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. 2000 Apr;74(7):3196-204.
doi: 10.1128/jvi.74.7.3196-3204.2000.

Human immunodeficiency virus type 1 pathogenesis in SCID-hu mice correlates with syncytium-inducing phenotype and viral replication

D Camerini  1 , H P Su, G Gamez-Torre, M L Johnson, J A Zack, I S Chen
Affiliations

Human immunodeficiency virus type 1 pathogenesis in SCID-hu mice correlates with syncytium-inducing phenotype and viral replication

D Camerini et al. J Virol. 2000 Apr.

Abstract

Human immunodeficiency virus type 1 (HIV-1) patient isolates and molecular clones were used to analyze the determinants responsible for human CD4(+) thymocyte depletion in SCID-hu mice. Non-syncytium-inducing, R5 or R3R5 HIV-1 isolates from asymptomatic infected people showed little or no human CD4(+) thymocyte depletion in SCID-hu mice, while syncytium-inducing (SI), R5X4 or R3R5X4 HIV-1 isolates from the same individuals, isolated just prior to the onset of AIDS, rapidly and efficiently eliminated CD4-bearing human thymocytes. We have mapped the ability of one SI HIV-1 isolate to eliminate CD4(+) human cells in SCID-hu mice to a region of the env gene including the three most amino-terminal variable regions (V1 to V3). We find that for all of the HIV-1 isolates that we studied, a nonlinear relationship exists between viral replication and the depletion of CD4(+) cells. This relationship can best be described mathematically with a Hill-type plot indicating that a threshold level of viral replication, at which cytopathic effects begin to be seen, exists for HIV-1 infection of thymus/liver grafts in SCID-hu mice. This threshold level is 1 copy of viral DNA for every 11 cells (95% confidence interval = 1 copy of HIV-1 per 67 cells to 1 copy per 4 cells). Furthermore, while SI viruses more frequently achieve this level of replication, replication above this threshold level correlates best with cytopathic effects in this model system. We used GHOST cells to map the coreceptor specificity and relative entry efficiency of these early- and late-stage patient isolates of HIV-1. Our studies show that coreceptor specificity and entry efficiency are critical determinants of HIV-1 pathogenesis in vivo.

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Figures

FIG. 1
FIG. 1
Two-color flow cytometric immunofluorescence assay of CD4 and CD8 expression on human thymocytes derived from SCID-hu mice 6 weeks after mock infection or infection with sequential NSI and SI patient A-derived biological clones of HIV-1. Cells were isolated from thymus/liver grafts in SCID-hu mice, incubated with CD4-PE and CD8-FITC, washed, and run on a FACScan flow cytometer. The data are representative of those presented in Table 1.
FIG. 2
FIG. 2
HIV-1 DNA copies per 105 cells detected in thymus/liver graft cells derived from SCID-hu mice 6 weeks after infection with sequential NSI and SI isolates and biological clones derived from patients A, B, and D. Cells were isolated and lysed, nucleic acids were purified, and PCR was performed using a primer pair complementary to HIV-1 LTR DNA and separately with a primer pair complementary to the human β-globin gene. One oligonucleotide of each primer pair was labeled with 32P, and the PCR products were resolved on a 6% polyacrylamide gel and quantitated using a set of standards and a PhosphorImager as described in Materials and Methods.
FIG. 3
FIG. 3
Time course of HIV-1 DNA copies per 105 cells detected in cells derived from SCID-hu mice 3, 6, 9, and 13 weeks postinfection with sequential NSI and SI biological clones derived from patient B. Not all grafts were biopsied at time points after 6 weeks postinfection due to death of the mice. Only grafts 3 and 4 were also biopsied 7 weeks postinfection. The number of copies of HIV-1 DNA per 105 cells derived from human thymus liver grafts in SCID-hu mice at each time point was determined as described in the legend to Fig. 2.
FIG. 4
FIG. 4
Alignment of predicted V3 regions of gp120 encoded by the env genes of HIV-1 strains used in this study. The patient (Pt.) from which the isolates are derived or clone name and MT-2 cell syncytium induction phenotype of each viral isolate is shown along with the predicted amino acid sequence and charge of the disulfide-bound V3 loop domain. For the primary isolates sequenced and characterized in this study, the date of viral isolation is also given. Amino acid positions where charge differences exist among the residues predicted for the two isolates from each patient are underlined. The sequences of JR-CSF and NL4-3 were obtained from the Los Alamos National Laboratory HIV sequence database.
FIG. 5
FIG. 5
Two-color flow cytometric immunofluorescence assay of CD4 and CD8 expression on human thymocytes derived from SCID-hu mice 9 weeks after mock infection or infection with 200 TCID50 of JR-CSF, JR-CSF/V1-V3 A-NSI Env, and JR-CSF/V1-V3 A-SI Env molecular clones of HIV-1. Cells were isolated from thymus/liver grafts in SCID-hu mice, incubated with CD4-PE and CD8-FITC, washed, and run on a FACScan flow cytometer. The data are representative of those presented in Fig. 6.
FIG. 6
FIG. 6
HIV-1 DNA copies versus percentage of CD4 CD8 DP cells in human thymus/liver graft cells derived from SCID-hu mice. The number of copies of HIV-1 DNA per 105 cells derived from human thymus liver grafts in SCID-hu mice 3, 4, or 6 weeks postinfection was determined as described in the legend to Fig. 2. In each case, the number of viral DNA copies reached its maximum measured value at this time point. The percentage of CD4 CD8 DP cells recovered 6 or 7 weeks postinfection was determined as described in the legend to Fig. 1 and plotted against the viral load at 3. 4, or 6 weeks postinfection for each graft. Each symbol represents a separate human thymus/liver graft infected as defined in the key.
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