It has recently been shown that rare individuals can experience remission of HIV infection after early initiation and long duration of drug therapy. The objective of this work is to identify means by which such remissions can be achieved in more HIV-infected people. In addition to early and sustained drug therapy, all people who have been placed in remission (or, when sustained, functional cure) demonstrate very low residual viral DNA in long-lived resting CD4+ T cells, a population 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 CD4+ T cells, thereby eliminating such cells, reducing the size of the reservoir, and hopefully facilitating cure. We hypothesize that functional cure of perinatally-infected infants requires bot complete viral suppression and rapid degradation of reservoirs under ART treatment. If this hypothesis is correct, then we predict that functional cure is facilitated by therapeutic depletion of CD4+ T cells.
Our specific aims are: 1. To determine the extent of viral load suppression and restriction of virus establishment in reservoirs that is achievable with a three-drug regimen in infants. We monitor viral reservoirs in infants treated with a completely suppressive ART regimen adapted from a combination shown to be effective in adults. 2. To test if early aggressive treatment of infants can lead to durable virologic control after therapy interruption despite presence of the virus in CD4+ reservoirs. In this Aim, infants are infected at birth, treatment with optimal ART is initiated 3 or 7 days after infection, and treatment is withdrawn 84 days later. The occurrence of functional cure and levels of vRNA and vDNA found in various reservoirs will then be followed. We expect to identify a time point and treatment regimen that can induce functional cures with similarities to the known human cases. 3. To determine if CD4+ T cell depletion facilitates and CD8+ T cell depletion inhibits functional cure. A time point for treatment will be selected at which functional cure sometimes but not always occurs. Eight individuals infected perinatally and treated at this time point will be administered CD4-depleting antibody at days 1 and 15 following ART initiation; eight will be administered CD8-depleting antibody. ART will be discontinued after 84 days and the frequency of cure in each group assessed.
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 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.
