Like Berlin patient Timothy Ray Brown before him, London patient Adam Castillejo, whose case was top story of the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), energized the HIV cure research field by his sheer existence.
Curing HIV, Pablo Tebas told the audience at a themed discussion on curative strategies, “has been considered [for] a long time the holy grail.”
But Tebas, who is a professor of medicine at the University of Pennsylvania Perelman School of Medicine, said he thinks that the real grail should be remission.
Cure, he pointed out, “has only been attained two times,” and by a method that will not scale, due to both the cost and the high health risk of the procedure.
But the fatal flaw of an eradication cure may be something else.
An eradication cure “does not prevent reinfection of the individual,” Tebas said at the 2020 all-virtual CROI meeting. And so in the absence of a vaccine, “it basically substitutes antiretroviral therapy for PrEP.”
Berlin patient Brown has said publicly that he takes PrEP, and in general, Tebas told BioWorld, “people… have a sexual life and they could be at risk of HIV infection.”
CD4 cells lacking CCR5 would be resistant to reinfection, he said, “but the cells that are not derived from the bone marrow still carry CCR5, and although those cells are not a significant reservoir, and probably cannot support high level HIV replication,… these patients can theoretically get infected.
“For all that, I think remission is the real holy grail. Maybe the mechanism that would prevent HIV from reactivation will also prevent reinfection. The immune response to the residual HIV may maintain those responses,” Tebas said. “At least that is a theoretical possibility.”
Steven Deeks, professor of medicine at the University of California at San Francisco, told BioWorld by email that “it is generally assumed that "elite" controllers are protected against new infections, or control them once they occur, suggesting… that an immunotherapy that induces a "remission" could very well protect against new infections.”
Deeks’ take on the Berlin and London patients is that they “are both probably cured (it depends on the definition) and highly (although not fully) protected against re-infection.”
More broadly, Deeks said, “developing a cure strategy that prevents re-infection may be necessary if we are to have a global impact. Modeling suggests that to really stop the epidemic in places such as sub-Saharan Africa, strategies that prevent re-infection might be key.”
Block and lock or shock and kill
One strategy to reduce the viral reservoir has been the so-called shock-and-kill approach, which attempts to force the virus out of latency and make infected cells with actively replicating virus visible to the immune system.
The shock part of shock and kill is accomplished by latency reversing agents (LRAs), while the kill part is accomplished – well, actually, it is not accomplished very well yet at all. At a plenary session on the HIV reservoir, Shannon Lewin, of the University of Melbourne, highlighted the need for both more potent and less toxic LRAs, and the “need to get the kill into shock and kill,” for example, in the form of pro-apoptotic drugs.
At the meeting, Lewin and her team presented data showing that in ex vivo-treated T cells, combining the LRA romidepsin with any of four pro-apoptotic drugs “led to a greater decline in integrated HIV DNA versus either romidepsin or pro-apoptotic drug alone,” the authors wrote. Venclexta (venetoclax, Abbvie Inc.) plus romidepsin was a particularly effective combination.
Multiple groups and companies have used Toll-like receptor (TLR) agonists as LRAs, with mixed results to date. At the conference, Gilead Sciences Inc. gave several updates on its TLR7 agonist, vesatolimod (GS-9622), including an oral presentation demonstrating that vesatolimod treatment followed by analytical treatment interruption (ATI) slightly delayed rebound in a group of 25 HIV-positive individuals.
The goal, principal investigator Deeks said, was to “enhance immune function in people whose immune system was good but not great at controlling the virus, hoping to turn them from partial to more full controllers. We had hoped to do this by both enhancing immune function and reducing the reservoir during therapy, and controlling the virus after treatment was interrupted.”
The delay was statistically but not clinically significant – though Deeks pointed out that it was “the first study done in people that has shown with an immunotherapy that you can enhance immune function resulting in both a smaller viral reservoir and an increased time to viral rebound after treatment is interrupted.”
Two papers published January 2020 in Nature reported on different molecular mechanisms to reverse latency, both of which successfully reversed HIV and SIV in animal models. One paper described the use the IL-15 superagonist N-803 in combination with an antibody that depleted CD8-expressing T cells, while another tested the SMAC mimetic and noncanonical NF-kB activator AZD-5582.
Another possibility is the induction of “deep” or permanent latency, achieved by so-called block-and-lock strategies. Data presented at the meeting showed that elite controllers showed unique patterns of viral integration that might lead to deep latency via block-and-lock like mechanisms, and that the anti-inflammatory drug ABX-464 (Abivax Inc.) could decrease reservoir size via block-and-lock mechanisms.