Role of Apoptosis Induction in Both Peripheral Lymph Nodes and Thymus in Progressive Loss of CD4+ Cells in SHIV-Infected Macaques

Abstract

To investigate the role of apoptosis in the progressive loss of CD4+ lymphocytes in HIV infection, we have used macaques infected with SHIV, a hybrid virus of HIV and simian immunodeficiency virus (SIV). In the present study, we sequentially analyzed apoptosis induction in the acute phase of SHIV infection. Four macaques infected with a pathogenic SHIV, SHIV89.6P, and four macaques infected with a nonpathogenic SHIV, NM-3rN, were analyzed during the first 2 or 4 weeks postinfection. In the 89.6P-infected macaques the number of peripheral CD4+ cells sharply decreased at 2 weeks postinfection and was maintained below 50/microl until 4 weeks postinfection, while in the NM-3rN-infected macques the number of the CD4+ cells did not change significantly. Plasma viral loads peaked at 2 and 2-3 weeks postinfection, and the peak values were about 1 x 10(9) and 10(6)-10(7) copies/ml in the 89.6P- and the NM-3rN-infected macaques, respectively. In the 89.6P-infected macaques, Fas antigen expression and the extent of apoptosis in PBMCs and peripheral lymph nodes increased at 1-2 weeks postinfection. A high number of apoptotic cells was also observed in thymus sections 2 and 4 weeks postinfection. On the other hand, apoptosis was scarcely induced in the NM-3rN-infected macaques. These results suggest that the extent of apoptosis induction is closely correlated with the pathogenicity of SHIV and that the apoptosis induction in peripheral lymphoid tissues and thymus, where T cell maturation occurs, may play an important role in the depletion of CD4+ lymphocytes in 89.6P infection.

Postnatal Passive Immunization of Neonatal Macaques with a Triple Combination of Human Monoclonal Antibodies against Oral Simian-Human Immunodeficiency Virus Challenge

“…In adult rhesus monkeys, i.v. inoculation of SHIV89.6P led to high initial viral peak RNA loads and to profound, persistent depletion of CD4 ϩ T cells within 2 weeks after virus challenge (4,25,53,59,63). According to most reports (42,53,63), SHIV89.6P infection leads to rapid disease progression and to AIDS in adult macaques, leaving the animals unable to seroconvert or mount any virus-specific CTL responses.…”

Influence of Peak Viral Load on the Extent of CD4+ T-Cell Depletion in Simian HIV Infection

“…The rapid decay rate of CD4 + T cells is supported by experimental observations of the proportion of apoptotic cells during acute infection. 21 At the start of the chronic phase of infection, by day 35, the average predicted proportion of infected cells was only 0.37% (range: 0.003%Y1.7%). This estimate is also consistent …”

Fusion-Induced Apoptosis Contributes to Thymocyte Depletion by a Pathogenic Human Immunodeficiency Virus Type 1 Envelope in the Human Thymus

“…Furthermore, recovery of thymic function after highly active antiretroviral therapy has been correlated with immune recovery (15)(16)(17)36). Thymic sections from HIV-1-infected humans or SIV/SHIV-infected macaques show increased apoptosis, suggesting that HIV-1 can either directly or indirectly hasten thymocyte depletion (28,29,45,47,56). A number of studies addressing mechanisms of CD4 ϩ thymocyte death in the thymus organ have indicated that both direct viral lysis and bystander apoptosis occur during thymocyte depletion (5,6,30,48).…”