Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Abstract

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the common causes of cognitive dysfunction and morbidity among infected patients. However, to date, it remains unknown if a transmitted/founder (T/F) HIV-1 leads to neurological disorders during acute phase of infection. Since it is impossible to answer this question in humans, we studied NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ mice (NSG) reconstituted with human PBMC (NSG-HuPBL), followed by the peritoneal challenge with the chronic HIV-1JR-FL and the T/F HIV-1BJZS7, respectively. By measuring viral load, P24 antigenemia and P24(+) cells in peripheral blood and various tissue compartments, we found that systemic infections were rapidly established in NSG-HuPBL mice by both HIV-1 strains. Although comparable peripheral viral loads were detected during acute infection, the T/F virus appeared to cause less CD4(+) T cell loss and less numbers of infected cells in different organs and tissue compartments. Both viruses, however, invaded brains with P24(+)/CD3(+) T cells detected primarily in meninges, cerebral cortex and perivascular areas. Critically, brain infections with HIV-1JR-FL but not with HIV-1BJZS7 resulted in damaged neurons together with activated microgliosis and astrocytosis as determined by significantly increased numbers of Iba1(+) microglial cells and GFAP(+) astrocytes, respectively. The increased Iba1(+) microglia was correlated positively with levels of P24 antigenemia and negatively with numbers of NeuN(+) neurons in brains of infected animals. Our findings, therefore, indicate the establishment of two useful NSG-HuPBL models, which may facilitate future investigation of mechanisms underlying HIV-1-induced microgliosis and astrocytosis.

Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice

“…To prepare for in vivo efficacy experiments, the anti-HIV-1 activity of BiIA-SG was evaluated using 2 authentic live viral strains, the R5-tropic HIV-1 JR-FL (subtype B) and the R5-tropic T/F virus HIV-1 BJZS7 (subtype CRF01_AE). Both HIV-1 JR-FL , a tier-2 virus relatively resistant to antibody neutralization (8), and HIV-1 BJZS7 established robust systemic and mucosal infections in NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ-human peripheral lymphocyte (NSG-HuPBL) mice, as we recently described (41). We found that live HIV-1 JR-FL was resistant to IA-Hu5A8 neutralization but was sensitive to IA-PGT128 with an IC 50 value of 12.07 nM (Figure 3C, left).The combined equimolar IA-Hu5A8 and IA-PGT128 displayed enhanced neutralizing activity with the IC 50 value improved by 6.4-fold to 1.88 nM compared with IA-PGT128.…”

“…BiIA-SG confers sterile protection against genetically divergent HIV-1 challenges in humanized mice. To determine the protection efficacy in vivo, we examined the effect of a single injection of BiIA-SG in the HIV-1/NSG-HuPBL model ( Figure 5A) (41). A bioreactor product of BiIA-SG generated a peak of 90% purity by size exclusion chromatography analysis ( Figure 5B).…”

“…Groups of NSG-HuPBL mice were injected with either BiIA-SG or a placebo (PBS) 1 hour before intraperitoneal (i.p.) inoculation with 10 ng P24 of HIV-1 JR-FL (41). All placebo mice (n = 5, 3 M, 2 F) were infected with peak plasma viral loads up to 10 7 copies/ml ( Figure 5D), and exhibited P24 antigenemia ( Figure 5E), a trend of CD4 + T cell loss over time ( Figure 5F), and P24 + T cells in blood and spleens (Figures 5, G and H) at 2 weeks postinfection (wpi).…”

T cells establish and maintain CNS viral infection in HIV-infected humanized mice

“…Other humanized mouse models used to study neuroHIV infection are created by the transplantation of human cells, either peripheral blood mononuclear cells (PBMCs) or CD34 + hematopoietic stem cells, into immunodeficient mice. HIV-infected human T cells were observed in the meninges and cortex of HIV-infected human PBMC-transplanted (hPBMC-transplanted) mice along with microgliosis and neuronal dropout (42). In humanized NSG (hNSG) mice, a CD34 + stem cell-reconstituted model, HIV RNA was detected in the brains of a portion of HIV-infected mice, although the levels of HIV DNA were below the limit of detection (43).…”

Promoting Global Health — Prevention and Treatment of Substance Abuse and HIV in Asia

“…Yang et al investigated how viral proteins and nicotine modulated the expression of immune-related genes in the brains of the HIV-1 transgenic rats (Yang et al, 2016). Wu et al determined how a transmitted/founder HIV-1 led to neurological disorders during the acute phase of infections in humanized mice (Wu et al, 2016). Wei et al examined how chronic administration of delta9-tetrahydrocannabinol D led to reduction of IgE+B cells without enhancing pathogenicity in SIVmac251-infected male Chinese-derived rhesus macaques (Wei et al, 2016).…”