Since the earliest days of HIV research, the idea of trying to enhance immune responses to the virus using therapeutic vaccination has been extensively explored, but with little success. The ability of the virus to compromise CD4 T cells, which would normally coordinate antiviral immunity, may be one contributor to the generally disappointing results. Virus-induced damage to the lymph node environment where immune responses are initiated has also been suggested to play a role. Researchers have not given up, however, and a recent study in SIV-infected macaques has produced encouraging results.
The study was conducted by investigators involved in one of the newly created Martin Delaney Collaboratories, which have been funded by the National Institute of Allergy and Infectious Diseases (NIAID) to pursue a cure for HIV infection. Named “I4C: Combined Immunologic Approaches to Cure HIV-1,” the collaboratory is co-led by Dr. Dan Barouch at the Beth Israel Deaconess Medical Center, Dr. John Mellors at the University of Pittsburgh, and Col. Nelson Michael at the U.S. Military HIV Research Program. Two industry partners are also involved: Janssen, who have developed the adenovirus serotype 26 (Ad26) and modified Vaccinia Ankara strain (MVA) vaccine vectors used in this experiment, and Gilead Sciences, who contributed a TLR7 agonist that has previously shown some potential as a single agent.
The investigators infected 36 rhesus macaques with the highly pathogenic SIVmac251 and initiated ART a week later, during the acute phase of infection. After 24 weeks, the animals were divided into four groups of nine. One group served as controls, while the others received either Ad26 + MVA vaccines (encoding SIV antigens), the TLR7 agonist, or a combination of the vaccines and the TLR7 agonist. After 72 weeks, ART was stopped and viral load rebound assessed. The crux of the results is that animals in the combination group exhibited significantly enhanced control of SIV viral load when ART was interrupted, with three animals controlling viral replication to undetectable (<200 copies/ml) levels after an initial spike. Set point viral loads in this group averaged around 1,500 copies/ml, which was 1.74 logs lower than controls. Viral load rebound was also delayed by a median of 25 days compared to 10 days in controls.
Additional analyses showed that the breadth of SIV-specific T cell immune responses induced by the vaccines correlated with viral load control. Levels of SIV DNA measured in peripheral blood and lymph nodes were undetectable (cutoff <3 copies per million CD4 T cells) in the majority of vaccine recipients prior to ART interruption, and reductions in SIV DNA correlated with the delayed time to viral load rebound.
As is always the case with animal model studies, it will be important to assess if the results translate to humans. Janssen is now sponsoring a clinical trial of the Ad26 + MVA combination in acutely infected individuals in Thailand, and a separate evaluation of Gilead's TLR7 agonist is ongoing in the United States, potentially laying the groundwork for combination studies.
Additional information on the I4C: Combined Immunologic Approaches to Cure HIV-1 collaboratory can be gleaned from presentations at the recent NIAID Strategies for an HIV Cure meeting – see the webcast of day one, starting at the 5:49:45 mark.