thankfully). One speculative possibility under consideration is that inflammation caused by stress might have triggered the activation of a latently infected cell (or cells). Samples were collected throughout follow up and are now being evaluated to try and gain a better understanding of what occurred.
The potential for rare latently infected cells to persist in a dormant state for extended periods despite ART interruption was emphasized in a symposium talk by Louis Picker from the Vaccine & Gene Therapy Institute at Oregon Health Sciences University. Picker's effort to develop a CMV-based vaccine for HIV has attracted considerable publicity due to unprecedented results achieved in the SIV/macaque model: when immunized with a version of the vaccine encoding SIV antigens, half the recipient macaques exert strict control over a pathogenic SIV challenge and appear to eventually clear the infection. Picker outlined two possible explanations for this outcome:
To try and discern which explanation is correct, Picker and colleagues conducted a therapeutic study in which the CMV-based vaccine was administered to SIV-infected macaques on ART (a version of the vector encoding TB antigens served as a control). The timing of ART initiation in the experiment was guided by the detection of monocyte activation after SIV challenge, because previous work suggested this coincided with the initial formation of the viral reservoir. The approach allowed the researchers to divide macaques into various groups depending on how many days after SIV challenge ART was first administered.
After 600 days of treatment, ART was interrupted in all animals. Receipt of the CMV vaccine encoding SIV antigens did not affect viral load rebound, indicating it lacked any therapeutic effect. But Picker highlighted that timing of ART showed a major influence: all six macaques started earliest, on day 4 or 5 post-challenge, did not experience any viral load rebound. Necropsy studies were eventually conducted and only rare traces of SIV genetic material could be detected in tissues. Large volumes of cells sampled from these animals were unable to transmit SIV to uninfected macaques. CD8 T cells were depleted to assess if SIV-specific CD8 T cells were suppressing the virus, but there was no return of viral load, arguing against immunological control.
Out of 35 animals administered ART from day 6 or later, only one (initiated on day 6) displayed a similar lack of rebound. But after eight months, shortly before a planned necropsy, this macaque experienced a rebound in SIV viral load. Picker noted the parallel between this outcome and those observed in the human remission cases of the Mississippi baby and Boston patients.
Picker drew several conclusions from this work:
Picker also mentioned that there does appear to be a case of ultra-early ART leading to temporary remission in an adult human; this is an individual who acquired HIV infection in a short period between screening for a pre-exposure prophylaxis (PrEP) demonstration project and starting on the Truvada PrEP regimen. When HIV was detected in the sample taken on the first day of PrEP administration, ART was immediately substituted for Truvada (this occurred within a matter of days). Hiroyu Hatano from UCSF described the case at CROI in 2014, and cited plans to eventually conduct an ART interruption. Early last year, ART was stopped, and the individual displayed no sign of HIV activity for 220 days before rebound was detected and treatment restarted. A full presentation of the data is expected at the International AIDS Society (IAS) conference in July.
Sex Differences in HIV Persistence
At the IAS conference in 2015, Jonathan Karn reported that the biology of HIV latency is influenced by the estrogen receptor on CD4 T cells, leading to sex differences in the activity of candidate latency-reversing agents (LRA). Specifically, the hormone estradiol significantly inhibited the effect of LRAs in women but not men, whereas drugs that antagonize the estrogen receptor -- including the breast cancer treatments tamoxifen and fulvestrant -- enhanced latency reversal. At CROI 2017, Eileen Scully from Johns Hopkins University presented a poster describing results from a study comparing measures of HIV persistence in carefully matched cohorts of women and men.
Contrary to a previously published retrospective analysis, levels of HIV DNA were not significantly different between the groups. However multiple measures indicated that expression of HIV RNA from the viral reservoir was lower in women compared to men. These included cell-associated HIV RNA and low-level viremia (measured with an assay capable of capturing a single HIV RNA molecule), as well as the ratio between the amount of integrated HIV DNA detected and the ability to induce HIV RNA production from the reservoir (using the TILDA assay). Consistent with the lower HIV expression, markers of T cell activation were also significantly reduced in women compared to men. Scully concluded that biologic sex is an important consideration in cure research, and that the manipulation of sex hormones may have a role to play in efforts to target the HIV reservoir.
Jintanat Ananworanich drew attention to Scully's poster in an excellent plenary overview of the cure research field, and emphasized the need to do more to facilitate increased participation by women.
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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