The HIV-1 pandemic has claimed over 20 million lives, with 38.6 million people worldwide currently infected, and will continue to be a significant global health problem as there is no vaccine available. Currently, the only effective treatment available to HIV-1 infection is HAART (highly active antiretroviral therapy), which has led to a profound reduction in HIV-1-related morbidity and mortality. However, HAART fails to eliminate the virus in vivo, mainly due to the persistent existence of long-lived latently-infected cells harboring replication-competent proviruses. Efforts to purge these infected cells have focused on reactivation of the proviruses. It is presumed that these infected cells will be killed after reactivation of virus gene expression by viral cytopathic effects (CPEs), host immune responses or both. Several stimulants including IL-7, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and prostratin have been explored to force activation of proviruses in latently-infected resting CD4+ T cells that constitute the major reservoir of HIV-1 in vivo. However, treatment with IL-7 or VPA in patients on HAART has failed to reduce HIV-1 latency, suggesting that these agents alone are not sufficient to induce killing of latently-infected cells. We propose to develop an """"""""activation-killing"""""""" approach by combining provirus stimulants with an agent that is able to allow anti-HIV-1 immunity naturally mounted in patients during HIV-1 infection to specifically kill latently-infected cells after provirus reactivation. Studies have shown that both HIV-1-infected cells and virions use their surface regulators of complement activation (RCA) to resist antibody- dependent complement-mediated lysis (ADCML), which explains why vigorous and sustained anti-HIV-1 envelope (Env) antibody (Ab) responses in almost all infected individuals fail to control HIV-1 infection. We and others have reported that blocking human CD59 (hCD59), a key member of RCA, renders both HIV-1-infected cells and virions sensitive to ADCML. We therefore hypothesize that addition of an hCD59 inhibitor to SAHA, prostratin or both will enable anti-HIV-1 Env Abs naturally present in HIV-1-infected individuals to trigger ADCML of latently-infected T cells after provirus reactivation. The provirus stimulants will activate proviruses to express viral proteins on the surface of latently-infected cells that will be killed by ADCML if hCD59 is inhibited. We will use the human T cell line ACH2, a well-characterized model of HIV-1-latency, to develop such an approach (Aim 1, R21 Phase). We will verify whether the approach is able to trigger ADCML of the primary CD4+ T cells latently infected with HIV-1 in vitro (Aim 2, R33 Phase). We will then determine if this approach can allow anti-HIV-1 Abs naturally present in the sera of infected patients to trigger autologous ADCML of their own latently-infected resting CD4+ T cells (Aim 3, R33 Phase). Our project is innovative and significant because we aim to develop a novel approach for purging the persistent reservoir of HIV-1 in patients on HAART. This approach may simultaneously target various latently infected cells and residual viremia, potentially leading to a broader impact and improved efficacy against the various persistent HIV-1 reservoirs.
The long-lived latently infected cells harboring replication-competent proviruses represent a major obstacle for achieving a cure for HIV-1 infection. Our research aims to develop an approach to enable anti-HIV-1 antibodies mounted vigorously in infected patients to specifically kill latently HIV-1-infected cells after activation of provirusesin these cells.
|Xing, Yanyan; Shepherd, Nicole; Lan, Jie et al. (2017) MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders. Brain Behav Immun 65:161-172|
|Meng, Zhefeng; Du, Ling; Hu, Ningjie et al. (2016) Antiretroviral Therapy Normalizes Autoantibody Profile of HIV Patients by Decreasing CD33?CD11b?HLA-DR? Cells: A Cross-Sectional Study. Medicine (Baltimore) 95:e3285|
|Yang, Kai; Lan, Jie; Shepherd, Nicole et al. (2015) Blockage of CD59 Function Restores Activities of Neutralizing and Nonneutralizing Antibodies in Triggering Antibody-Dependent Complement-Mediated Lysis of HIV-1 Virions and Provirus-Activated Latently Infected Cells. J Virol 89:9393-406|
|Lan, Jie; Yang, Kai; Byrd, Daniel et al. (2014) Provirus activation plus CD59 blockage triggers antibody-dependent complement-mediated lysis of latently HIV-1-infected cells. J Immunol 193:3577-89|
|Hu, Sishun; Ghabril, Marwan; Amet, Tohti et al. (2014) HIV-1 coinfection profoundly alters intrahepatic chemokine but not inflammatory cytokine profiles in HCV-infected subjects. PLoS One 9:e86964|
|Byrd, Daniel; Shepherd, Nicole; Lan, Jie et al. (2014) Primary human macrophages serve as vehicles for vaccinia virus replication and dissemination. J Virol 88:6819-31|
|Byrd, Daniel; Amet, Tohti; Hu, Ningjie et al. (2013) Primary human leukocyte subsets differentially express vaccinia virus receptors enriched in lipid rafts. J Virol 87:9301-12|