HIV Cure Research at CROI 2014
The search for a cure has been a major theme at recent HIV meetings, and the 21st Conference on Retroviruses and Opportunistic Infections last week in Boston was no exception. While a cure is not yet on the horizon, a number of advances and some setbacks provide additional clues about how HIV persists in the body and how it might be eradicated.
Another Baby Cure?
At last year’s CROI, Deborah Persaud from Johns Hopkins reported on an infant in Mississippi born to an HIV-positive mother who did not take antiretroviral drugs to prevent mother-to-child transmission. Given the high-risk situation, the baby was started on combination antiretroviral therapy (ART) within about 30 hours after birth. After 18 months, the girl’s guardians removed her from care and she stopped treatment. But when she returned to care several months later, she still had undetectable viral load despite being off antiretrovirals.
This year Persaud provided an update on the Mississippi case (abstract 75LB). The girl—now three years old and off treatment for two years—still has undetectable blood viral load and extensive testing has not found HIV in her peripheral blood mononuclear cells (PBMCs) or other reservoirs. Persaud’s team concluded that the child remains in “remission” from HIV, suggesting that very early therapy for infants may lead to a “functional cure.”
Persaud also described a second baby in Long Beach (near Los Angeles) who also started combination antiretroviral treatment very early—within hours after birth—and appears not to have detectable HIV using the most sensitive tests. While the media widely reported this as a second case of a cured baby, this child has not yet been taken off antiretroviral treatment, so cannot yet be said to represent another possible cure.
The ethical issues surrounding taking a child off treatment that appears to be working are obvious. Persaud suggested that this baby—and a handful of other children who start treatment very early—will remain on ART for at least two years before treatment interruption is considered.
Stem Cell Setbacks
Timothy Henrich from Brigham and Women’s Hospital provided more information on two Boston bone marrow transplant patients who for a while appeared to be controlling HIV during ART interruption, but have both since experienced viral rebound (abstract 144LB).
The men received bone marrow, which contains stem cells that give rise to all blood cells, as treatment for lymphoma. Unlike Timothy Brown, the Berlin Patient—who remains HIV-free seven years after stem cell transplants from a donor with the double CCR5-delta-32 mutation that makes cells resistant to HIV entry—the Boston patients received normal or “wild-type” stem cells. However, both were CCR5-delta-32 heterozygotes, meaning they each had a single copy of the mutation and their cells were naturally partially resistant.
Also unlike the Berlin Patient, the Boston men received what Henrich called “kinder and gentler” chemotherapy that did not kill off their original immune cells. This enabled them to remain on ART throughout the transplant process.
The transplants were successful and the men’s own blood cells were progressively replaced by donor cells. Both men maintained undetectable blood plasma viral load, and virus also could not be found in PBMCs, lymph nodes, or gut tissue. After HIV could not be detected for 2.6 and 4.3 years, the men and their doctors agreed to try a careful experimental treatment interruption to see if the virus would return.
As Henrich first reported last December at the International Workshop on HIV Persistence During Therapy in Miami, viral rebound did occur, in one case after 12 weeks and in the other after eight months off ART. Both men developed symptoms of acute retroviral syndrome, similar to those that sometimes occur when people first become infected—as if their new immune systems were seeing the virus for the first time. Both men were able to regain viral suppression after restarting ART and are doing well.
These cases suggest that curing HIV will be difficult if even a tiny amount of residual virus remains in the body. In fact, in one man all the detected virus was identical, suggesting it was a clone from a single residual virus. Unfortunately, they also suggest that HIV may be hiding in long-lived reservoirs that are inaccessible to current tests.
“We believe [viral] rebound from only one or a few cells is enough to cause detectable virus,” Henrich said. “It’s going to need to be cleared out,” suggesting that a cure will likely require a combination of approaches.
Gene Therapy Update
CROI also featured the latest update on Sangamo BioSciences’ zinc finger gene therapy approach (abstract 141).
Sangamo’s technology uses a zinc finger nuclease to disrupt the gene in CD4 T-cells that controls expression of the CCR5 co-receptor that HIV uses to enter cells. In clinical trials, samples of CD4 cells are collected from HIV-positive participants, treated with the zinc finger protein in a laboratory, and allowed to multiply. The modified cells—called SB-728-T—are then re-infused back into the same patient.
The idea is that these modified cells, being protected from HIV entry, will have a survival advantage while normal T-cells are killed off by the virus. In effect, this approach artificially mimics the protective CCR5-delta-32 mutation.
