Antiretroviral therapy has revolutionised the lives of people living with HIV. In many countries, the life expectancy for someone living with the virus is now almost the same as someone who isn’t infected.
But antiretroviral therapy is not a cure. When it is stopped, the virus rebounds within a few weeks in almost all infected individuals – even after many years of suppressive therapy.
So HIV research continues to search for a cure. The focus is on understanding where and how HIV persists on antiretroviral therapy. These insights are then used to develop therapies that will ultimately enable us to cure HIV infection – or allow people living with HIV to safely stop antiretroviral therapy and keep the virus under control.
There has been a substantial increase over the past decade in our understanding of where and how HIV persists when someone is on antiretroviral therapy. It is now clear that integration of the HIV genome into long-lived resting cells is a major barrier to a cure. This state is called HIV latency.
The virus can also persist on antiretroviral therapy in other forms. In both monkey models of HIV and in HIV-infected individuals on antiretroviral therapy, the virus has been found in T follicular helper cells, which are found in a specialised compartment in the lymphoid tissue. These cells are found in a part of the lymph node where penetration of immune fighting cells, or cytotoxic T cells, is limited.
In some tissues, antiretrovirals may not penetrate well. This could also contribute to persistence. Finally, there is also some evidence that, in at least some individuals and some sites, the virus may still be replicating at very low levels.
To date there has been just one case of a cure for HIV. This was in the context of haematopoietic stem cell transplantation for leukaemia with HIV-resistant donor cells. This is clearly not a feasible curative strategy for HIV. But what we have learnt is that the complete eradication of HIV is theoretically possible. Similar approaches have been tried, but no others have yet been successful. All six individuals receiving a similar transplant died of infection or cancer relapse within 12 months of transplantation.
Other case reports have confirmed that haematopoietic stem cell transplantation, even from a regular stem cell donor, can drastically reduce the frequency of infected cells. But when antiretroviral therapy was subsequently discontinued, the virus still rebounded – though it took months and not weeks.
These cases demonstrate that although reducing the frequency of latently infected cells might delay time to viral rebound, there’s a need for continued effective immune surveillance against HIV to keep whatever remains in check.
Using gene therapy to either make a cell resistant to HIV or to literally remove it from the cell is now being actively investigated. The initial target of gene therapy was CCR5. This same gene is missing in some rare individuals who are naturally resistant to HIV.
There have been safe clinical trials of gene therapy that eliminate the CCR5 gene and make other cells resistant to HIV. But a lot of work still needs to be done to increase the numbers of gene-modified cells.
Other work, still at the stage of test-tube experiments, uses gene scissors to target the virus itself. This approach might be trickier than targeting CCR5. This is because the virus can rapidly mutate and change its genetic code so that the gene scissors no longer work.
By starting antiretroviral therapy very early – within days to weeks of infection – it is possible to substantially reduce the number of latently infected cells. This also helps preserve immune function. Although not an option for the majority of HIV-infected individuals who are diagnosed too late, early diagnosis and treatment could be an effective strategy to maintain immune control for some patients.
Several years ago, French investigators described that post-treatment control was possible in up to 15% of individuals treated within months of infection. These data remain a little controversial, as in other cohorts post-treatment control is far less common. We still don’t fully understand what factors are important for post-treatment control, but it seems that the nature of the immune system is critically important.
Interestingly, post-treatment control may differ in different ethnic groups. A recent report from Africa suggests that post-treatment control could occur at far higher frequencies in African populations than in Caucasians.
And the early treatment of infants may potentially shift the virus from hiding in long-lived to short-lived T cells. Understanding the differences in where the virus persists in children and in adults could provide important insights into novel strategies to find a cure for HIV.
‘Shock and kill’
Activating the expression of HIV proteins in latently infected cells by drugs called latency-reversing agents could drive the elimination of virus-expressing cells through immune- or virus-mediated cell death. This approach is usually referred to as “shock and kill”.
A substantial body of research has helped identify latency-reversing agents that have now been tested in experimental clinical trials. These studies demonstrated that although HIV expression can be induced in patients on suppressive antiretroviral therapy, this did not reduce the frequency of infected cells. In other words, shock but no kill.
Ongoing studies are looking at ways to augment the killing of these cells by boosting the immune system, for example through vaccines or medications that trigger suicide of the infected cells.
Prevention and boosting immune responses
Cure research is likely to benefit from the very significant investment in vaccines that have been developed to protect people from getting infected. Some of these could work in a cure too. These vaccines are now being investigated in the setting of clinical trials in infected individuals on antiretrovirals.
There have been spectacular recent advances in the treatment of some cancers using drugs that boost the immune response. These are called immune checkpoint blockers.
These drugs reinvigorate exhausted T cells so they can move into action – against cancer cells and in the same way, against HIV-infected cells. These drugs are now in the clinical trial stage in HIV-infected patients being treated for different cancers.
Another way to boost the immune system is to trigger a very primitive immune response designed to respond to infections. These drugs are called toll-like receptor (TLR) agonists. In monkeys, TLR-7 agonists stimulate latently infected cells and an effective immune response. This leads to a modest reduction in infected cells. Clinical trials are now under way in HIV-infected individuals on antiretrovirals.
Other interventions are needed
A successful strategy is likely to need two components: reducing the amount of virus that persists on antiretroviral treatment and improving long-term immune surveillance to target any residual virus. Far more work must be done on an HIV cure in low-income settings to better understand the effects of different HIV strains, the effects of co-infection and the impact of host genetics.
Lessons from other fields, particularly oncology, transplantation and fundamental immunology are all relevant to inform the next advances needed in cure research. Finally, we have to ensure that any intervention leading to a cure is cost effective and widely available.
The implementation of combination antiretroviral therapy in the mid-1990s is still regarded as one of the most remarkable achievements in modern medicine. Life-long antiretroviral therapy remains the single best option for any person infected with HIV. Finding a cure for HIV remains a major scientific challenge, but many believe it to be within the realm of possibility and it will hopefully play an important role in seeing an end to HIV.
By Sharon Lewin and Thomas Aagaard Rasmussen