Memory CD4 ⁺ T Cells Are the Earliest Detectable Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells in the Female Genital Mucosal Tissue during HIV-1 Transmission in an Organ Culture System

Abstract

The virologic and cellular factors that are involved in transmission of human immunodeficiency virus type 1 (HIV-1) across the female genital tissue are poorly understood. We have recently developed a human cervical tissue-derived organ culture model to study heterosexual transmission of HIV-1 that mimics the in vivo situation. Using this model we investigated the role of phenotypic characteristics of HIV-1 and identified the cell types that are first infected during transmission. Our data indicate that the cell-free R5 HIV-1 was more efficiently transmitted than cell-free X4 HIV-1. Cell-free and cell-associated HIV-1 had comparable transmission efficiency regardless of whether the virus was of R5 or X4 type. We have demonstrated that memory CD4 Heterosexual transmission accounts for the majority of worldwide human immunodeficiency virus type 1 (HIV-1) infections in women (17,20,21). Very little is known about the role of biologic and molecular characteristics of HIV-1 during sexual transmission. Since semen has been shown to contain free infectious HIV-1 and HIV-1-infected cells (19,26,(32)(33)(34)(35), transmission could potentially occur via cell-free and cell-associated HIV-1. Studies on the viral envelope sequence in men during primary infection suggest that virus transmitted during sexual contact was mostly homogeneous and had macrophagetropic and non-syncytium-inducing phenotypes (35, 37). However, recent data of Long et al. (16) indicate that heterogeneous HIV-1 was found in women, whereas homogeneous virus was detected in men soon after sexual contact, indicating that the mechanism of sexual transmission of HIV-1 in women could be different than that in men.There are no in vivo data to indicate the cell types that first become infected in the reproductive tract of women. Although in chronically HIV-1-infected women T cells, macrophages, and Langerhans cells in cervical tissue are infected with HIV-1 (25, 26), analysis of lymph nodes in HIV-infected men during the acute phase of infection indicates that actively virus replication occurs in activated and resting CD4 ϩ T cells (36). A number of studies have demonstrated that productively HIV-1-infected cells in vivo are memory T cells (CD4 ϩ CD45RO ϩ ) that respond to antiretroviral therapy (22,24). There is controversy in the simian immunodeficiency virus (SIV)-rhesus monkey model system about the types of cells that become first infected during sexual transmission. Spira et al. (28) found that cells which initially become infected in the female genital tract are Langerhans cells present in the lamina propria, but the identity of these cells could not be determined by specific immunohistochemical staining on contiguous tissues. Moreover, this study could not determine whether these HIV-1 DNA-containing cells were productively infected. On the other hand, using simultaneous in situ hybridization and immunohistochemical staining, Zhang et al. (36) recently found that CD4 ϩ T (both activated and resting) cells and not dendritic cells were predominantly the...

Langerhans cells and viral immunity

“…There has been much debate about the mechanisms of HIV infection and entry via the female genital tract, including the importance of epithelial breaches or microabrasions and the cell types involved [16][17][18]. This has become of increasing importance because of the recent problems in vaccine development against , and therefore there is a need for alternative methods to prevent HIV-1 transmission.…”

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

“…4 Furthermore, studies have shown that accumulation of CD4 + T cells in human cervical tissue was detected within 6 h post-HIV infection. 17 Previous study has also reported an increased production of cytokines such as CXCL1 and CXCL10 in culture supernatant of HIV-exposed Ectocervical epithelia were exposed to HIV or control supernatant in an organ culture for 24 h. The tissues exposed to control supernatant were treated with or without 10 mM EDTA in the final 2-h incubation time. HIV-or control supernatantexposed tissues (with or without EDTA) were further exposed to FITC-labeled dextran (3 kDa) for 1 h at 37°C in a CO 2 incubator.…”

“…15,16 Studies have reported upregulation of TSLP in human cervical epithelial cell lines post-HIV exposure that strongly activates human myeloid dendritic cell (DC), 14 while others have shown accumulation of CD4 + T cells within 6 h post-HIV infection in human cervical tissue. 17 Therefore, epithelial cells may be the first target for HIV to induce local immune activation, which facilitates the establishment of initial HIV infection in the submucosal region.…”

Ex Vivo Modeling of Oral HIV Transmission in Human Palatine Tonsil

“…Partially overlapping information could be obtained by experimental analysis of tissue biopsies taken from newly exposed individuals but, in the context of community-acquired infections, characterization of the inocula may not be possible and anti-retroviral therapy may be instigated at the time of patient presentation. Thus, from the standpoint of both controlling and then adjusting experimental variables, there are numerous opportunities and benefits to be derived from studies relying on human organ cultures now that the systems have been validated (Glushakova et al 1995(Glushakova et al ,1999Collins et al 2000;Greenhead et al 2000;Gupta et al 2002;Zhao et al 2004). We have shown that cell-free HIV (HIV96-480, a low passage primary patient isolate) can establish infections in tonsillar leukocytes when infectivity is applied directly Original magnification ϫ100.…”