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Table 3 Rag2-/-γc-/- Mouse-based Human Chimeric Model

From: Summary of presentations at the NIH/NIAID New Humanized Rodent Models 2007 Workshop

 

Dr. Akkina

Drs. Speck and Luban

Dr. Su

Characteristics of Humanized Rodent Models

   

Strain

Balb/c-Rag2-/-γ c-/-

Balb/c-Rag2-/-γ c-/-

Balb/c-Rag2-/-γ c-/-

# mice/donor

40/donor

CD34+ cell isolation yields 1–2 × 106 cells/donor sufficient for 5–10 mice (1 litter)

20–50/donor

Source of human cells

Fetal liver

Cord blood

Fetal liver

Method of isolation

Magnetic bead enrichment for CD34+ cells

Magnetic bead enrichment for CD34+ cells

CD34+ MACS kit

Pre-transplant treatment-mice

Irradiation 350 rads; intrahepatic injection into newborns

Irradiation 200 rads given twice 4 h apart; intrahepatic injection into newborns

Irradiation 400 rad; intrahepatic injection into newborns

Pre-transplant treatment-cells

SCF, IL-3, IL-6

None

None or retroviral transduction

Time frame from construction to experimental use

12 weeks

12–16 weeks

>12 weeks

Location of human hematopoiesis

Bone marrow

Not investigated

BM, Spleen, LN

Location of human Thymopoiesis

Mouse thymus

Not investigated

Mouse thymus

Reproducibility of engraftment (% mice engrafted)

>95%

More than 90% of mice show human cells in periphery; about 50% of mice have levels >10% huCD45+ cells

>95% with >20% human CD45+ cells in blood

Identity of specific human leukocytes present

T and B cells, DCs, monocytes/macrophages and some granulocytes

B and T cells, monocytes, DCs

All human leukocytes

Populated tissues

Bone marrow, lymph nodes, thymus, spleen, liver, intestines, lungs

Thymus, spleen, blood, MLN, BM, liver; to some extent: gut

BM/thymus/spleen/LN (no significant Peyer's patches found)

Characteristics of HIV Infection of Humanized Rodent Models

   

HIV-specific immune response

Not detected

Some minor B cell response (1/25 animals tested); no T cell response detected

Low gag-specific responses/no IgG detected

Tropism/clade of infecting HIV

R5, X4, dual-tropic

YU-2 and NL4-3

R5-X4-dual or R5/clade B

Target cells infected

CD4 T cells

CD3+ cells and only occasionally non T cells such as CD68+ macrophages

CD4 T and DC

Level of plasma HIV viremia

~107 copies RNA/ml

Up to 2 × 106 copies/ml

105-106 copies/ml

Duration of the infection

at least 14 months

Up to 190 days; longest period followed

>22 weeks

Replication kinetics

Peak viremia at about 6 weeks followed by maintenance of viremia

HIV RNA levels peak 2–6 wpi, thereafter viremia mostly stabilizes at lower levels.

HIV RNA levels peaks at 2–3 (dual tropic) or 4–6 wpi (R5-tropic)

In vivo generation of ART resistance

Not done

Not tested

Not known

Treatment of HIV Infection Using Humanized Rodent Models

   

ART to block transmission

Not done

Not done

Not done

Microbicide to block transmission

Not done

Not done

Not done

ART to control replication

Not done

Not done

Yes.

Emergence of resistance to ART

Not done

Not done

Not done

Elimination of HIV reservoirs

Not done

Not done

Not done

HSC gene therapy to protect progeny cells

yes

Not done

Not done

CD4 T cell gene therapy to protect cells

Not done

Not done

Not done

Immune-based Therapy of HIV Infection Using Humanized Rodent Models

 

Not done

 

Preventive HIV vaccines

Not done

Not done

Not done

Treatment HIV vaccines

Not done

Not done

Not done

Adoptive Anti-HIV Ig therapy

Not done

Not done

Not done

Adoptive Anti-HIV CTL therapy

Not done

Not done

Not done

Immunoadjuvent therapy

Not done

Not done

Not done

Investigation of HIV Pathogenesis

   

Contribution of HIV genes to pathogenesis

yes

Not done

Env/Nef

HIV-mediated CD4-depletion-lymphoid

yes

yes

Yes

HIV-mediated CD4-depletion-mucosal

Not done

Not done

mesenteric LN, yes

Effects of co-factors on replication

Not done

Not done

Not done

Effects of co-infection e.g. mTb on replication

Not done

Not done

Not done

End organ dysfunction

Not done

Not done

Not done