Additional remission cases published: but eradication needs 10,000-fold reduction in viral reservoir

22 January 2018. Related: Cure-related research.

Richard Jefferys, TAG

Two recent case reports of temporary HIV remission, first presented at the CROI 2017 and IAS 2017 conferences, have been published in the open access journal PLoS Medicine.

Tim Henrich and colleagues from UCSF report on an adult male diagnosed with HIV and started on ART unusually early, due to acquiring the infection during a short window between a screening visit for a pre-exposure prophylaxis (PrEP) demonstration project and the day on which Truvada PrEP was initiated. Truvada was switched to ART with four active drugs (adding darunavir/ritonavir and raltegravir) as soon as the test result confirming the HIV diagnosis became available. The time from infection to PrEP initiation was estimated to be 10 days, and ART was begun seven days later. As first reported by Hiroyu Hatano at CROI in 2014, HIV rapidly became undetectable by multiple assays, including measures of the viral reservoir. [1]

ART was eventually interrupted and the individual did not experience an HIV viral load rebound until 225 days afterwards (at 36 copies/mL, that rose to 59,805 copies/mL six days later). Henrich’s talk at the IAS 2017 conference is available on youtube [2] and was covered on the blog in a report from the meeting. [3]

The new paper adds information on analyses of possible predictors of the viral load rebound, noting that expression of CD30 (a lymphoma tumor marker and member of the tumor necrosis factor super-receptor family) increased on the surface of both CD4 and CD8 T cells months before the HIV viral load rebound occurred. [4]

A similar increase in CD30 expression was observed in one of the Boston patients, who experienced a very similar period of HIV remission resulting from a stem cell transplant procedure for cancer. [5]

As mentioned on the blog previously, Henrich’s research group has a longstanding interest in CD30 as a possible biomarker of the HIV reservoir and is continuing to pursue investigations in this area. [6]

The paper also describes results obtained using a relatively new approach to HIV reservoir measurement, the murine virus outgrowth assay (mVOA). The mVOA involves transferring large numbers of sampled CD4 T cells into multiple immunodeficient mice and monitoring for evidence of the emergence of HIV RNA (the methodology is described in detail in a recent open access review by Kelly A. Metcalf Pate and Joel N. Blankson in the open access journal Retrovirology). [7]

After 18 months on ART (prior to the interruption), approximately 530 million CD4 T cells were sampled from the individual and divided among ten mice. One of the mice displayed a low HIV RNA level of 201 copies/mL in plasma after receiving an anti-CD3 antibody to activate the T cells, around five weeks after the transfer. Efforts to genetically sequence the virus in order to confirm the finding were unsuccessful however.

In discussing the mVOA result, the authors note that it may have represented the only evidence that HIV was still present, and go on to write: “our study suggests that sampling of hundreds of millions of PBMCs may, at times, be more sensitive than tissue-based studies for the detection of residual HIV infection since a much larger number of cells can be interrogated. Further studies comparing mVOAs with traditional ex vivo co-culture assays utilising rigorous positive and negative controls are certainly warranted.”

The researchers also provide information on a second individual diagnosed under similar circumstances – between screening for a PrEP demonstration project and starting Truvada. The timing was slightly later, with HIV infection estimated to have been acquired approximately 12 days before starting Truvada PrEP, and the switch to ART occurring after another 12 days. ART has not been interrupted in this study participant, and HIV RNA was more readily detected in the mVOA, with three of eight mice displaying viral loads of 1,000, 5,000, and 11,000 copies/mL, respectively (from a total of 50 million CD4 T cells transferred into each mouse).

A key takeaway highlighted in the paper is that PrEP programmes represent an opportunity to catch individuals at the very earliest stages of HIV infection and study the impact of rapid ART initiation. The authors recommend that PrEP programs conduct HIV RNA testing before starting PrEP, as well as prior to restarting if there is an interruption, and immediately switch to a full ART regimen if an individual is found to be infected.

The second paper is by Nathan Cummins and colleagues [8] and features a case of temporary HIV remission that was presented as a poster at CROI 2017. [9]

Similar to the Boston patients, the individual in question underwent a stem cell transplant for the treatment of a cancer (acute lymphoblastic leukaemia) and measures of the HIV reservoir subsequently declined to undetectable levels while ART was maintained.

Permission was ultimately obtained to conduct an analytical treatment interruption, which took place at day 784 post-transplant. Viral load remained undetectable for 288 days, at which point a rebound to 60 copies/mL was detected. Five days later the level had risen to 1,640 copies/mL and ART was restarted. Genetic sequencing of the rebounding virus indicated it emerged from a source that was not detected in blood samples prior to transplantation, and the authors write that it “may have originated from sanctuary tissue sites harboring archived viral species seeded during the extensive HIV-1 disease process preceding the patient’s oncologic history.”

The report adds to the evidence that stem cell transplantation can significantly reduce the size of the HIV reservoir, but the researchers note that the estimated decline was approximately 200-fold at most, considerably short of the 10,000-fold reduction that mathematical modelling studies have indicated may be needed to prevent HIV rebound for a lifetime. [10]

Source

Jefferys R. TAG Basics Science Blog (05 December 2017)
http://tagbasicscienceproject.typepad.com

References

1. Hatano H et al. Lack of detectable HIV DNA in a PrEP study participant treated during “hyperacute” HIV infection. CROI 2014. Late-breaker abstract 397 LB.
   http://www.croiconference.org/sites/default/files/abstracts/397LB.pdf (PDF)

2. Henrich TJ et al. Prolonged HIV-1 remission and viral rebound in an individual treated during hyperacute infection IAS 2017. Oral poster TUPDB01. Webcast.
   https://youtu.be/alWXYB4k2sU?t=8m41s

3. Jefferys R. HIV remission news form IAS 2017. TAG Blog. (25 July 2017).
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2017/07/hiv-remission-news-from-ias-2017.html

4. Henrich TJ et al. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study. PLoS Medicine (2017). DOI:10.1371/journal.pmed.1002417. (07 November 2017).
   http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002417

5. Henrich TJ et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319-327. DOI: 10.7326/M14-1027.
   http://annals.org/aim/article-abstract/1889547/antiretroviral-free-hiv-1-remission-viral-rebound-after-allogeneic-stem

6. Jefferys R. 2017 IAS HIV Cure & Cancer Forum. TAG Blog. (29 September 2017).
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2017/09/2017-ias-hiv-cure-cancer-forum.html

7. Metcalf Pate KA et al. The mouse viral outgrowth assay: avatars for the detection of HIV-1 reservoirs. Retrovirology201714:52. DOI: 10.1186/s12977-017-0376-z. (21 November 2017).
   https://retrovirology.biomedcentral.com/articles/10.1186/s12977-017-0376-z

8. Cummins N et al. Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study. PLoS Medicine. DOI: 10.1371/journal.pmed.1002461. (28 November 2017).
   http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002461

9. Cummins N et al. CROI 2017. Webcast.
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2017/03/capsules-from-croi-2017.html

10. Hioll AL et al. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci U S A. 2014; 111(37): 13475–13480 (14 September 2014). doi:  10.1073/pnas.1406663111.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169952