Researchers in the field of HIV have made impressive advances in the development of effective, life-saving antiretroviral therapy (ART). Nevertheless, HIV infection remains an incurable, chronic disease that requires expensive, lifelong treatment. In addition, while current therapies are highly effective, drug side effects, adherence requirements, and the risk of resistance present challenges to the long-term management of HIV. Given these realities, and inspired by recent scientific and clinical advances, research into the development of an effective, affordable cure has taken on a new urgency.

The search for a cure for HIV infection was reinvigorated following a few widely reported individual cases that have pointed to the potential for a cure. In 2007, an HIV-infected man, Timothy Brown (also known as the “Berlin patient”), was treated for leukemia with a transplant of hematopoietic stem cells from a donor with an uncommon genetic mutation that confers resistance to HIV infection. Following his treatment for leukemia, clinicians have been unable to find evidence of HIV infection in his blood or other potential reservoirs, and he remains free of the virus and doesn’t need antiretroviral therapy. More recently, in another widely reported case, an infant born to an HIV-infected mother, and shown to be infected with HIV at birth, appears to have been functionally cured following 18 months of ART initiated immediately following delivery.

Despite the optimism that followed the initial presentation of both of these cases, researchers have acknowledged that the specific circumstances of each case suggest that replicating their results may not be possible on a broader scale. Similarly, the early optimism that greeted the cases of 2 other HIV-infected individuals who developed Hodgkin lymphoma, and who, like Mr. Brown, were treated with bone marrow transplantation, has been short-lived. In both patients, HIV eventually reappeared within months of ART discontinuation. However, the lessons learned from all of these cases are informing new directions in cure research.

Building on these and other advances, in 2012, the International AIDS Society (IAS) Scientific Working Group on HIV Cure issued an ambitious list of priorities for HIV cure research and a call for greater collaboration among researchers. These priorities include5:

  Cellular and viral mechanisms that allow HIV to persist
  Tissue and cellular sources of persistent SIV/HIV in animal models and long-term ART-treated individuals
  Immune activation and dysfunction in the presence of ART
  Natural models of SIV/HIV control
  Assays to measure persistent infection
  Therapeutic and immunological approaches for eliminating persistent HIV infection
  Enhancement of immune response to control viral replication

In December 2013, the National Institutes of Health announced plans to increase funding toward a cure for HIV, investing an additional $100 million over the next 3 years. “Our growing understanding of the cellular hiding places or ‘reservoirs’ of HIV, the development of new strategies to minimize or deplete these reservoirs, and encouraging reports of a small number of patients who have little or no evidence of virus despite having halted antiretroviral therapy all suggest that the time is ripe to pursue HIV cure research with vigor,” explained Anthony S. Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases.

The search for a cure for HIV infection has been a subject of clinical study and basic scientific research since the arrival of combination therapy that could halt the replication of the virus and prevent many of the complications of uncontrolled HIV infection. Yet HIV is able to elude even the most potent antiretroviral agents available today by integrating its DNA into the genomes of certain long-lived immune cells called memory CD4 T cells, allowing it to remain hidden in a latent state, protected from clearance by the immune system. Thus, a focus of current cure research is on finding those hidden reservoirs and identifying therapies that can reverse the latency and clear infected cells. In addition, much work is being done to develop the highly sensitive assays necessary to accurately measure HIV reservoirs in the body.

In terms of pharmacologic agents for use in curative strategies, several groups have been studying histone deacetylase (HDAC) inhibitors, which may activate latent reservoirs of the virus, making it possible to kill it with potent antiretroviral drugs. The most widely studied such agent is vorinostat, a compound that’s approved for the treatment of cutaneous T-cell lymphoma. Vorinostat has been shown both in vitro and in vivo to have effects on stimulating latently infected CD4 T cells; however, a recent study in 20 patients found that vorinostat failed to stimulate any change in HIV DNA, suggesting that additional strategies will be needed to eliminate latently infected cells.

Recent work by researchers at Johns Hopkins suggests that the latent reservoir in as many as half of HIV-infected patients may be up to 60-fold larger than previously thought, highlighting the challenge faced by HIV cure strategies aimed at purging the latent reservoir. More accurate measures of the latent reservoir are needed so that complete eradication of the virus can be confirmed before ART can be safely discontinued.

In addition to eradication strategies, early intervention with potent ART during acute HIV infection may be able to reduce the size of the latent reservoir by preventing the seeding of viral reservoirs in long-lived memory CD4 T cells. A study looking at the potential benefits of early intervention with ART during acute HIV infection in 68 patients found that after 48 weeks of ART, integrated HIV DNA was reduced substantially in all subjects, with no detectable HIV DNA in memory CD4 T cells in the group receiving the earliest treatment with ART. This suggests that early ART may prevent the seeding of latent HIV reservoirs in long-lived central memory CD4+ T cells.

Building on the knowledge gained through years of developing optimal treatments for HIV infection, along with recent advances in the understanding of the persistence of HIV reservoirs, researchers are continuing to advance the search for potential strategies that might lead to a cure for HIV. However, there are still many unanswered questions, and this is likely to be a long-term project. The unfulfilled promise of vaccine research may have a parallel in research for an HIV cure.

Published: 03/03/2014