August 13, 2012
At the recent 19th International AIDS Conference in Washington DC (AIDS 2012), the research effort to develop a cure for HIV infection attained a higher profile than it ever has in the past. A confluence of factors contributed: the International AIDS Society (IAS) officially launched their Global Strategy "Towards an HIV Cure," in conjunction with a two-day symposium that immediately preceded the main conference. The IAS effort involves a multiplicity of stakeholders -- including TAG -- and a global consultative process that has spanned the two years since the first workshop on the topic in Vienna in 2010. In addition to the extensive press coverage of the IAS-led effort, the one individual considered cured of HIV, Timothy Brown, was in DC and gave a number of interviews.
Details on the IAS Global Strategy "Towards an HIV Cure" are available free online in a document titled Full Recommendations, 1st Edition July 2012. A shorter summary and commentary have been published in Nature Reviews Immunology and Nature, respectively, but unfortunately both reside behind the journal paywalls. In essence the strategy is a scientific review of the obstacles to curing HIV (as they are currently perceived) and possible strategies for overcoming them. Among the goals of the effort is to enhance collaboration between stakeholders and attract new sources of funding to support cure research.
Presentations from the IAS symposium, which was held on July 20 & 21, are due to be placed online soon. Because abstracts were selected from submissions to AIDS 2012, many of the studies discussed at the event were subsequently presented at the conference and can already be viewed online (links to relevant sessions and information on the formats available are appended below).
Among the most publicized data presented at the IAS symposium related to a French cohort (dubbed the VISCONTI cohort) comprising 14 individuals treated within 10 weeks of infection who, after an average of around three years on ART, interrupted treatment and have subsequently maintained control of viral load to less than 50 copies/mL for an extended period (a median of 6.6 years, range 4-9.5 years). This study was the focus of an overview talk by Asier Saéz-Cirión and an abstract presentation by his colleague Christine Bacchus (the latter was repeated at AIDS 2012 and a webcast was briefly available, regrettably it now seems to have been removed). Preliminary results have been published and presented before: in a letter to the journal AIDS in 2010, five cohort members controlling viral load off ART for a median 6.25 years -- designated post-treatment controllers (PTC) -- were described (out of a total of 32). At CROI in 2011, a poster presentation reported that the number of PTC had increased to 10 (median duration of control: 6 years) and, notably, five of these individuals were also showing a diminution of HIV reservoirs over time (as measured by HIV DNA levels).
Asier Saéz-Cirión updated these results with the information that a total of 14 PTC have now been identified. The number of individuals experiencing declines in HIV DNA levels has dropped from five to four since the CROI report. Saéz-Cirión highlighted a number of unusual features of this cohort that sets them apart from elite controllers. Most importantly, they lack the favorable HLA genes that are consistently associated with elite control, HLA B*57 and B*27. Instead, around half the PTC possess HLA B*35, which in untreated HIV infection is associated with a significantly increased risk of rapid disease progression. In addition, HIV-specific CD8 T cell responses are of lower magnitude than those typically seen in elite controllers, and levels of immune activation and HIV DNA are also low. Data on HIV-specific CD4 T cell responses is not yet available.
Saéz-Cirión attempted to assess how frequently the PTC phenomenon occurs after primary infection treatment. In a preliminary look at the French Hospital Database, 756 individuals were identified who started ART within 6 months of infection, and continued for at least a year. A subset of 74 eventually interrupted ART and, of these, 15.7% maintained undetectable viral load for a minimum of two years. Saéz-Cirión also cited a study by Cécile Goujard and colleagues that was published shortly after the meeting in the journal Antiviral Therapy; in this case, out of 164 participants, 8.5% maintained viral loads below detection for two years after interruption, and 7.2% at three years. In contrast, Saéz-Cirión noted that an analysis of 34,317 HIV-positive individuals in France only identified 81 elite controllers, putting the estimated proportion of individuals likely to attain control of viral load in the absence of any ART at around 0.24%.
The duration of viral load control in the VISCONTI cohort clearly makes them unusual, and they are understandably receiving attention as a possible model of a "functional cure" in which HIV is suppressed without treatment rather than eradicated. But there are many unanswered questions and apparent contradictions with other studies that need to be addressed and resolved. Saéz-Cirión noted that all but one of the 14 individuals had symptomatic primary infection, high viral loads and low CD4 counts at the time of initiating ART -- as he put it, their primary infection appeared "tougher" than is typical. Yet in the Goujard study he cited, the factors associated with becoming a PTC were opposite: high CD4 counts and low viral loads (in addition to female sex). An independent analysis of the frequency of PTC -- which the authors acknowledge was prompted by the VISCONTI data -- was published online in the Archives of Internal Medicine on July 23. A total of 259 individuals from the multi-country CASCADE cohort were identified who received ART within three months of infection. The probability of maintaining PTC status 24 months after ART interruption in this analysis was 5.5%, and the characteristics of these 11 individuals did not differ from the overall study population. Saéz-Cirión was questioned at the symposium regarding levels of inflammatory biomarkers and any clinical events in the VISCONTI cohort PTC; he responded that these analyses are ongoing and not yet complete. In terms of CD4 counts Saéz-Cirión stated that only one of the 14 is showing a decline over time. The reason for the apparent over-representation of HLA B*35 is as yet unclear, when quizzed on the issue Saéz-Cirión suggested that possession of this allele may have explained the high prevalence of symptoms in the cohort which, in turn, prompted them to start ART early. However, published studies do not appear to have found an association between HLA B*35 and primary infection symptoms. Further complicating the question is the fact that there are HLA B*35 subsets named Px and Py, and only people possessing HLA B*35 Px have been reported to experience rapid HIV disease progression: the distribution of Px vs. Py in the VISCONTI cohort PTC is not yet known.
