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We have a long way to go before we cure HIV, but we get closer every day as we explore new strategies and build on existing research. What do we know now, and what are the focus areas for future research? Irini Sereti, M.D., reviewed and analyzed the current strategies in cure research during a presentation at IDWeek 2016 in New Orleans.
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Eradication versus Remission
There are two main philosophies on establishing an HIV cure. One is the traditional "sterilizing cure," which would eradicate all replication-competent virus in the body and eliminate the HIV reservoir. The second is a "functional cure," or what's now commonly called "HIV remission," which, without antiretroviral therapy, would induce permanent or sustained viral suppression to levels that would prevent immunodeficiency and transmission. Currently, the more achievable goal would be HIV remission.
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Ways to Achieve HIV Remission
Sereti noted two ways to achieve HIV remission. One is through stem cell transplantation, which is a very risky procedure and mainly undergone by individuals with cancer. The second is through very early treatment, particularly during acute HIV infection, which is days or weeks after transmission.
The main obstacle to a cure or sustained remission is targeting the latent HIV reservoirs hidden in tissues.
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Stem Cell Transplantations
As has been widely reported, Timothy Ray Brown may be the only case of an HIV sterilizing cure, as far as tests can tell, because he has remained HIV free for over seven years after receiving a stem cell transplant to treat his leukemia. The donor had a rare mutation in which their CD4 cells had no CCR5 co-receptors (the main point of entry for HIV). This mutation was transferred to Brown, which made him resistant to HIV and subsequently eliminated the virus.
Two patients in Boston who were living with HIV and cancer received stem cell transplants (without the same CCR5 mutation as Brown received) to treat their cancer and appeared to be HIV free after stopping antiretroviral therapy. Unfortunately, their virus rebounded three and eight months after treatment interruption. However, as Sereti noted, the typical rebound happens less than two months after stopping treatment, so the Boston patients did show a bit of prolonged remission. Still, stem cell transplantations remain a risky procedure and are not widely applicable to the general HIV population.
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Very Early Treatment
Perhaps the most famous case of HIV remission after very early treatment is the Mississippi Baby, who was born to an untreated HIV-positive mother. The baby was given antiretroviral therapy within hours of birth and, after stopping treatment at 18 months, showed no signs of HIV for over two years until her virus suddenly rebounded.
However, there are other cases of sustained HIV remission after very early treatment, including the VISCONTI cohort and a French teenager, who are able to maintain undetectable viral loads without treatment. However, this doesn't happen for everyone who is treated very early and it remains unrealistic to identify everyone during acute HIV infection.
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Cell and Gene Therapy
Cell and gene approaches to target HIV hold the most promise, according to Sereti, but for now are the least scalable. Such approaches could include manipulating the aforementioned CCR5 co-receptor to make CD4 cells resistant to HIV, which was reported in a proof-of-concept study in 2014.
Other approaches could include doing gene editing of HIV itself, using chimeric antigen receptor (CAR) T cells to kill infected cells and using antibodies to kill infected cells via antibody-dependent cell-mediated cytotoxicity (ADCC).
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CRISPR/Cas9 Gene Editing
The method that has revolutionized the field is CRISPR/Cas9, according to Sereti. It uses guide RNA to recognize and attach to specific areas of DNA, which can then be cut and edited.
If the segment of DNA is cut out, this can lead to gene silencing, whereby the gene is disrupted and, in HIV's case, viral replication could be suppressed.
If the segment of DNA is cut out and replaced with a repair template, this can lead to gene editing, whereby the gene has a new sequence that it takes from the repair template. And, in HIV's case, this could also suppress viral replication.
The beauty of this, according to Sereti, is that CRISPR/Cas9 is very precise and also fairly inexpensive and very quick. Therefore, it's anticipated to change the field of gene therapy. However, one preliminary study showed that HIV was able to mutate and adapt to CRISPR/Cas9-edited cells. But CRISPR/Cas9 research is still in early phases and ongoing.
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Shock and Kill
The most tested strategy involves using a latency-reversing agent (LRA) to "shock" the latently infected cells out of hiding and then hopefully enhance the immune response to "kill" these cells, leading to a reduction in the viral reservoir.
One recent study tested romidepsin, an HDAC (histone deacetylase) inhibitor that can reverse latency, in combination with a peptide-based therapeutic HIV vaccine known as Vacc-4x, in a small group of HIV-positive individuals. Unfortunately, all study participants experienced viral rebound an average of 14 days after treatment interruption. However, romidepsin was shown to have reactivated latent HIV and reduced HIV DNA and IUPM (infectious units per million) by 40% -- an interesting finding for future research.
Future research could involve other LRAs to "shock," such as TLR7 agonists, which have shown strong pre-clinical results, and find ways to increase the immune system even more to "kill" latently infected cells.
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Broadly Neutralizing Antibodies
Broadly neutralizing antibodies (bNAbs) have become one of the main themes in HIV for the past several years, notes Sereti. Initially they were used in prevention strategies, but now they're also being researched for treatment. Not only can antibodies neutralize the virus and prevent infection, they can also induce ADCC and phagocytosis to eliminate infected cells in the body. These bNAbs can bind to many different sites to act against HIV. Two of the currently promising bNAbs being studied are 3BNC117 and VRC01.
In a small study of 13 HIV-positive individuals, 3BNC117 was shown to delay viral rebound an average of 6.7 weeks or 9.9 weeks (depending on dose schedule) after treatment interruption -- which was significantly later than the average of 2.6 weeks in historical controls who stop treatment. However, most of the participants' HIV developed resistance to 3BNC117 after viral rebound.
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Could SIV Remission Pave the Way for HIV Remission?
On Oct. 13, scientists from the National Institutes of Health and Emory University announced sustained SIV remission in macaques given an experimental treatment regimen including a laboratory-derived antibody that works against a cell receptor known as a4b7 integrin. Macaques in the study have been able to maintain SIV remission for up to two years so far after treatment interruption.
The researchers are unsure of which mechanism causes the remission, co-author Anthony S. Fauci, M.D., said at HIVR4P 2016. However, the results are so clear and stunning that a small pilot study in humans has begun enrollment. The study will use a human drug vedolizumab (Entyvio), which is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of ulcerative colitis and Crohn's disease, and has a very similar effect to the monkey antibody. We will see whether the monkey results translate into human effects.
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