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Towards an HIV Cure: Early Developments in the Field

By Muirgen Stack

July/August 2012

After the announcement of the IAS Towards an HIV Cure scientific strategy at this third IAS pre-conference symposium, held this year from 20-21 July, any advances in the field of cure research will come under a new emphasis.

This strategy outlines the important areas of research where advances needed to be made if a cure (functional or sterilising) is to be realised.1 Fortunately, some promising cure-related research was presented at AIDS 2012 and this will become a trend that hopefully continues and is expanded upon at further meetings.


Latency, Persistence and Locating the Hiding Virus

The mechanisms underlying viral latency are complex and not fully understood. Despite the success of ART, replication competent yet transcriptionally silent HIV-1 provirus goes unnoticed by the immune system.2 Before new treatments can target the latent reservoirs, the biology underlying persistence needs to be better understood.

Lina Josefsson from the Karolinska institute in Sweden presented results on quantifying which sub types of CD4+ T cells were infected by persistent HIV-1. All patients were on long-term suppressive ART but had either started during acute or chronic infection.3

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Memory and naive CD4 T cells in the peripheral blood (PB) were infected 13 and 24 fold times higher respectively, in patients treated during chronic compared to acute infection. Another reservoir of latent HIV is the gut-associated lymphoid tissue (GALT). For patients that started treatment during chronic infection, their effector memory T cells were 6 fold more likely to be infected.

Together, these results suggest that early initiation of therapy reduces the viral reservoir size in the blood and the gut. Although the number of participants in the study was low (n=8), it highlights the importance of the heterogeneity in both how much virus persists and where it resides. Additional research focusing on other plausible reservoirs sites including the central nervous system and kidney (and ideally with patients from different drug regimen backgrounds) is now needed.4,5

Another group led by Charline Bacchus of the Pierre and Marie Curie University further investigated reservoir distribution in patients spontaneously controlling HIV infection after treatment interruption.6

The VISCONTI cohort (Virological and Immunological Studies in CONtrollers after Treatment Interruption) enrolled 12 patients who had controlled HIV for a median of 76 months (IQR 67.5-84.5) after interruption of a 3 year (range 1.7-5.9) HAART, initiated within 10 weeks of infection. This group was compared to 8 untreated elite controllers (spontaneously suppressing HIV infection without treatment: 90% with viral load below 200 copies/mL) over 12 (range of 9-14) years. A similar profile of reservoir distribution was seen in both groups, but with differences. In the VISCONTI group, activated CD4 T cells had significantly higher HIV-DNA levels than resting ones, median 2.7 log copies/million cells (range: 2.4-3.4) compared to 2.0 (range: 1.8-2.5), p=0.005. HIV-DNA was detected in all CD4 T cell subsets except for 8/12 treatment-naive patients (TN) CD4+ T cells which were 10 fold less infected than all memory subsets; TN: median 1.5, central-memory (TCM): 2.5, transitional-memory (TTM): 2.6 and effector-memory (TEM): 2.4 log copies/million cells, p<0.0007. Whereas in the VISCONTI group, 56% of the reservoir was made up of TTM cells, elite controllers had a more even mix of TCM and TTM cells contributing to their HIV reservoir.

Although the reservoir phenotype of the VISCONTI group is similar to the elite controllers, the fact that they are not identical and yet both groups successfully control the virus is encouraging, and it will hopefully allow for researchers to identify a more general CD4 T cell profile that manages the viral reservoir without ART.

A poster from Maria Jose Buzón from the Ragon Institute in Massachusetts and colleagues showed results from a study looking at the characteristics of a cohort of patients who started treatment early during infection and remained on suppressive HAART for >10 years.7

Eight early treated (ET) patients who initiated ART within 90 days of seroconversion were compared to 10 chronic treated (CT) and 37 Elite Controllers (EC). All patients had undetectable viraemia for >10 years. They reported that those from the ET group had significantly lower levels of HIV-1 specific T and B cell responses and lower levels of integrated, total HIV-1 DNA and 2-LTR circles when compared to the CT and EC groups. Both gene expression patterns and miRNA expression profiles were more similar between ET and EC than those of CT. Also, EC and ET had comparable viral reactivation levels, whereas significantly more replication-competent virus was retrieved from CT. The authors concluded, "Prolonged therapy with HAART initiated early during acute infection induces an HIV-1 disease status that in many aspects is reminiscent of the elite controller phenotype."

While these results are supportive of the effectiveness of ART and its early initiation being potentially enough to fully control infection, people identified so early in infection are clearly a small and special sub group. Moreover, as more novel therapeutic approaches are being developed8-12 and a functional cure being advanced, this will need to overcome now relatively clear physiological disparities between people treatment in chronic early treated infection.


References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th International AIDS conference 22-27 July 2012, Washington.

  1. International AIDS Society (IAS). Towards and HIV Cure: Global Scientific Strategy. July 2012.
  2. Finzi D et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278. 1295-1300 (1997).
  3. Josefsson L et al. Characterization of persistent HIV-1 in broad spectrum CD4+ T cells isolated from peripheral blood and gut associated lymphoid tissue from patients on long-term suppressive therapy. Oral abstract THAA0105.
  4. Gray L et al. Unique regulatory mechanisms of CNS-derived HIV-1 LTRs associated with latency. Oral abstract TUAA0201.
  5. Fierer DS & Klotman ME. Kidney and central nervous system as reservoirs of HIV infection. Current Opinion HIV AIDS 1(2): 115-20. March 2006.
  6. Bacchus C et al. Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption. Oral abstract THAA0103.
  7. Buzon MJ et al. Approaching an elite controller status through early initiation of antiretroviral therapy. Poster abstract THPE003.
  8. Garrido C et al. Gold nanoparticles to improve drug delivery to the central nervous system: targeting HIV reservoirs in the brain. Poster abstract THPPE014.
  9. Hofmann-Sieber H et al. Towards HIV eradication: eradication of HIV-1 proviral DNA by Tre-recombinase in HIV-positive humanized mice. Oral abstract TUAA0302.
  10. Henrich T.J. et al. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals. Oral abstract THAA0101.
  11. Kitchen S et al. In vivo suppression of HIV antigen specific T cells derived from engineered hematopoietic stem cells. Oral abstract TUAA0303.
  12. Trautmann L. Novel approaches: treatment and HIV pathogenesis. Immunopathogenesis and its treatment. Symposia Session. 23 July 2012, 2.30-4.00pm, Washington.
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