The Relative Resistance of HIV Type 1-Infected Chimpanzees to AIDS Correlates with the Maintenance of Follicular Architecture and the Absence of Infiltration by CD8+ Cytotoxic T Lymphocytes

Abstract

Lymphoid tissues are the focus of critical events in HIV pathogenesis. Persistent and high levels of virus production, extensive trapping of virus particles in germinal centers, and progressive degenerative changes in lymph node architecture are characteristics of progressive HIV-1 infection. Infiltrates of granzyme B- and TIA-expressing CD8+ "cytotoxic" T lymphocytes (CTLs) precede involution of germinal centers in humans who develop AIDS. Similar to humans, HIV-1 infection in chimpanzees is active and persistent. However, in contrast to humans, they remain relatively resistant to AIDS. Lymph node biopsies from chimpanzees infected with HIV-1 or a related chimpanzee lentivirus were studied for the level and pattern of virus expression, changes in lymphoid architecture, CD8+ T cell infiltrates and the presence or absence of CTL markers. In stark contrast to HIV-1-infected humans, lymph nodes from infected chimpanzees had little virus deposition in germinal centers and a paucity of virus-expressing cells. Although some of the lymph nodes examined from infected animals had moderate follicular hyperplasia with infiltrating CD8+ T cells, none had evidence of follicular fragmentation. Most importantly, in marked contrast to infected humans, CD8+ T cells infiltrating the germinal center were negative for the CTL marker granzyme B. This evidence suggests that the infiltration of CD8+ CTLs into the germinal centers of lymph nodes may be a key determinant in AIDS pathogenesis.

Simian Immunodeficiency Virus Infection of Chimpanzees

“…Even in captive chimpanzees, only seven naturally infected individuals have been identified (17,24,51,63,64), and among these, only one (Noah) has been subjected to virological and immunological analyses (13,40,41,54,(56)(57)(58). Observational studies of both captive and wildliving apes seem to suggest that SIVcpz-infected chimpanzees do not become noticeably immunodeficient or succumb prematurely to opportunistic infections or neoplasms, although an obvious caveat here is that it is difficult in field studies to distinguish between these and other natural causes of death.…”

“…In this context, it is of interest that chimpanzee and human CD4 and CCR5 molecules differ at several potentially significant amino acid residues (15,85,96). In vivo, SIVcpz establishes a persistent infection and replicates to relatively high titers (10 4 to 10 5 viral RNA copies/ml) (58) but does not seem to be associated with CD4 cell decline or loss of CD4 cell function (40), increased apoptosis of CD4 ϩ T-lymphocytes (29), or extensive trapping of virus particles in germinal centers and degenerative changes in lymph node architecture (41). In this way, SIVcpz seems to resemble other nonpathogenic lentiviral infections, e.g., those of sooty mangabeys and African green monkeys (49,60,70,79), although an obvious caveat of these studies is that the in vivo chimpanzee data are derived from only a single naturally infected individual.…”

Function of CD4+CD3− cells in relation to B- and T-zone stroma in spleen

“…[41][42][43] HIV localizes on FDCs, 44 with which CD4 ϩ CD3 Ϫ cells are directly associated; therefore, they are potentially susceptible to infection. Destruction of CD4 ϩ CD3 Ϫ cells, either by CXCR4-tropic HIV variants or, more likely, by the host CD8 immune response that invades B follicles, 45 predicts the signature of progressive disease: loss of the discrete B follicle structure (follicular fragmentation and lysis), disruption of the FDC network, 46 and loss of the functional capacity to make de novo high-affinity antibody responses. 47 The impairment of the capacity to mount neutralizing antibodies is associated with rising viral titers and loss of T cells from the T zone.…”

Increased Neutralization Sensitivity and Reduced Replicative Capacity of Human Immunodeficiency Virus Type 1 after Short-Term In Vivo or In Vitro Passage through Chimpanzees

“…However, HIV-1 viruses highly adapted to replicate in chimpanzee PBMC through multiple in vivo or repetitious in vitro passages could form syncytia, replicated in macrophages, and induced apoptosis in CD4 ϩ T cells (14,18,47,59). Other proposed mechanisms for long-term survival of chimpanzees are the lack of impaired CD4 ϩ T-cell renewal (24), major histocompatibility complex polymorphisms (2), differences in production of CD8 ϩ T-cell factor (22), and the role of infiltration of CD8 ϩ T cells in lymphoid tissue (29), which all remain to be clarified (25).…”