Abstract
Pharmacological reactivation of human immunodeficiency virus (HIV) expression from latent proviruses coupled with fully suppressive antiretroviral therapy (ART) has been suggested as a strategy to eradicate HIV infection. In order for this strategy to be effective, latently infected cells must be killed either by the cytopathic effect of reactivated HIV gene expression, or by HIV-specific cytotoxic T lymphocyte (CTL). However, a review of current data reveals little evidence that CTL retain an antiviral effector capacity in patients on fully suppressive ART, implying that the HIV-specific CTL present in these patients will not be able to eliminate HIV-infected CD4+ T cells effectively. If this is due to functional impairment or a quantitative deficit of HIV-specific CTL during ART, then therapeutic vaccination may improve the prospects for eradicating latent reservoirs. However, data from the macaque simian immunodeficiency virus (SIV) model indicate that in vivo, SIV-specific CTL are only effective during the early stages of the viral replication cycle, and this constitutes an alternative explanation why HIV-specific CTL do not appear to have an impact on HIV reservoirs during ART. In that case, immunotoxins that target HIV-expressing cells may be a more promising approach for HIV eradication.
Highlights
Pharmacological reactivation of human immunodeficiency virus (HIV) expression from latent proviruses coupled with fully suppressive antiretroviral therapy (ART) has been suggested as a strategy to eradicate HIV infection
During partially effective ART, in patients with active HIV replication and viral load (VL) > 1000 copies/mL, the accumulation of cytotoxic T lymphocyte (CTL) escape mutations in virus sequences, and the inverse correlation between Gag-specific CTL and VL both indicate that HIV-specific CTL continue to have an impact on HIV replication
With respect to HIV eradication strategies based on pharmacological reactivation of latent proviruses, the available data suggests that the HIV-specific CTL present in patients on fully suppressive ART will not be able to eliminate HIV-infected CD4+ T cells effectively
Summary
EA4271 Laboratoire d’Immunovirologie et Polymorphisme Génétique, Faculté de Médecine et de Pharmacie, Université de Nantes, LUNAM Université, Nantes, France. These are: (1) associations between human leukocyte antigen (HLA) class I alleles and disease progression; (2) HIV sequence evolution and polymorphism indicating selection pressure exerted by CTL in vivo; (3) inverse correlation of viral load (VL) with Gag-specific CTL responses; and (4) ability of CTL to inhibit HIV replication ex vivo For each of these types of evidence, I will briefly summarize what the approach has revealed about the CTL response during untreated HIV infection, review the relevant data in patients on ART, in order to assess to what extent HIV-specific www.frontiersin.org. A powerful longitudinal analysis of virus sequences from
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