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Table 3 Considerations in model choice for evaluating vectored delivery of bNAbs against HIV-1

From: Adeno-associated virus gene delivery of broadly neutralizing antibodies as prevention and therapy against HIV-1

Characteristics

Hu-PBMC-NSG mice

Hu-CD34-NSG mice

Bone marrow-liver-thymus (BLT) mice

Macaques

Construction

Injection of expanded human PBMCs into NSG mice

Injection of fetal hu-CD34+ hematopoietic stem cells into newborn irradiated NSG mice

Injection of fetal hu-CD34+ hematopoietic stem cells into newborn irradiated NSG mice, along with surgical implantation of autologous thymus and liver tissue

Not needed

Antibody immunogenicity

(+) No strong anti-drug antibody response, permitting sustained antibody expression

(+) No strong anti-drug antibody response, permitting sustained antibody expression

(+) No strong anti-drug antibody response, permitting sustained antibody expression

(−) Strong anti-drug antibody responses, which is not fully resolved with antibody simianization

Immune functionality

(−) Activated human T-cell engraftment, but largely lacking other lineages, no hematopoietic regenerative source, no HLA-restriction, and no primary immune response

(-) Multi-lineage hematopoiesis with functional human T cell compartment that is mouse H2-restricted, but inconsistent humoral and Fc receptor effector responses

(+/−) Multi-lineage hematopoiesis with functional human T cell compartment that is HLA-restricted, but inconsistent humoral and Fc receptor effector responses

(+/−) Functional immune system, but is simian

Model longevity

(−) Up to 8 weeks due to GvHD

(+) Up to a year

(+) Up to a year

(+) Many years

HIV replication

(+) Supports HIV replication

(+) Supports HIV replication

(+) Supports HIV replication

(−) Does not support HIV replication (have to use either SIV or SHIV)

Challenge routes

(−) Intravenous only

(−) Intravenous only

(+) Intravenous, Intravaginal, Intrarectal

(+) Intravenous, Intravaginal, Intrarectal

Genetic homogeneity

(+) Genetic homogeneity within cohort with same graft, increasing reproducibility

(+) Genetic homogeneity within cohort with same graft, increasing reproducibility

(+) Genetic homogeneity within cohort with same graft, increasing reproducibility

(+/−) Genetic diversity, which can complicate analysis with small numbers

Similarity to human physiology and size

(−) Less

(−) Less

(−) Less

(+) More

Costs

(+) Lowest cost

(+) Low cost

(+/−) Moderate cost, but requires surgery

(−) High cost