Cytopathicity of human immunodeficiency virus type 1 primary isolates depends on coreceptor usage and not patient disease status - PubMed (original) (raw)
Cytopathicity of human immunodeficiency virus type 1 primary isolates depends on coreceptor usage and not patient disease status
J F Kreisberg et al. J Virol. 2001 Sep.
Abstract
It has been hypothesized that human immunodeficiency virus type 1 (HIV-1) evolves toward increased cytopathicity in conjunction with disease progression in infected patients. A viral property known to evolve in some but not all patients is coreceptor utilization, and it has been shown that a switch in coreceptor utilization is sufficient for the development of increased cytopathicity. To test the hypothesis that the evolution of other viral properties also contributes to accelerating cytopathicity in vivo, we used human lymphoid tissue explants to assay the cytopathicity of a panel of primary HIV-1 isolates derived from various stages of disease characterized by the presence or absence of changes in coreceptor preference. We found no evidence of coreceptor-independent increases in cytopathicity in isolates obtained either before coreceptor preference changes or from patients who progressed to AIDS despite an absence of coreceptor evolution. Instead, the cytopathicity of all HIV-1 isolates was determined solely by their coreceptor utilization. These results argue that HIV-1 does not evolve toward increased cytopathicity independently of changes in coreceptor utilization.
Figures
FIG. 1
Cytopathic potential of primary HIV-1 isolates correlates with coreceptor utilization but not stage of disease. (A) Dispersed human tonsil tissue in replicate microtiter wells (three for experimental viruses and two for NL4-3) was inoculated with the indicated viruses (Table 1). Biol. Clone, biological clone. Tissue was harvested, immunostained, and analyzed by fluorescence-activated cell sorting 13 days after infection as described previously (14, 22). The total height of the column in the graph represents the ratio of CD4+ T cells to CD8+ T cells. The standard error of the mean is represented by the error bars. (B) The samples shown in panel A were analyzed for depletion of memory and naive cells. Naive CD4+ T cells were defined as CD4+ T cells that were CD45RA+ CD62L+, and all other CD4+ T cells were defined as memory CD4+ T cells (19, 20). (C) Culture supernatant was assayed for HIV-1 p24 by an enzyme-linked immunosorbent assay to monitor viral replication. Experiments with different donor specimens were conducted twice with dispersed cultures and once with tissue blocks; data from a representative experiment are presented.
FIG. 2
Primary R5 HIV-1 isolates from advanced disease in the absence of X4 viremia retain selective cytopathicity for CCR5+ T cells. Experiments were performed with the indicated viruses (Table 1) as described in the legend to Fig. 1. (A) Depletion of CD4+ T cells, including total CD4+ T cells, and CCR5+ and CCR5− subsets. (B) Depletion of memory and naive subsets of CD4+ T cells. (C) HIV-1 replication kinetics. Experiments with different donor specimens were conducted twice with dispersed cultures and once with tissue blocks; data from a representative experiment are presented.
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