Researchers have previously reported that the gene therapy procedure is generally safe and well tolerated. The modified SB-728-T cells engraft themselves, proliferate, and distribute themselves throughout the body like normal T-cells. Study participants experienced substantial CD4 cell gains and decreased virus levels.
At CROI, Gary Blick from the Circle Care Center in Norwalk, Connecticut, reported findings from a study cohort that was pre-treated with the cancer chemotherapy drug cyclophosphamide (Cytoxan). The rationale was that killing off some normal T-cells “makes room” for the altered cells.
This study included 12 participants with high CD4 counts and undetectable viral load on ART. They received intravenous cyclophosphamide at doses of 200, 500, or 1,000 mg/m2 given one to three days prior to a re-infusion of modified SB-728-T cells. Six weeks later they started an analytic ART treatment interruption.
Pre-treatment with cyclophosphamide promoted proliferation and activity of the modified T-cells, and people receiving the highest dose saw the greatest reductions in HIV viral load during ART interruption. One participant in the 1,000-mg dose group saw a viral load decrease of 1.9 log; this patient remains off ART with detectable but low and stable viral load. Cyclophosphamide was generally well tolerated. Some participants experienced nausea, but this was successfully managed with anti-emetic drugs.
“Cytoxan conditioning may be a useful strategy to maximize the engraftment and anti-viral effects of SB-728-T adoptive T-cell therapy in HIV subjects and may be an important immunomodulatory chemotherapeutic agent for immunotherapy in HIV,” the researchers concluded.
Blick explained at a media briefing that the 1,000-mg dose appears to approach the threshold for a functional cure, leading the researchers to look at a higher dose of 1,500 mg to see if they can push up response rates further without unacceptable toxicity. “We can probably get a functional cure if we get enough engraftment,” Blick said.
Very Early Treatment
Other research presented at CROI is at earlier stages, examining how HIV reservoirs are established and how they might be eliminated in animal and laboratory studies.
Afam Okoye and colleagues from the Oregon Health and Science University looked at the effect on viral reservoirs in macaque monkeys infected with SIV—a primate virus similar to HIV—when ART is started prior to peak viral replication, at or near the time of peak replication, or during early chronic infection (abstract 136LB).
Monkeys were started on multidrug therapy at day 7, day 10, or day 42 after being intravenously exposed to SIV. ART consisted of tenofovir and emtricitabine (the drugs in Truvada), the integrase inhibitor dolutegravir (Tivicay), and ritonavir-boosted darunavir (Prezista).
The researchers measured viral load in blood plasma, cell-associated virus in PBMCs, and SIV in bone marrow, small intestine gut tissue, and lymph node biopsy samples.
Starting ART prior to peak virus replication led to lower peak plasma viral load and earlier viral suppression. In the two monkeys treated from day 7, plasma viral load peaked by day 12, then declined to undetectable after six weeks on ART. But among the 18 monkeys not treated until day 42, some never achieved complete viral suppression even after 32 weeks on ART.
Early ART was associated with decreased levels of SIV genetic material in PMBCs and lower virus levels in all tested tissues. In fact, there was greater increase in virus levels by delaying treatment from day 7 to day 10 than there was from day 10 to day 42.
Virus was undetectable by co-culture in all monkeys started on ART at day 7 or day 10, but detected in all those started at day 42. However, even in monkeys treated early, viral rebound occurred soon after stopping treatment, indicating that replication-competent virus was still present.
“A delay as short as three days during the ‘hyperacute’ phase can result in 1–2 logs higher tissue-based reservoir size, once therapy is started and maintained,” the researchers concluded. “Aggressive monitoring for acute infection with immediate introduction of ART could profoundly influence treatment outcomes and enhance viral eradication strategies.”
Speaking from the audience, Persaud suggested that seven days is perhaps already too late to not just minimize but block establishment of viral reservoirs. At a press conference following his presentation, Okoye acknowledged that to achieve the best results, “we may have to treat within 36 hours.”
Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.
Blick. G. and others. Cyclophosphamide enhances SB-728-T engraftment to levels associated with HIV-RNA control. Conference on Retroviruses and Opportunistic Infections (CROI 2014). March 3–6, 2014. Boston. Abstract 141.
Henrich, T. and others. HIV-1 rebound following allogeneic stem cell transplantation and treatment interruption. CROI 2014. Abstract 144LB.
Okoye, A. and others. Early treatment in acute SIV infection limits the size and distribution of the viral reservoir. CROI 2014. Abstract 136LB.
Persaud, D. and others. very early combination antiretroviral therapy in perinatal HIV. CROI 2014. Abstract 75LB.