Understanding HIV infection through dynamical modelling: Why preventative vaccines, therapeutic vaccines, and IL-2 therapy are not working

Analyzing rare viral load data of an HIV-infected patient in the acute infection stage with a novel dynamical model analysis suggests that the failure to clear the infection is primarily caused by a failure of the cellular arm of the immune system to destroy productively infected CD4 + cells at a sufficient rate. This failure of the cellular arm is traceable to the existence of a pool of productively infected CD4 + cells whose half-lives in vivo are relatively long so that their numbers are easily replaced by newly infected, similarly relatively long-lived, CD4 + cells. One compartment of this pool consists of CD4 + Natural Killer cells that are HIV-1 infectable, have higher survival half-lives than typically infected CD4 +   T cells, and are unaffected by highly active anti-retroviral therapy (HAART). This pool cannot be cleared by the immune system, primed by vaccines and/or IL-2 or not, and is responsible for the observed, characteristic, plateauing of the viral density curve at the viral set-point. Thus, this pool of productively infected, relatively long-lived CD4 + cells as well as the well-known pool of latently infected, still longer lived CD4 + memory T cells make clearance of HIV infection impossible. gh HAART has proven effective in controlling HIV infection for a time, it has not led to clearance or a cure of the disease. Because of viral mutation, the efficacy of HAART in controlling the viral load eventually wanes and the infection rebounds. Thus, HAART is not effective against all strains of HIV. In addition to the CD4 + molecule, a virulent virion needs at least one of a handful of co-receptor molecules (e.g. CCR5 and CXCR4 cell surface receptors) to be present on a target cell in order to infect it. However, the CD4 + cells in about 1% of Caucasians lack any of these co-receptor molecules and are, therefore, immune to HIV infection. If a safe and effective fusion blocker could be discovered that acts against every co-receptor molecule that HIV-1 uses to infect CD4 + cells, then the major deficiencies of HAART would be overcome. Such a blocker would reduce the value of the infectivity of target cells to zero (or close to it). Because the number of these co-receptor molecules is small, it should be easier to find such a fusion blocker than it is to discover a HAART therapy that would be effective against all possible strains of HIV. If such a fusion blocker could be discovered, then administered as a prophylactic to uninfected people engaged in high-risk behavior would prevent infection and administered to those already infected with HIV would prevent the transition to AIDS.