Primary Human Immunodeficiency Virus Type 1 Nef Alleles Show Major Differences in Pathogenicity in Transgenic Mice

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Abstract
We previously reported that the human immunodeficiency virus type 1 NL4-3 Nef is necessary and sufficient to induce a severe AIDS-like disease in transgenic (Tg) mice when the protein is expressed under the regulatory sequences of the human CD4 gene. We have now assayed additional Nef alleles (SF2, JR-CSF, YU10x, and NL4-3 [T71R] Nef alleles), including some from long-term nonprogressors (AD-93, 032an, and 039nm alleles) in the same Tg system and compared their pathogenicities. All these Nef alleles downregulated cell surface CD4 in human cells in vitro and also, with the exception of NefYU10x, in Tg CD4+ T cells. Depletion of double-positive and single-positive thymocytes occurred with all alleles but was less pronounced in NefYU10x Tg mice. A loss of peripheral CD4+ T cells was observed with all alleles but was minimal in NefYU10x Tg mice. In Nef032an and NefSF2 Tg mice, T-cell loss was severe despite lower levels of Tg expression, suggesting a higher virulence of these alleles. All Nef alleles except the NefYU10x and NefNL4-3(T71R) alleles induced an enhanced activated memory (CD25+ CD69+ CD44high CD45RBlow CD62Llow) and apoptotic phenotype. Also, all could interact with and/or activate PAK2 except the NefJR-CSF allele. Organ (lung and kidney) diseases were present in NefNL4-3(T71R), Nef032an, Nef039nm, and NefSF2 Tg mice, despite very low levels of Tg expression for the last strain. However, no organ disease or minimal organ disease developed in NefYU10x and NefAD-93 Tg mice and NefJR-CSF Tg mice, respectively, despite high levels of Tg expression. Our data show that important differences in the pathogenicities of various Nef alleles can be scored in Tg mice. Interestingly, our results also revealed that some phenotypes can segregate independently, such as CD4+ T-cell depletion and activation, as well as severe depletion of thymic CD4+ T cells and peripheral CD4+ T cells. Therefore, expression of Nef alleles in Tg mice under the CD4C regulatory elements represents a novel assay for measuring their pathogenicity. Because of the very high similarity of this murine AIDS-like disease to human AIDS, this assay may have a predictive value regarding the behavior of Nef in infected humans.