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. 2004 Apr 13;101(15):5640-5.
doi: 10.1073/pnas.0308425101. Epub 2004 Apr 2.

Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection

Zhi-Qiang Zhang  1 , Stephen W Wietgrefe, Qingsheng Li, Marta Dykhuizen Shore, Lijie Duan, Cavan Reilly, Jeffrey D Lifson, Ashley T Haase
Affiliations

Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection

Zhi-Qiang Zhang et al. Proc Natl Acad Sci U S A. .

Abstract

In studies of sexual mucosal transmission and early stages of simian immunodeficiency virus (SIV) and HIV infections, productive infection predominates in CD4(+) T cell populations, in both ostensibly resting and activated cells. The surprising ability of SIV and HIV to replicate in resting cells in vivo, in contrast to propagation of infection in vitro, suggested a model in which during the early stages of infection these viruses exploit the greater availability of resting cells to maintain unbroken chains of transmission from an infected resting cell to another resting cell nearby. Because immune activation in response to infection provides more activated CD4(+) T cells, these viruses take advantage of the greater efficiency of virus production and spread in activated cells for propagation and dissemination of infection. In this article, we report the results of experimental tests of this model, including visualization at the light microscopic level and direct analysis of virus production by cells in tissues. Analysis of tissues of rhesus macaques inoculated intravaginally or i.v. with SIV supports the proposed roles of target cell availability, susceptibility, and virus production by infected resting and activated CD4(+) T cells in mucosal transmission and early infection, and points to a potential role for topical anti-inflammatory agents in moderating the initial propagation of infection.

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Figures

Fig. 1.
Fig. 1.
Target cell substrate availability and virus production by infected resting and activated CD4+ T cells in transmission and acute infection. Virus that crosses the mucosal barrier and spreads to LTs can infect susceptible DCs, macrophages, and both resting and activated CD4+ cells at the portal of entry and in LTs. Because the population of resting CD4+ cells is larger than the other cell types, most of the productively infected cells initially are resting CD4+ T cells. They propagate infection by infecting other nearby resting CD4+ T cells. Infected activated CD4+ T cells produce more virions and transmit infection to cells at greater distances than infected resting cells. Over time, infection-related immune activation leads to an increasing proportion of activated CD4+ T cells in infected cell pool at the portal of entry and LTs, to which infection is disseminated.
Fig. 2.
Fig. 2.
Immune activation, availability, and infection of resting and activated CD4+ T cells. (A and B) There are increased numbers of Ki67+ (brown stained) T cells in the paracortex, and B cells in follicles in sections of LN at 4 weeks after i.v. inoculation of SIV, compared with 1 week. (C and D) There are increased numbers of Ki67+ (blue gray nuclei) and CD4+ T cells (red cytoplasm; arrows) at 4 weeks, compared with 1 week. (E and F) There are more Ki67+ (brown nuclei) and SIV RNA+ (black silver grains; long arrows) cells at 4 weeks, compared with 1 week, where most of the SIV RNA+ cells are Ki67– (short arrows).
Fig. 3.
Fig. 3.
(A) Proportions of CD4+ Ki67+ or Ki67– T cells and SIV RNA+ Ki67+ or Ki67– cells. The proportions of SIV RNA+ Ki67+ or Ki67– T cells were determined as described in the text and plotted as averages for the four animals (solid lines and symbols) and individual animals (red dashed lines and open symbols). (B) Changes in frequency of Ki67+- and Ki67–-infected T cells and plasma SIV RNA level from weeks 1 to 4 after i.v. inoculation. Plasma SIV RNA and frequency of SIV RNA+ cells were determined as described in Methods.
Fig. 4.
Fig. 4.
Detection of virions by ISH/TSA/ELF. Virions embedded in agarose were detected in sections as described in Methods. The brightest and largest viral particles in the figure are in the plane of focus. [Original magnifications: ×600 (A) and ×2,000 (B).]
Fig. 5.
Fig. 5.
Detection by ISH/TSA/ELF of SIV RNA in virions and in large Ki67+ and small Ki67– T cells in axillary LN. See text for explanation.
Fig. 6.
Fig. 6.
Virus production by resting and activated T cells 12 days after intravaginal inoculation of SIV. (A) Predominance of small over large SIV RNA+ cells in ectocervical submucosa. (B and C) At higher magnification, virions are evident at the surface and surrounding large activated T cells, in addition to the bright yellow staining associated with intranuclear SIV RNA. In C, arrows point to the small number of virions associated with small T cells. [Original magnification: ×600 (B), ×800 (C), and ×1,600 (Inset).]
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