[HTML][HTML] Opening Fronts in HIV Vaccine Development: Targeting reservoirs to clear and cure

RF Siliciano - Nature medicine, 2014 - nature.com
Nature medicine, 2014nature.com
BETWEEN BEDSIDE AND BENCH that the half-life of the cells that produce most of the
plasma virus is very short, only 1 day14, whereas a second population of productively
infected cells, which may include CD4+ T cells in a low state of activation, turns over with a
half-life of 2 weeks14. Some of these cells may survive and revert back to a resting state that
is nonpermissive for viral gene expression and that allows for viral latency. During the
considerable time required for this transition (weeks), the cells remain susceptible to lysis by …
BETWEEN BEDSIDE AND BENCH that the half-life of the cells that produce most of the plasma virus is very short, only 1 day14, whereas a second population of productively infected cells, which may include CD4+ T cells in a low state of activation, turns over with a half-life of 2 weeks14. Some of these cells may survive and revert back to a resting state that is nonpermissive for viral gene expression and that allows for viral latency. During the considerable time required for this transition (weeks), the cells remain susceptible to lysis by virus-specific CTLs; thus, in vaccinated individuals, the preexisting effector memory CTL response can clear infected cells before latency is established (Fig. 1). In contrast, ART, which rapidly stops new infection of susceptible cells, has no effect on the fate of cells that are already infected. Because it takes some time for de novo T cell responses to develop, treatment with ART has not yet led to clearance except in the unique situation mentioned above, although it can largely halt new infection events. Thus, there is an important difference between vaccine-induced clearance and early ART with respect to the fate of infected cells. Although the clearance of SIV infection in the vaccinated animals may not be interpreted as a cure because a stable reservoir was never generated in these animals, this study highlights the possibility of controlling the infection and clearing infected cells before a stable reservoir is established with an appropriately primed CTL response and suggests that a CTL-based vaccine could be effective. The disappointing results seen in the clinical trials of CTL-based vaccines to date have focused attention on neutralizing antibodies, which in principle can prevent any host cells from becoming infected. However, Picker and his colleagues have now shown that viral clearance can occur even after disseminated infection in animals with strong vaccine-induced T cell responses1. The CMV-based vaccines do not elicit neutralizing antibodies6. The ability of vaccine-induced CTLs to lyse infected cells before latency can be established could be an important component of a successful AIDS vaccine and, when combined with vaccine strategies that induce neutralizing antibodies, could provide an additional layer of protection should some virus particles escape neutralization and initiate infection of host cells. With regard to curing patients with established HIV-1 infection, it will probably be necessary to use pharmacologic approaches to reverse latency so that the infected cells will begin to produce viral proteins and become susceptible to lysis by virus-specific CTLs. However, recent evidence suggests that the CTL response in most patients on ART is not effective in eliminating infected cells without boosting15. Whether CMV-based vaccine vectors can be safely used for this purpose is not clear, but they certainly deserve consideration.
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