MODULATION OF APOPTOSIS IN THE THYMUSES OF INFECTED INDIVIDUALS
Influence of HIV on Thymocyte Apoptosis Rate
Because apoptosis plays such a critical role during thymocyte maturation, it is not surprising that modifications in thymocytes’ apoptosis rates were observed in the presence of HIV at different steps of maturation.
An early study by the group of McCune et al. showed that thymocyte depletion resulted from apoptotic cell death in human thymuses implanted in SCID-hu mice and infected with various HIV strains.65 Experiments performed in FTOC confirmed that in the presence of HIV, thymocyte loss occurred by programmed cell death and resulted in the preferential destruction of CD4+ cells.72 Another study confirmed the rapid CD4+ cell loss after HIV infection of thymic implants in SCID-hu mice, although very low levels of apoptosis were reported in vivo by using either the TdT-mediated dUTP nicked-end labeling (TUNEL) assay or Annexin-V staining.73 Increases in the apoptotic rate and the number of apoptotic cells were observed in the thymus 7 to 14 days after infection of macaques by SIV74 and 14 to 28 days after infection by the chimeric virus SHIV 89.6P.75 Increases in DNA fragmentation and caspase activity were detected in CD4+ thymocytes 14 to 21 days after infection just after peak viremia.76 Therefore, the rate of thymocyte apoptosis is elevated during HIV or SIV infection.Results obtained using different experimental models confirm that HIV or SIV infection causes the apoptosis of several thymocyte subsets (Figure 20.3). During SIV infection, early thymocyte progenitors (CD34+ cells) were shown to undergo apoptosis 7 to 14 days after infection, leading to a decrease in CD34+ cells in SIV-infected thymus at day 21.74 In a case of HIV-1 neonatal infection, a marked depletion of DP and CD4+ SP thymocytes was also demonstrated.77 HIV infection of human thymocytes seems to be directly responsible for the destruction of CD4+ CD-3 ISP thymocytes.65 This subset, which can sustain in vitro a low HIV replication in the presence of TEC, is even more sensitive to HIV-induced apoptosis than DP thymocytes.78 In macaques, SIVmac239 infection first results in a slight and transient decrease in the percentage of DP thymocytes 7 to 14 days after infection. Then, a gradual loss of CD4+ SP cells occurs 21 days after infection.74-76 Recent evidence in humans also suggests that thymocyte apoptosis is the direct consequence of infection in vivo, because patients infected with protease inhibitor-resistant HIV strains that do not replicate in thymocytes have an abundant thymic mass, as shown by CT.32 Overall, these observations indicate that HIV infection is directly responsible for an increase in the apoptotic rate of ISP, DP, and CD4+ SP thymocytes.
Apoptosis in the Thymic Stroma
HIV infection was also associated with the disruption of the thymic microenvironment.79 TEC function is affected in the presence of HIV, although conflicting observations were published regarding their susceptibility to HIV infection. Several studies described HIV replication in TEC cultures in vitro using HΓV1-IΠB and HIVl-NDK but not HIVl-LAI.80-82 Another group reported that TECs were not infected by HIV1/IIIB or HIVl/Ba-L.83 In the SCID-hu mice model, TECs were shown to endocytose large amounts of HIV/JR-CSF, but productive infection of this cell type could not be confirmed.84 However in the same study, uninfected TECs undergoing apoptosis were observed, suggesting that TEC survival is altered in the presence of HIV.
Thymic dendritic cells (DCs) were also shown to be susceptible to HIV infection by macrophagetropic strains85 but not HIV-l/IIIB,86 although DC survival decreased in the presence of HIV1/IIIB in vitro.86 Therefore, survival of thymic epithelial and dendritic cells may be reduced in the presence of HIV.
mechanisms involved in the modulation