HIVfree
More than four decades after the first cases of AIDS were described, a cure and a preventive vaccine for HIV infection remain elusive goals.
The natural history of HIV infection was profoundly altered by the development of potent and well tolerated drugs, transforming a once uniformly fatal disease into a chronic one, enabling a near normal life expectancy for people who have access and adhere to treatment. However, current treatment does not eliminate the infection and the virus reappears in peripheral blood shortly after treatment is interrupted. Thus, life long treatment is necessary. Furthermore, stigma and discrimination associated with HIV infection remain a major problem for those affected.
Individualized medicine aims to tailor treatment to match each patient’s needs, aiming to treat each one based on their own characteristics. In the case of vaccines, individualized medicine aims to develop products that will maximize each person´s capacity to fight the precise microorganism that their body needs to defend against.
This is the approach we at CorpoRx have taken to cure HIV infection based on exciting preliminary results of a clinical trial we conducted in Brazil.
In that trial, HIV infected adult males who had been on successful antiretroviral treatment for over two years were randomized to various treatment groups. In one of these groups, in addition to the treatment they were already on, participants received a potent antiretroviral drug, dolutegravir, plus nicotinamide (vitamin B3), a drug that can “wake up” cells that are latently infected with HIV, and a gold salt (auranofin), which has been in clinical use for many years for the treatment of rheumatic diseases and is capable of promoting the death of HIV infected cells. This intervention was maintained for 48 weeks. The objective of this part of the intervention is to decrease the size of the reservoir of HIV-infected cells in the body of the patient.
After the 48-week intervention, participants received three doses, one week apart, of a tailor-made vaccine. In brief, white blood cells from the individual are separated and made to transform in vitro into dendritic cells, which are cells that specialize in presenting antigens to the immune system. In parallel, a region from viruses from that individual which is known to be very immunogenic is sequenced. Using a computer program we developed, peptides predicted to induce the most efficacious immune response are synthetized and are added to cultures of the patient´s dendritic cells. Finally, these sensitized dendritic cells are infused back into the patient (Figure 1). The objective of this part of the intervention is to “teach” the immune system how to better attack the virus that infects that person.
After the full intervention, participants returned to the treatment they were using before they joined the study for one and a half year, after which period, all drugs were stopped.
Figure 1: Preparation of the Individualized vaccine
PBMC = peripheral blood mononuclear cells; IFNa = interferon alpha; GM-CSF = granulocyte-macrophage colony stimulating factor; DC = dendritic cells; LPS = lipopolysaccharides; QC = quality control
One the most accurate ways to measure the impact of any intervention that is aimed to cure HIV infection is to measure total proviral DNA present in peripheral blood cells of the infected individual and in biopsies of rectal tissues. As shown in Figure 2, over the period of the intervention, the amount of proviral DNA significantly decreased in participants who received dolutegravir, nicotinamide, auranofin, and the individualized vaccine (group 6), whereas in all others it actually increased over time. Figure 3 shows measurements of total DNA in blood and in rectal biopsies of two individuals at baseline (control) and after receiving dolutegravir, nicotinamide, auranofin, and the individualized vaccine. In fact, in one of the duplicates of peripheral blood of one of the individuals, the quantity of total DNA was so low as to be undetectable.
Given these unprecedented results, we will expand this intervention to another 60 patients. HIV chronically infected patients who fulfill inclusion criteria, which include being on successful antiretroviral therapy for at least two years and a CD4 count (a measure of their immunity) greater than 500 cells/uL will receive dolutegravir (if not already on this drug), nicotinamide, and auranofin for 48 weeks, followed by three doses one week apart, of individualized vaccines. After the intervention, all drugs will be stopped and participants closely monitored for virus rebound, in which case treatment will be promptly resumed. The primary endpoints of the trial are reduction of proviral DNA in peripheral blood and rectal biopsy, as well as undetectable plasma viral load 48 weeks after treatment interruption.
Figure 2: Total HIV DNA in peripheral blood before and after the intervention
G6 = participants who received dolutegravir, nicotinamide, auranofin, and individualized vaccine
Figure 3: Total HIV DNA in peripheral blood and rectal biopsies before and after the intervention
PBMC = Peripheral Blood Mononuclear Cells; RB = Red blood cells