Pathways to an HIV Cure
Antiretroviral therapy suppresses HIV to very low levels, restoring and preserving health in those who have access to it and who take it as prescribed. The medicines do not, however, get rid of the virus, and HIV-infected people need to take these medicines for life. Efforts to eliminate the virus (a “sterilizing” cure) or to control the virus in the absence of ART for long period of time (a “functional cure” or “remission”) are therefore being explored. The principal strategies, which amfAR is helping to advance, can be roughly divided into three categories: pharmacologic, immunologic and cell therapy.
Starting ART during acute HIV infection has been shown to limit seeding of the viral reservoirs and to improve the chance of controlling virus when ART is discontinued. The most famous example of this is probably the HIV-infected baby born in Mississippi in 2010, who was initially believed cured of her HIV when no virus could be found in her body for more than 2 years after stopping treatment that was begun during the peripartum period. A cohort of 20 persons in France, the VISCONTI cohort, who started ART within the first few weeks of HIV infection and stopped treatment an average of eight years ago, have successfully controlled HIV at very low levels and remain free of disease progression. And a cohort of 15 children in Thailand, who were treated an average of 17 weeks after HIV infection and are still on treatment, show levels of HIV DNA even lower than those of the VISCONTI cohort, prompting investigators to explore methods for safely interrupting therapy.
LATENCY REVERSING AGENTS
A class of drugs known collectively as Latency Reversing Agents (LRAs) is being tested to see if they can waken dormant virus from its hiding places in cells, rendering it recognizable to the immune system and vulnerable to antiretroviral drugs or to targeted cytotoxic therapies: the “kick and kill” strategy. The lead candidate groups in the LRA class are histone deacetylase (“HDAC”) inhibitors and protein kinase activators.
LATENCY SECURING AGENTS
An opposite “lockdown” approach is also being explored by several research teams where HIV-infected cells would be induced into a permanent sleep state by, among other methods*, interfering with a viral gene called tat that is responsible for transactivation and transcription of the HIV viral genome.
The very earliest experiments with immune-based therapies for the treatment of HIV infection were on interferons and interleukins—immune system proteins (alpha interferon having antiviral properties itself) that help to orchestrate the immune response. No quantifiable benefit was found for the interferons studied to date, but both interleukin-2 and interleukin-7 were shown to increase CD4+ T-cell numbers.
Passive immunotherapy was also experimented with as an HIV therapy early on, based on the observation that broadly neutralizing HIV-specific antibodies (bNAbs) were gradually lost as asymptomatic HIV infection progressed to AIDS. While the early, crude attempts to do this failed, newer approaches offer hope that, whether used alone or in combination with other therapies, bNAbs may be able to control HIV in the absence of ART.
An additional and innovative approach at antibody therapy entails the development of a two-tailed “bi-specific” immunoglobulin that specifically links CD3+ immune cells to the HIV envelope protein, mediating the destruction of cells that harbor HIV.
Immune-boosting therapies employing different parts (or synthetic analogues) of the HIV virus have been studied as both preventive and therapeutic vaccines. The goal of the use of such vaccines “therapeutically” in persons already infected with HIV is to induce new HIV-specific immune responses once the virus has been successfully suppressed. While some studies demonstrated an ability to induce HIV-specific CD4 and CD8 T-cell responses, they never quite translated into a measurable health benefit. The key question for therapeutic vaccination research going forward—and quite possibly a linchpin for many cure research protocols—is whether future vaccine candidates can generate HIV-specific immune responses capable of controlling HIV replication in the absence of ART.
Researchers have also experimented with strategically interrupting antiretroviral therapy as a way to boost immunity (by exposing the immune system to uncontrolled virus) after reconstitution during a period of sustained suppression of virus. Under the most favorable conditions, however, even a reconstituted immune system was unable to control virus in the absence of ART.
HIV-specific poisons would specifically target and destroy HIV-expressing cells while leaving other cells unharmed. Their efficacy, however, would require active virus transcription. For this reason, they would probably be combined with latency reversing agents, likely as part of a “kick and kill” strategy.
CELL THERAPY APPROACHES
The apparent cure of an HIV-infected man in Berlin and two cases of HIV remission in Boston after bone marrow transplants has led research teams around the world to hunt for additional such cases. While the Berlin patient received stem cells from a donor with a rare genetic mutation (CCR5 delta 32) rendering his immune cells resistant to HIV infection, the donor cells in the case of the two Boston patients did not have this mutation. Identification and study of additional HIV-infected patients undergoing bone marrow transplants are expected to help scientists understand whether the ablative procedure or graft-versus-host effects themselves contributed to the Berlin patient cure.
Discovery of the CCR5 delta 32 mutation that confers resistance to HIV spurred efforts to genetically engineer HIV-resistant cells by silencing the CCR5 gene. These bioengineered immune cells would then be re-infused, or transplanted, into the body, creating an entire immune system invulnerable to HIV. Additional gene therapy approaches include the use of different enzymes to achieve modification of the genetic material, and targeting other genes for deletion and/or insertion.
* Other “Latency Securing” approaches include the short hairpin “interfering” RNA (aka RNAi or shRNA) experiments (mostly in Japan and Korea) as well as the mTOR pathway inhibitors of Eric Verdin.