Allogeneic Stem Cell Transplant Leads to “Functional Cure” of HIV
Immunovative has conducted a feasibility study in an HIV+ patient to determine if AlloStim could elicit the Mirror EffectTM in the patient resulting in control of the virus without the use of anti-viral medication. As of December 1, 2015, this patient has been on holiday from his daily Highly Active Anti-Retroviral Treatment (HAART) for over 7 months. Over this time, his CD4 counts have remained over the peak levels exhibited prior to AlloStim therapy. While he still has detectable viral load, the maintenance of the CD4 counts without anti-viral drugs is a significant milestone toward a “functional cure”.
HIV hides within CD4 T-cells as genetic material. When the CD4 T-cells are activated they unwittingly begin to manufacture HIV particles. These particles then are shed into the circulation which causes the host CD4 T-cell to perish. The circulating virus then attaches to other CD4 cells through the CD4 receptor and enter the cells. The newly infected cells form a latent viral pool. Upon activation of a latently infected cell, the cycle begins again. Eventually, this cycle leads to increasing viral load and decreasing CD4 counts.
CD4 cells are critical for maintenance of normal immune function. Loss of CD4 cells leads to AIDS (Acquired Immune Deficiency Syndrome). AIDS is a lethal condition. In order to prevent and treat HIV infection, researchers have tried to develop prophylactic and therapeutic vaccines. These attempts of harnessing the immune system in HIV infection have been major disappointments.
The ability of HIV to hide within CD4 cells as genetic material is part of the reason it has been so difficult to use immunotherapy methods to clear the virus. The immune system is unable to identify genetic material inside of normal cells. These latently-infected CD4 cells form the so-called “viral reservoir”. Clearing this viral reservoir poses what seems to be an insurmountable challenge to HIV cure strategies.
Shock and Kill for Cure
One approach of HIV cure research is called the “shock and kill” approach. This approach seeks drug candidate which are able to “shock” the reactivation of virus-infected cells from the viral reservoir. This shock would then cause the activated CD4 cells to begin to manufacture virus. Cells producing virus become noticeable by the immune system. If there is pre-existing immunity to the virus, the immune system can then kill the reactivated cells. However, not all HIV patients have pre-existing immunity to the virus. Thus an effective “shock” therapy will most likely need to be accompanied by a vaccination strategy to elicit anti-HIV immunity.
However, vaccination against HIV has proven difficult. As with cancer cells, HIV has evolved similar mechanisms to evade immune attack. These include production of immunosuppressive cytokines (e.g., IL-10) and deviation of the immune response to the virus from an effective Th1 cellular response to an ineffective Th2 response. Thus a vaccine not only must elicit an effective anti-viral immune response, this response must be imprinted and dominate over a failed response while overcoming the immunosuppressive and immunoavoidance mechanisms mediated by the virus.
These technical tasks are overwhelmingly difficult to overcome. This is part of the reason why we currently are not close to a cure for HIV infection.
Hope Emerges for Cure
A HIV patient named Timothy Ray Brown a/k/a “the Berlin Patient” (originally from Seattle), has reinvigorated the hope and interest in HIV cure research. He was diagnosed with HIV in 1995 and began antiretroviral therapy (HAART). In 2006, Timothy was diagnosed with acute myeloid leukemia (AML). His physician, Dr. Gero Hütter, at Charité Hospital in Berlin, arranged for him to receive a hematopoietic stem cell transplant from a donor with the "delta 32" mutation on the CCR5 receptor. This mutation, found in 16% of Northern Europeans, results in a mutated CCR5 protein. The majority of HIV cannot enter a human cell without a functional CCR5 gene. An exception to this is a small minority of viruses that use alternative receptors, such as CXCR4 or CCR2. Those individuals who are homozygous for the CCR5 mutation are resistant to HIV and rarely progress to AIDS. Timothy received two stem cell transplants from one donor homozygous for the delta32 mutation: one in 2007 and one in 2008. Timothy stopped taking his HAART medication on the day of his first transplant. Three months after the first stem cell transplant, levels of HIV rapidly plummeted to undetectable levels while his CD4 T cell count increased. In addition, blood and tissue samples from areas of the body where HIV is known to hide were tested. The results were published in the New England Journal of Medicine. At the time remained off HAART therapy for 5 years and was considered cured.
However, in 2012 HIV was detected again in Timothy’s blood and lymphoid cells. Interestingly, the genotype of the rebounding virus was different than the original virus present prior to the stem cell transplant. One possibility for this finding was that he was re-infected with a new virus, a possibility vehemently denied by the patient. The other explanation is that new viral pools of previously latent virus was released into the circulation. Because the immune system had not previously been exposed to this new virus, it was not able to mount a controlling immune response.
Today leading HIV cure scientists agree that Timothy may not have had what is called a “sterilizing cure”, but instead has a “functional cure”. A functional cure is where a patient can stop daily HAART medication and avoid a fall in CD4 counts and AIDS.
Allogeneic stem cell transplantation with a tissue matched donor with a CCR5 delta 32 mutation is not a feasible way to provide functional cure for HIV patients. Such an elaborate, expensive and life-threatening procedure could never be used as a broad-spectrum approach for the world's 34 million HIV patients.
The rationale for using the AlloStimTM approach for eliciting a functional cure in HIV patients is that AlloStimTM has both the ability to “shock” and the ability to vaccinate, leading to an immune-mediated kill response. In short, AlloStim has the components of a potential cure already built in. The mechanism of allogeneic stem cell transplant lead to the long-term functional cure of the Berlin patient. AlloStim elicits the Mirror EffectTM which causes the same immunological effects of the transplant procedure, but without the toxicity or need for a matched donor with a CCR5 mutation.
Our “San Francisco” patient now approaching 8 months off of HAART drugs after AlloStimTM therapy is proof-of-concept for the potential of this approach. While the San Francisco patient remains with high detectable viral load, his CD4 counts have remained stable and even risen since being off HAART. Thus, he meets the definition of a functional cure. Interestingly, like the Berlin patient, the virus in the San Fransisco-treated patient has changed over the course of immunotherapy. This may represent the awakening of viral pools containing genetic material from the original infection.
The next step is to conduct a large, randomized, controlled study powered sufficiently to detect a statistically significant benefit from the immunotherapy.