Journal Article

Determinants in HIV-1 Nef for enhancement of virus replication and depletion of CD4+ T lymphocytes in human lymphoid tissue ex vivo

Baumann, Ingo, Keppler, Oliver T, Fackler, Oliver T, Sertel, Serkan, Homann, Stefanie, Tibroni, Nadine

2009

Overview

Background HIV-1 Nef critically contributes to AIDS in part by augmenting virus titers in infected individuals. Analyzing which of Nef's activities contribute to HIV pathogenesis has been hampered by the lack of a cell culture model in which Nef exerts pronounced effects on HIV replication. The human lymphoid aggregate culture (HLAC) from tonsil maintains the cell populations and cytokine milieu found in vivo , supports a productive infection without exogenous stimulation, and Nef contributes to efficient HIV-1 replication as well as CD4 + T cell depletion in this experimental ex vivo -model. Results To identify determinants in Nef that mediate these activities, we infected HLAC with a panel of isogenic HIV-1 NL4-3 strains that encode for well-characterized mutants of HIV-1 SF2 Nef. Determination of HIV-1 replication revealed that enhancement of the virus spread by Nef is governed by a complex set of protein interaction surfaces. In contrast, increased CD4 + T lymphocyte depletion depended on only two protein interaction surfaces in Nef that mediate either downregulation of cell surface CD4 or interaction with the NAKC signalosome. Consistently, in HLAC from 9 out of 14 donors, Nef enhanced CD4 + T cell depletion in the absence of a significant effect on virus replication. Moreover, our results suggest that this Nef-dependent enhancement in depletion occurred predominately in uninfected bystander CD4 + T cells. Conclusion Our findings suggest that Nef facilitates depletion of CD4 + T lymphocytes in HIV-1-infected lymphoid tissue ex vivo by increasing the pool of productively infected cells and by sensitizing bystander cells for killing. This ability might contribute to Nef's pathogenic potential in vivo .

• Publisher: BioMed Central,BMC
• Subject: Antibodies / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD4-Positive T-Lymphocytes - virology / HIV-1 - physiology / Humans / Infectious Diseases / Lymphoid Tissue / nef Gene Products, Human Immunodeficiency Virus - genetics / nef Gene Products, Human Immunodeficiency Virus - physiology / Organ Culture Techniques / Protein Structure / Vaccine / Virology / Virulence Factors - genetics / Virulence Factors - physiology / Virus Replication