At the 2014 International AIDS Conference in Melbourne Francoise Barre Sinoussi, President of the International AIDS Society (IAS) in her presentation ‘Towards an HIV Cure‘ spoke about the IAS HIV cure consortium initiative implemented in 2011 to promote and accelerate research towards a cure. The initiative advocates for increased investment and the provision of clear and accurate information to the broader community on the topic of cure. The scientific research on progress and the limitations were also discussed by a number of leading scientist and researchers.
The science behind developing an HIV cure is complex, but the diversity of current research approaches (exploring the science) is exciting as it moves towards finding a cure. The following is brief summary of current research, some of which may result in remission of HIV (needing only periodic or intermittent therapy) although a permanent cure (needing no further therapy or treatment) is the goal. These have otherwise been known as a functional cure or sterilising cure respectively.
1) Presently there is no type of either cure for HIV, with one exception – Timothy Brown – permanently cured by receiving stem cell transplant for leukaemia without the HIV co-receptor surface molecule (called the Delta 32 mutation of the CCR5 receptor molecule that HIV uses to gain entry into the human host cell). This striking case has led to two (2) proposed studies – suitable only suitable to HIV-positive people that require such for cancer – which are difficult studies to conduct by identifying stem cell donors with this CCR5 mutation. One study is proposed in adults (IMPACT P1107) the other in children (BMT CTN 0903). The other approach is to modify stem cells in other gene sequences, and studies are underway in that regard as well among HIV-positive people with lymphomas.
2) The “Kick and Kill” approach – This method is of great interest to cure eradication. It seeks to find way to ‘kick’ the virus from its hiding place (viral reservoirs) then ‘kill’ virus once it is circulating in the bloodstream (where HIV drugs work to disable the virus from replicating). Latently infected resting memory T cells have been identified as target cells in this approach in order purge them of residual virus by switching on the cytotoxic T cell (CTL) responses. The drug agents under current research in the attempt to reverse latency are called “HDAC Inhibitors” (e.g. romidepsin, vorinostat), among other candidates (e.g. Poly-ICLC, disulfiram).
3) Long Term Non-Progressors (LTNPs) and Elite Controllers – research on viral and host immunity continues among this minority group of people that don’t require HIV treatment in the presence of their low level virus replication. A number of mechanisms have been proposed for this observation. These people give birth to the idea of remission (or host control) of HIV, although there is often a time when then they may require HIV treatment although that time is long delayed usually. A similar response (although more likely a treatment response) was seen in the recent case of the “Mississippi Baby” who was treated immediately at birth until 18 months of age, then a long 27 months without treatment was initially thought to be cured until virus did re-emerge although it did so much later than is normally observed (2-4 weeks) when stopping treatment. Delayed viral re-emergence also occurred recently in two (2) patients in Boston, who also had received stem cell transplants but without the co-receptor deletion. A study is underway in the US using standard antiretroviral HIV treatment among HIV Controllers (who normally don’t need treatment) so it seems to see if their immune activation (fighting off HIV) may vary to others and how rapidly HIV virus is eliminated from their blood. Treatment intensification (with additional drugs) and early treatment studies (before CD4 count decline) are also underway among other people, including babies in the possible pursuit of remission – or the very least to lesson HIV impact and improve future outcomes. One of these may be if there is less virus in reservoir sites, then a future cure might be easier to achieve (although that is yet to be proven).
4) Broadly Neutralising Monoclonal Antibodies – This approach has been enlivened by the development a mouse model with a said “human immune system” and in SIV-infected monkeys. These agents boost the antibody response – recognition by the immune system to kill infected cells. 3BCN117 and VCR 01 are two such studies. BMS 936559 takes the approach of blocking immune cell signals (called PD1-L1) and while early results (in monkeys) show that it slows virus replication, its safety is under question.
5) Therapeutic Vaccines – This concept for cure is one of sending the virus into remission or if sterilisation also occurs then these vaccine candidates may also have preventative value. A number of candidate vaccines are under phase II study in this cure approach (e.g. TAT Protein Vaccine. GSK 732462, VAC-3S) including a number of dendritic cell vaccines (e.g. DermaVir, AGS-004,DVC-2).
6) Gene Therapies – This approach seeks to harvest and modify the host’s own cells and return them to the body in an altered or disabled form that blocks HIV replication. SB-728-T is one such agent under investigation, by modifying the CCR5 genes taken from HIV-positive people and reinfuse them back into the body hopefully giving HIV nowhere to hook onto (unable to enter human cells devoid of the receptor).
7) Immune Based Therapies – These too are in early trail development and are intended to bolster immune capabilities that target HIV for eradication. Various cytokines and anti-inflammatory drugs are under study, as well as vitamins, probiotics and Chinese Herbs (although history shows natural agents may be considered as a complementary adjunct to more potent drug therapies, and may provide only weak benefit and certainly not control least of all assist in eradicating HIV).
8) Combination Approaches – There may need to be multiple concurrent methods employed at the same time to enact a cure. Thus, some of the methods suggested above are under combined study (e.g. romidepsin + Vacc 4X; SB728T + a chemotherapy drug).
Before HIV can be eradicated through one of these means – or perhaps another means yet to be discovered – several obstacles need to be unveiled in this current research, with great hope that they will pave the way to further advances in cure. The keys to better understanding the nature of the persistence of virus include:
1) how the viral reservoir is established and maintained.
2) what various body tissues and organs do in facilitating HIV to reproduce or persist (e.g. the gut, lymph, brain).
3) the origins and mechanisms of viral rebound when HIV treatment is stopped.
4) the effect of the immune activation upon HIV and development of immune therapies to co-assist viral eradication therapies.
5) Developing new tests to measure the outcomes of cure agents.
6) Last, but not least, the experience and willingness of HIV-positive people to participate in highly experimental research that could also inadvertently cause unforseen harm.