Bob Siliciano presented data at the symposium suggesting that the amount of replication-competent HIV DNA in people on ART has been underestimated. The most commonly cited figure is that only around one out of every 100 latently infected resting CD4 T cells harbors replication-competent virus (the reason for the difference being that the majority of the viral DNA is mutated in ways that render it non-functional). Siliciano looked at 179 samples of CD4 T cells containing latent HIV that could not be induced to replicate by PHA stimulation. He found that while the majority of the HIV DNA proviruses were indeed defective (due to deletions, lethal hypermutation and other alterations), an average of 16.8% (range 6-36%) were fully intact. Siliciano's laboratory has cloned these intact sequences and confirmed that the viruses are able to replicate. The results imply that the size of the replication-competent HIV reservoir in people on ART may be 50-fold larger than previously thought. However, among the questions that remain to be answered are whether these viruses can be induced to replicate in vivo, and if approaches other than PHA stimulation might be able to coax them out of hiding.
As covered previously on the blog, the laboratory of Fabio Romerio at the Institute for Human Virology in Baltimore has developed an in vitro model of latent HIV infection that attempts to closely mimic the in vivo situation using primary CD4 T cells (as opposed to immortalized cell lines). In a presentation at the symposium, Romerio described the use of this model to identify cell surface markers that may be preferentially expressed by latently infected cells. The lead candidate that emerged from this work is CD2, which was expressed at higher levels on infected vs. uninfected CD4 T cells. Romerio is collaborating with Nicolas Chomont from the Vaccine & Gene Therapy Institute in Florida to investigate whether these results are also reflected in vivo: a preliminary study involving six individuals on long-term ART found that, in all cases, HIV DNA was more commonly present in CD4 T cells expressing high levels of CD2. Romerio also presented this work at AIDS 2012 and the webcast is available online.
One of the challenges for anyone attempting to follow the immunology literature is the ever-expanding panoply of cell subsets that are being described. The most recent addition to the T cell family is the T memory stem cell or TSCM for short. According to a study published in Nature Medicine last year, TSCM represent the least differentiated form of memory T cells; they are said to have stem cell-like properties because they can proliferate extensively and give rise to the many more specialized types of memory T cell that exist (central memory cells, transitional memory cells, effector memory cells and effector cells). María José Buzón from the Ragon Institute of MGH, MIT and Harvard gave a presentation at the symposium on the contribution of TSCM to the HIV reservoir in individuals on ART and elite controllers. Buzón showed that while TSCM only make up a small proportion of circulating T cells (0.5-1%), HIV DNA could be detected in TSCM and they accounted for around 17% of the total detectable reservoir. The number of latently infected TSCM appeared stable and Buzón's preliminary data hinted that their relative contribution to the HIV reservoir might increase over time in individuals on ART.
Timothy Henrich from Brigham and Women's Hospital and Harvard Medical School presented two case reports relating to individuals with HIV who had undergone allogeneic stem cell transplantation for the treatment of cancer. Replication competent HIV cannot be detected in either individual but both remain on ART so it is unclear if they are cured. Unlike Timothy Brown, who received a stem cell transplant from a donor homozygous for the CCR5delta32 mutation, transplants in both these cases came from individuals with normal CCR5 expression. Further study may thus help reveal whether the CCR5delta32 mutation was necessary for achieving a cure in Brown, or whether the transplant itself and associated factors -- such as graft-versus host disease, where the new immune system that develops from the transplant attacks the older host cells -- can be sufficient. Henrich's talk at AIDS 2012 is available as a webcast and the slides can be downloaded.
MOLBA Late Breaker Track A (Powerpoints, Webcasts)
TUPL01 Challenges and Solutions (Powerpoints, Webcasts)
TUAA02 Mechanism of HIV Latency (Powerpoints, Webcasts)
TUAA03 Novel Drugs and Treatment Strategies (Powerpoints, Webcasts)
WEAX01 The Future of Genomics in HIV Medicine (Powerpoints, Webcasts)
THSY03 HIV Persistence and Eradication (Powerpoint, Webcasts)
THAA01 HIV Reservoirs: Where and How is the Virus Hiding? (Powerpoints, Webcasts)
MOSY06 Immunopathogenesis and its Treatment (Powerpoints, Webcasts)
MOAA02 Immune Function and Dysfunction (Powerpoints)
WEAA02 HIV/SIV Pathogenesis (Powerpoints, Webcasts)
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.