A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness

Abstract

We created a model of HIV-1 infection of conventional mice for investigation of viral replication, control, and pathogenesis. To target HIV-1 to mice, the coding region of gp120 in HIV-1/NL4-3 was replaced with that of gp80 from ecotropic murine leukemia virus, a retrovirus that infects only rodents. The resulting chimeric virus construct, EcoHIV, productively infected murine lymphocytes, but not human lymphocytes, in culture. Adult, immunocompetent mice were readily susceptible to infection by a single inoculation of EcoHIV as shown by detection of virus in splenic lymphocytes, peritoneal macrophages, and the brain. The virus produced in animals was infectious, as shown by passage in culture, and immunogenic, as shown by induction of antibodies to HIV-1 Gag and Tat. A second chimeric virus based on clade D HIV-1/NDK was also highly infectious in mice; it was detected in both spleen and brain 3 wk after tail vein inoculation, and it induced expression of infection response genes, MCP-1, STAT1, IL-1beta, and complement component C3, in brain tissue as determined by quantitative real-time PCR. EcoHIV infection of mice forms a useful model of HIV-1 infection of human beings for convenient and safe investigation of HIV-1 therapy, vaccines, and potentially pathogenesis.

Vaccine-induced protection from infection of mice by chimeric human immunodeficiency virus type 1, EcoHIV/NL4-3

“…Serological responses to HIV-1 Gag were measured as a simple readout for immunization. Most infected mice mounted immune responses to HIV-1 Gag one week after the challenge infection; two of five control mice mounted responses, indicating that EcoHIV/NL4-3 infection itself induces humoral responses, as previously observed [3] (Figure 1). VRC 4306 immunized mice had higher titres than the control group and four out of five mounted responses but the differences did not reach statistical significance (by t Test p=0.07 or by Chi-square test, p=0.197).…”

“…EcoHIV/NL4-3 burden was reduced in both spleen cells and macrophages in VRC 4306 immunized mice compared to controls. Using magnetic bead purification of CD4 bearing T lymphocytes from spleens of infected mice, we have previously shown that lymphocytes account for the majority of Eco/NL4-3 infected cells in the spleen [3], however we cannot rule out the possibility that some of the infection observed in unfractionated spleen arises from macrophages. The magnitude of the reduction of virus burden with immunization shown here was greater in macrophages than in spleen cells.…”

“…In this model, HIV-1 proteins expressed by infected lymphocytes and macrophages assemble to form infectious HIV-1 [3], a system closely analogous to the infected human host. Like infected humans, infected mice mount serological responses to HIV-1 proteins.…”

“…Adult female C57BL6/J mice were immunized by four intramuscular injections of 100 μg VRC 4306 or control plasmid pUC19 at two week intervals with five mice per group. Seven weeks and ten weeks after the first immunization, mice were infected with 5 × 10 6 pg p24 EcoHIV/NL4-3 by intraperitoneal injection of cell-free virus, prepared as described [3]. One week after the challenge EcoHIV/ NL4-3 infection, mice were euthanized by carbon dioxide asphyxiation and blood, spleen, and peritoneal macrophages were collected.…”

“…To permit the use of conventional mice for investigation of HIV-1 replication and control, we switched the tropism of HIV-1 from human to rodent [3]. The regions encoding gp120 of subtype B NL4-3 [4] and subtype D NDK [5] were replaced with that of the gp80, the envelope of ecotropic murine leukemia virus (MLV).…”