It has recently been shown that rare individuals can be cured of HIV infection after early initiation and long duration of drug therapy. We wish to achieve such cures in more HIV-infected people. In addition to early and sustained drug therapy, all people who have been cured of HIV infection demonstrate very low residual viral DNA in long-lived resting CD4+ T cells, a population that is widely acknowledged as an important viral reservoir. Therefore, many scientists have proposed that achieving functional cure in more people will require reducing the amount of viral DNA in reservoirs, particularly among CD4+ T cells with a long lifespan. We propose to use monoclonal antibodies to reduce the lifespan of CCR5+ T cells and antigen-presenting cells, thereby eliminating such cells, reducing the size of the reservoir, and hopefully facilitating cure. We hypothesize that CCR5+ memory T cells are an important SIV reservoir, particularly in early infection, and that degradation of this reservoir under ART treatment will facilitate functional cure. If this hypothess is correct, then we predict that functional cure is facilitated by depletion of CCR5+ cells.
The aims are: 1. Develop and test the in vitro function of three CCR5 depletion reagents: bispecific CCR5/CD3 antibody, RANTES-PE38, and RANTES-DT390. The first reagent is a bispecific Ab that binds simultaneously to CCR5 and CD3 and thereby redirects CD3+ T cells against CCR5+ targets. The second and third are fusion proteins of the chemokine RANTES with truncated versions of Pseudomonas exotoxin A and diphtheria toxin, respectively. These reagents will be produced in milligram quantities and tested in vitro. 2. Evaluate the extent of CCR5 depletion achievable in vivo with the developed reagents. The three reagents described above, as well as PEGylated versions, will be tested in animals. We will evaluate both the pharmacokinetics of the administered drugs and their efficacy in depleting CCR5+ T cells and macrophages. We will pay particular attention to tissue-resident CD69+ memory T cells that are difficult to deplete. 3. Determine if CCR5 depletion reduces the reservoir in infected infants receiving fully-suppressive ART. Infants will be infected soon after birth, treatment with optimal ART will be initiated three days after infection, and tissue collection will be performed 60 days later. Half of each treatment cohort will receive CCR5+ cell depletion beginning immediately after ART. Levels of vRNA and vDNA found in various reservoirs will be assessed to determine if the reservoir decays more rapidly with CCR5+ cell depletion. 4. Test if CCR5 depletion facilitates functional cure among infants receiving early ART. Animals will be infected and treated as described in Aim 1; half will receive CCR5+ cell depletion beginning immediately after ART. ART will be discontinued after 60 days and parameters including viral load, immune response to virus, and presence of the virus in reservoirs assessed during the following five months. This experiment will allow us to test if CCR5+ cell depletion slows virus rebound from reservoirs and/or permits functional cure.
This project will provide new understanding of how rare individuals can be functionally cured of HIV infection after extended therapy, while others are not cured. The project also tests the idea that cure may be facilitated by targeted depletion of cells that harbor HIV. If successful, the work in this project will provide hints as to how we can make progress in curing HIV-infected people across the world, including more than one million infected Americans.
| Merriam, David; Chen, Connie; Méndez-Lagares, Gema et al. (2017) Depletion of Gut-Resident CCR5+ Cells for HIV Cure Strategies. AIDS Res Hum Retroviruses 33:S70-S80 |
