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HIV rebounds despite significant reduction in reservoir size
The two patients with HIV who achieved long-term remission after hematopoietic stem cell transplantation with HIV-1 susceptible wild-type donor cells have both experienced a viral load rebound shortly after stopping ART, according to a case report.
“Although allogeneic [hematopoietic stem cell transplantation] may lead to significant, sustained reductions in the HIV-1 reservoir, infected tissue or cell-bound virus persists,” the researchers wrote in the Annals of Internal Medicine. “Persistence of these small numbers of residual infected cells seems to be sufficient to rekindle HIV-1 replication.”
The researchers extracted DNA from peripheral blood mononuclear cells and gut tissue in two patients with HIV who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning for hematologic tumors.
After allogeneic HSCT, the researchers observed substantial reductions in HIV-1 reservoirs in both patients; their levels of HIV-1 RNA, proviral HIV-1 DNA and viral outgrowth were undetectable for several years after the procedure. In fact, they found a minimum 3-log10 reduction in the number of circulating cells with proviral HIV-1 DNA.
The researchers monitored the patients’ viral loads each week for the first 10 weeks after ART was stopped and every 1 to 2 weeks thereafter.
Delayed viral rebound
Typically, HIV usually rebounds 1 to 8 weeks after discontinuation of ART; however, in this case report, both patients rebounded much later. Patient A’s viral load rebounded at 12 weeks and patient B at 32 weeks. Both patients showed symptoms of acute retroviral syndrome. Viremia rebound was seen within 2 weeks of the last negative plasma HIV-1 RNA test, the researchers wrote. The patients resumed ART immediately, leading to viral decay and symptom resolution.
Viral rebound may be attributed to long-lived tissue reservoirs, such as host macrophages, which are replaced more slowly than T-lymphocytes after HSCT.
“In summary, our results suggest that allogeneic HSCT with CCR5 wild-type donor cells may lead to a loss of detectable HIV-1 from blood and rectal mucosa, but viral rebound may nevertheless occur after ART interruption despite a significant reduction in reservoir size,” the researchers wrote. “The definition of the nature and half-life of residual viral reservoirs is essential to achieve durable, ART-free HIV-1 remission.”
HIV cure remains elusive
In an accompanying editorial, Sharon Lewin, FRACP, PhD, said these findings offer some good news, but a functional cure for HIV remains elusive.
The researchers demonstrated that it is possible to get substantial reductions in HIV-1 reservoirs, which appeared to be linked to delayed viral rebound. In addition, the research highlighted the areas that need work. For instance, currently used assays are not sensitive enough to detect residual virus. The only test of cure available now is treatment interruption, Lewin wrote.
The research also showed that a significant decrease in the number of latently infected T cells may not be enough to achieve long-term HIV remission. These findings indicate that the total elimination of the HIV virus to achieve lifelong remission may be out of reach, Lewin wrote, adding that new approaches for achieving HIV remission are necessary.
The results for “purging” the virus from long-lived, latently infected T cells or using multiple latency-reversing agents have demonstrated modest results in activating the virus from latency, Lewin said. Despite some evidence that the virus is activated from latency, there is no evidence that the amount of residual infectious virus or HIV DNA has not changed. Using gene therapy to make CD4+ T-cell HIV-resistant shows some promise, although it is invasive and expensive.
“We are making some progress in putting HIV into remission, but we have a long way to go to keep the virus permanently under control off antivirals,” Lewin told Infectious Disease News. “This paper showed us that transient remission is possible, at least following stem cell transplantation, but most likely we need both a reduction in virus as well as a boost to the immune system to keep the virus under long term control off antivirals.”
Disclosure: See the study for a full list of researchers’ financial disclosures.