Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro

181

We have evaluated the in vivo distribution of the major human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) coreceptors, CXCR4, CCR3, and CCR5, in both rhesus macaques and humans. T lymphocytes and macrophages in both lymphoid and nonlymphoid tissues are the major cell populations expressing HIV/SIV coreceptors, reaffirming that these cells are the major targets of HIV/SIV infection in vivo. In lymphoid tissues such as the lymph node and the thymus, approximately 1 to 10% of the T lymphocytes and macrophages are coreceptor positive. However, coreceptor expression was not detected on follicular dendritic cells (FDC) in lymph nodes, suggesting that the ability of FDC to trap extracellular virions is unlikely to be mediated by a coreceptor-specific mechanism. In the thymus, a large number of immature and mature T lymphocytes express CXCR4, which may render these cells susceptible to infection by syncytium-inducing viral variants that use this coreceptor for entry. In addition, various degrees of coreceptor expression are found among different tissues and also among different cells within the same tissues. Coreceptor-positive cells are more frequently identified in the colon than in the rectum and more frequently identified in the cervix than in the vagina, suggesting that the expression levels of coreceptors are differentially regulated at different anatomic sites. Furthermore, extremely high levels of CXCR4 and CCR3 expression are found on the neurons from both the central and peripheral nervous systems. These findings may be helpful in understanding certain aspects of HIV and SIV pathogenesis and transmission.

mentioning

confidence: 99%

In Vivo Distribution of the Human Immunodeficiency Virus/Simian Immunodeficiency Virus Coreceptors: CXCR4, CCR3, and CCR5

Zhang

Tian

Talal

et al. 1998

181

“…HIV-1 infection of non-CD4-bearing cells has been shown to occur in implants in the SCID-hu mouse and in vitro in cultured thymocytes (2,39,44). Others have reported HIV-1 infection of CD4-negative thymocytes, but these studies did not rule out involvement of a CD4-mediated pathway in infection (15,47). HIV-1 has also been found harbored in CD8 SP lymphocytes in vitro in various culture systems and in the peripheral blood and lungs of patients with AIDS (11,27,31,38).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of human immunodeficiency virus type 1 localization in CD4-negative thymocytes: differentiation from a CD4-positive precursor allows productive infection

Kitchen

Uíttenbogaart

Zack

1997

Human immunodeficiency virus (HIV) infection of the thymus could have profound effects on development of the immune response, particularly in children. We and others have established that in addition to infecting and depleting CD4-bearing thymocytes, functional HIV proviruses are found in thymocytes lacking surface CD4 expression. Using in vitro thymocyte cultures, we show that neither HIV-mediated down regulation of CD4 nor CD4-independent infection contributes to the localization of HIV in cells lacking the primary virus receptor. Rather, infection of a CD4-positive precursor cell (CD4 positive/CD8 positive) with subsequent differentiation into a mature CD4-negative phenotype results in productively infected CD4-negative cells. This novel mechanism may contribute to pathogenesis by distributing viral sequences into functional subsets of T cells typically refractory to HIV infection and could account for the presence of viral DNA in CD8-positive lymphocytes recently observed in patients.

“…These culture conditions form the basis of the slow/low versus rapid/high biological phenotype of CCR5 and CXCR4 tropic primary isolates in PBMC (5). In both PBMC and the SCID-hu mouse, the distribution of thymocyte coreceptors described in this study is a major determinant of the biological phenotype of NL4-3 and JR-CSF (27,28,64,71,74). The expression of CXCR4 on the immature CD3 Ϫ /CD4 ϩ/low / CD8 ϩ thymocytes may lead to a rapid productive infection and destruction of this actively proliferating cell population.…”

Section: Fig 6 Infection Of Total Thymocytes and Cd69 ϩ And Cd69mentioning

confidence: 89%

Differential Tropism and Replication Kinetics of Human Immunodeficiency Virus Type 1 Isolates in Thymocytes: Coreceptor Expression Allows Viral Entry, but Productive Infection of Distinct Subsets Is Determined at the Postentry Level

Pedroza-Martins¹,

Gurney²,

Torbett

et al. 1998

Human thymocytes are readily infected with human immunodeficiency virus type 1 (HIV-1) in vivo and in vitro. In this study, we found that the kinetics of replication and cytopathic effects of two molecular isolates, NL4-3 and JR-CSF, in postnatal thymocytes are best explained by the distribution of chemokine receptors used for viral entry. CXCR4 was expressed at high levels on most thymocytes, whereas CCR5 expression was restricted to only 0.1 to 2% of thymocytes. The difference in the amount of proviral DNA detected after infection of fresh thymocytes with NL4-3 or JR-CSF correlated with the levels of CXCR4 and CCR5 surface expression. Anti-CCR5 blocking studies showed that low levels of CCR5 were necessary and sufficient for JR-CSF entry in thymocytes. Interleukin-2 (IL-2), IL-4, and IL-7, cytokines normally present in the thymus, influenced the expression of CXCR4 and CCR5 on thymocytes and thus increased the infectivity and spread of both NL4-3 and JR-CSF in culture. NL4-3 was produced by both immature and mature thymocytes, whereas JR-CSF production was restricted to the mature CD1−/CD69+ population. Although CXCR4 and CCR5 distribution readily explained viral entry in mature CD69+ and immature CD69− cells, and correlated with proviral DNA distribution, we found that viral production was favored in CD69+ cells. Therefore, while expression of CD4 and appropriate coreceptors are essential determinants of viral entry, factors related to activation and stage-specific maturation contribute to HIV-1 replication in thymocyte subsets. These results have direct implications for HIV-1 pathogenesis in pediatric patients.