CCR5-tropic Infection Research Articles

Overview on Chemokine Co-Receptor-5 (CCR-5) HIV-1 Entry Inhibitors

In the 21st century, HIV-1 has turned into a noteworthy global challenge in medication. As per WHO report 2017, HIV is one of the deadliest diseases adding to an aggregate of 36.7 million contaminations until December 2016 among which 1.8 million were analyzed in 2016 itself. In 2016, 19.5 million individuals experienced to anti-retroviral treatment summing up to US$ 11 billion. With regards to rising resistance from anti-retroviral medication in HIV treatment, the advancement of most recent medication classes with a newer mode of action stays essential. The CCR5 co-receptor inhibitors suppress the fusion of HIV with the host cell by upsetting the connection of gp-120 protein with the CCR5 receptor. Though severalCCR5 antagonists are assessed in clinical trials, just Maraviroc has been endorsed for clinical use in the treatment of HIV infected patients. The efficacy and safety profile of CCR5 adversaries with a consideration on maraviroc are assessed here in conjunction with their use in newer and developing clinical trials. In the beginning time of HIV-1 infection in the most of patients, the HIV utilizes CCR5 receptor for passage in CD4 cell of the host (CCR5-tropic infection). Maraviroc did not decrease virus load (compared to optimized background therapy) in patients with CXCR4 or dual-tropic virus. Before prescribing a CCR5 blocker HIV tropism testing is recommended. Viral tropism is defined as the capability of the viruses to enter as well as infect the host cell, and it is based on the binding capacity of the viruses to receptors on those host cells. The co-receptor type should be recognized before the treatment started with a CCR5 blocker. Keywords: CCR5, CXCR4, HIV-1, CD4 cell, Tropism, CYP3A4.

Estimating the Infectivity of CCR5-Tropic Simian Immunodeficiency Virus SIV mac251 in the Gut

CD4+ T-cell depletion during acute human immunodeficiency virus infection occurs predominantly in the gastrointestinal mucosa. Using experimental data on SIV(mac251) viral load in blood and CD4+ T cells in the jejunum, we modeled the kinetics of CD4+ T-cell infection and death and estimated the viral infectivity. The infectivity of SIV(mac251) is higher than previously estimated for SHIV89.6P infection, but this higher infectivity is offset by a lower average peak viral load in SIV(mac251). Thus, the dynamics of target cell infection and death are remarkably similar between a CXCR4- and a CCR5-tropic infection in vivo.

Lentiviral CCR5 Intrabody Gene Delivery Provides Protection and Enrichment during CCR5-Tropic Infection.

The molecular mechanism of human immunodeficiency virus type 1 (HIV-1) entry into target cells is a multistep mechanism. The viral envelope glycoproteins (env) binds first to CD4 and subsequently interacts with the V3 loop with a chemokine receptor, CCR5 or CXCR4, triggering the fusion event. Several findings suggest that viruses using CCR5 for entry (R5-tropic HIV-1) is the predominant species transmitted among patients. Importantly, CCR5 expression levels determine disease progression. CCR5 does not seem to be necessary for normal cell function, since individuals with a homozygous mutation (Δ32) do not appear to have clinical, immune alterations. Furthermore, these individuals are highly protected against transmission of R5-tropic HIV-1. Therefore, intervention strategies aimed at altering or blocking CCR5 expression may be beneficial for cellular protection and provide a clinical benefit against HIV-1 infection. We have constructed an HIV-1 derived vector, CAD-R5, expressing an intracellular single-chain antibody (intrabody) specific for CCR5 coupled to a KDEL endoplasmic reticulum retention signal. Intrabody expressing primary T-cells efficiently disrupted CCR5 cell surface expression with a 4.3-fold reduction in CCR5 mean fluorescence intensity (MFI) as compared to the control vector without the intrabody gene (7.9 and 33.6 MFI, respectfully). CAD-R5 transduced primary CD4 T-cells expressing the intrabody gene were resistant to R5-tropic HIV infection as shown by a 50 to 60-fold reduction in HIV-1 p24 concentration. Moreover, intrabody gene expressing cells demonstrated a selective advantage and enriched by 6.4-fold in a population of infected cells as compared to uninfected or infected cells containing vector without the intrabody gene. The SCID-human mouse model, produced by conjoining fetal human thymus and liver under the renal capsule, has become a staple for in vivo testing of T cell anti-retroviral therapy. When CAD-R5 transduced, fetal liver derived CD34+ stem cells were used for reconstitution of the human implants in SCID-hu mice (n = 2, 2 groups), 6-weeks later the human thymi displayed an average of 25% reporter gene expressing T cells. Thymocyte development was not altered by vector integration or loss of CCR5 cell surface expression as determined by the CD4+/CD8+ staining profile. Importantly, CCR5 intrabody expressing thymocytes were also highly resistant to ex vivo R5-tropic HIV-1 challenge with a 3-fold reduction in viral load. These results validate the efficacy of lentiviral delivered CCR5 intrabody mediated protection from R5-tropic HIV-1. The findings also underscore the potential advantage of intrabody gene delivery to CD34+ stem cells, which allows differentiation of protected T cell progeny.