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A gutsy talk, and a new paper: report from third workshop on HIV persistence

1 April 2008. Related: Basic science and immunology.

Richard Jefferys, TAG

In December 2007, the third workshop on HIV persistence during therapy took place on the Caribbean island of St. Maarten, where the weather is sunnier than prospects for eradicating HIV infection currently appear to be. [1] The meeting is the brainchild of French researcher Alan Lafeuillade and aims to bring together researchers interested in the topic of curing HIV infection, either by eradication or inducing lifelong control or tolerance of the virus without the need for ongoing drug therapy.

The submitted abstracts ranged widely in both subject matter and quality, with much attention focused on the struggle to accurately assess residual HIV replication in people on long term ART and the best methods for measuring levels of integrated, replication-competent virus in both the blood and body tissues.

One highlight of the meeting was a presentation on the last day by NIH researcher Tae-Wook Chun. Chun has been studying the latent HIV reservoir in people on therapy for over a decade now, and he offered a pithy summation of his views on the subject in a provocative talk entitled “10 questions you might have been afraid to ask at this workshop.” This is a brief summary of his fear-inducing questions, along with his current thoughts as to the answers. Chun’s recent work on HIV persistence in gut CD4 T cells has just been published online by the Journal of Infectious Diseases, along with an accompanying commentary by Steven Yukl and Joseph Wong; abstracts and links are appended below.

Tae-Wook Chun’s 10 questions you might have been afraid to ask at the 3rd Workshop on HIV Persistence During Therapy

1. Does the reservoir of HIV in the body decline on effective antiretroviral therapy (ART)?

Yes. In a cohort of individuals treated early with combination ART, Chun observed that the half-life of HIV-infected cells was 4-6 months. [2] He explained that this observation was restricted to resting memory CD4 T cells, suggesting that this reservoir of HIV could potentially be eradicated after around 7 years of treatment. However, he stressed that this would not necessarily apply to infected cells of other types (e.g. macrophages, stem cells).

2. Is there ongoing viral replication on ART?

Yes. Some researchers think viral replication can be completely shut down by ART, but in Chun’s experience there is always some ongoing low-level replication that can be difficult to detect.

3. Does ongoing HIV replication contribute to the reservoir?

Yes, but activation of CD4 T cells also contributes. He cited a study published by his research group several years ago showing that HIV DNA is detectable in both activated and resting CD4 T cells in people on long term ART. [3]

Chun also noted that the gut contains more activated CD4 T cells than other sites in the body and is therefore a major reservoir of HIV; he has found HIV DNA in activated CD4 T cells from the terminal ileum (see JID cites, below). Chun also showed several images showing the presence of lymphoid aggregates in the gut of HIV-infected individuals on ART and mentioned that these were “a little different from previously published papers” (likely an oblique reference to a notorious single image from the gut of an HIV-infected individual lacking lymphoid tissue, shown by Danny Douek several years ago in support of this theory that gut CD4 T cell depletion is central to HIV pathogenesis). To investigate whether viruses sampled from the gut were different from those found in the blood, Chun compared the genetic sequences and found that they overlapped, meaning that there was no evidence that HIV was somehow compartmentalized in the gut.

4. Is there a specific mechanism for HIV latency in resting CD4 T cells?

Probably not. This topic was addressed by a number of other presentations at the workshop, some of which suggested there may be specific mechanisms HIV uses to make itself quiescent or latent (as opposed to actively replicating). Chun stated that while he admired these presentations, he actually doubted that HIV had evolved such a mechanism. Rather, he believes that viral latency occurs as a byproduct of the physiology of the infected cell; for example, when an HIV-infected activated CD4 T cell returns to a resting state (a normal occurrence when an immune response is ending).

5. Do you think reactivation of the latent reservoir on ART would be sufficient to lead to eradication?

Probably not. At least two studies have investigated activating resting CD4 T cells to try and reduce the HIV reservoir, but the results were disastrous because the treatment (a T cell-depleting antibody called OKT3) led to severe decreases in CD4 T cell counts and illness.

6. Is early ART a good thing?

Yes, in terms of reservoir reduction, but Chun acknowledged the question is not so straightforward from the perspective of an HIV-infected individual or a clinician, because of the potential for drug toxicities and the challenge of long term adherence.

7. Is eradication possible?

Chun stated that five years ago, his answer would have been no. Now he is “cautiously optimistic in a subset of patients.” He has studied some individuals on long term ART who started relatively soon after becoming infected, and in one he can’t find virus anywhere (including the gut), by any technique (RNA or DNA). This individual has not tried stopping ART yet, however. Chun has also compared the proviral burden (amount of integrated HIV DNA) in small groups on long term ART (>7yrs) that started early vs. during chronic infection. The early group averaged 4.6 copies HIV DNA, with 44% of the group having levels of less than 1.5 copies, while the group that started later averaged 949.4 copies of HIV DNA and only 11% showed levels

8. Is intensification a good idea for trying to reduce reservoir?

Yes. He is starting a randomized raltegravir (Isentress) intensification study that will recruit 24 people who have been on ART for over 4 yrs with viral loads less than 50 copies. Twelve will add raltegravir while 12 will receive placebo and the HIV reservoir will be measured regularly during follow-up.

9. Should “mild immunosuppressants” be studied?

Yes. Chun showed a DNA microarray analysis (which measures the activity of different genes) of CD4 T cells from people on long term ART (started in chronic vs. acute infection) and there were more activation and proliferation related genes upregulated in the former group. He suggested that mild immunosuppressants should be studied as part of a multi-pronged attack on HIV reservoirs that could potentially include ART intensification, enhancement of HIV-specific immunity, and drugs which activate HIV transcription in resting cells.

10. Which is more important, the latent HIV reservoir or cells supporting low-level HIV replication?

Equally important. Chun believes both have to be addressed if the aim is to work toward a cure. In response to questions from the audience, Chun said the western blot HIV antibody test was “very faint” in the person he’d mentioned where no virus could be detected. He also described this individual’s CD4/CD8 T cell ratio as “normal.” He hasn’t yet measured immune activation levels in his cohort of individuals treated early in infection, but he described their gene expression profiles as “calm.”

References:

  1. Third International Workshop on HIV Persistence during Therapy, St Maarten, West Indies, December 4-7, 2007
    http://www.informedhorizons.com/persistence2007
    The abstract book s available to be downloaded from:
    http://www.ihlpress.com/gaj_issues_new.html
  2. Chun T-W et al. Decay of the HIV Reservoir in Patients Receiving Antiretroviral Therapy for Extended Periods: Implications for Eradication of Virus. Journal of Infectious Diseases 2007;195:1762–1764.
    http://www.journals.uchicago.edu/doi/abs/10.1086/518250
  3. Chun T-W et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J. Clin. Invest. 115(11): 3250-3255 (2005).
    http://www.jci.org/cgi/content/full/115/11/3250

See also:

Source: TAG Basic Science Web Log (Feb 2008)

Links to other websites are current at date of posting but not maintained.