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Abstrato

Nef Deletion in HIV-1eli Eliminates Peripheral CD4 T-Cell Loss in a Humanized BLT Mouse Model of HIV Disease

Clever JL, Tam SM, Rold CJ, Strings VR, Wadekar S, Lira V, Fatehi E, Bansal N, Martin V and Apte S

Background: Humans infected with HIV-1 containing nef gene deletions show very slow or non-progression to AIDS. Therefore, a nef-deleted HIV-1 may be useful in generating a pathogenically-attenuated candidate therapeutic HIV-1 vaccine. We have created a mutant of HIV-1_eli lacking a functional nef gene. In this study we have characterized the pathogenic phenotype of this mutant in an animal model of HIV-1 disease.

Methods and findings: We determined the contribution of the nef gene to replication and infectivity in cell culture and to pathogenesis in humanized BLT mice after infection with HIV-1_eli, a CXCR4-tropic subtype D virus. We constructed a nef-null virus to create HIV-1_eliΔnef. Human peripheral blood mononuclear cell cultures from 13 different donors were infected and viral growth was monitored for 14 days. HIV-1_eli produced higher p24 levels compared to HIV-1_eliΔnef, indicating lower viral replication. HIV-1_eli and HIV-1_eliΔnef were then used to infect humanized BLT mice. Viremia was delayed several weeks in the HIV-1_eliΔnef-infected mice compared to HIV-1_eli. Viremia was evident in the majority of mice infected with HIV-1_eli by 3 weeks post-infection while viremia was not evident in any HIV-1_eliΔnef infected mice until 7 weeks post-infection. Mice infected with HIV-1_eli harbored an average of 2.94e5 ± 1.6e5 copies of viral RNA/ml in blood. In contrast, blood from mice infected with HIV-1_eliΔnef harbored an average of 4.4e3 ± 4.5e3 copies of viral RNA/ml; a ~1.5-log reduction in average viremia. Flow cytometry revealed that all mice infected with HIV-1_eli showed a precipitous decline in the ratio of human CD4⁺ to CD8⁺ T-cells in peripheral blood from week 1 to week 7 post-infection. In sharp contrast, none of the mice infected with HIV-1_eliΔnef showed a sustained decline of CD4⁺ to CD8⁺ T-cells from week 1 to week 10 post-infection.

Conclusions: We conclude that nef is necessary for high levels of viral replication both in vitro and in vivo and for depletion of peripheral CD4⁺ T-cells in HIV-1_eli, a pathological hallmark of HIV-1 disease. We have generated and characterized a pathogenically-attenuated mutant of HIV-1_eli lacking a functional nef gene in a humanized mouse model of HIV-1 disease.