AUTOLOGOUS CELL-MEDIATED KILLING RESULTS IN IMMUNE SUPPRESSION

Immune Suppression

The degree of apoptosis in lymph nodes obtained from HIV-positive persons is three to four times higher than that observed in the lymph nodes obtained from HIV-negative persons.⁹⁶ A significant correlation is observed between intensity of apoptosis and degree of activation of the lymphoid tissue associated with HIV infection.⁹⁶ In lymph nodes from HIV-positive individuals, in vivo apoptosis is detected predominantly in uninfected bystander cells,¹² arguing for indirect mechanisms of cell destruction, as also indicated by the presence of apoptotic CD8⁺ T cells, B cells, and DCs in the lymphoid organs of HIV-positive individuals.^96,97 The destruction of HIV-specific CD4⁺ T cell precursors might occur in vivo in lymph nodes after HIV binding and ligation of the homing receptor CD62L.^98,99 Large numbers of CD8⁺CD45RO⁺ T cells infiltrate both the paracortex and the germinal centers.

Numerous studies show that apoptosis in lymph nodes, rectal mucosa, and peripheral blood lymphocyte (PBL) subsets from patients infected with HIV decreases dramatically in response to protease inhibitor-based HIV treatment.^103-109 This effect is seen for spontaneous apoptosis, apop­tosis in response to T cell receptor ligation, apoptosis in response to mitogenic stimulation, and apoptosis in response to Fas receptor ligation.^{103,106,108,109} The decrease in apoptosis is rapid and is seen as early as 4 days after protease inhibitor therapy is initiated¹⁰³; it occurs in all patients within 14 days.^106-109 Because the decrease precedes significant changes in viral replication, it has been suggested that protease inhibitors may be antiapoptotic,^110,111 possibly by virtue of inhibiting the activity of effector proteases involved in apoptosis (Figure 15.2).

In animal models, CD4⁺ and CD8⁺ T cells from SIVmac251-infected macaques undergo caspase-dependent death after Fas ligation.¹¹² During the first 2 weeks of infection of rhesus macaques with SIVmac251 isolate, peak numbers of apoptotic cells in the lymph node T cell areas were significantly higher in the future rapid progressors than in the future slow progressors and were correlated with subsequent viremia levels measured 6 months after infection. Thus, extensive apoptosis induction in peripheral lymphoid organs is an early and predictive event that may play a crucial role in impairing the capacity of the immune system to control viral replication and progression toward disease.¹¹³ A recent study using a mouse model showed that chronic immune activation has an important role in T cell immunodeficiency. Transgenic mice that constitutively express CD70, a molecule that is induced by antigen activation of stimulated lymphocytes, develop features that are characteristic of HIV infection—that is, a progressive conversion of naive T cells to effector memory cells, which leads to the depletion of the naive T cell pool and ultimately to death from opportunistic infections.¹¹⁴ Collectively, these observations provide further evidence that chronic immune activation is a principal cause of T cell dysfunction and apoptosis, contributing markedly to AIDS pathogenesis. Lymphocytic choriomeningitis virus (LCMV)-specific T cells in the peripheral tissue (peritoneal cavity, lung, fat pads) react much less with the apoptotic marker annexin-V than those in the spleen and lymph nodes. In comparison to lymphoid tissue, T cells in the periphery express lower levels of Fas and FasL and are resistant to AICD in vitro,¹¹⁵ suggesting a critical role for lymphoid tissues, and potentially APC, in T cell-mediated apoptosis.

Reservoirs

The main obstacle to viral eradication in HIV-infected patients is the presence of chronically infected latent reservoir cells, such as M0, and latently infected CD4⁺ T lymphocytes.^116-119 In these cellular populations, HIV infection is not associated with apoptosis but with a chronic productively infected phenotype. CD4⁺ T cells that contain latent proviral DNA form reservoirs for HIV, as they can survive for a long time with HIV integrated in their genomes.¹²⁰ By infecting M0, HIV can favor the recruitment of T cells, and the viral protein Nef has been shown to be a major player in this scenario. Infection of M0 by HIV-1 bearing a functional Nef gene, or by an adenovirus engineered to express Nef, results in two phenotypic consequences.¹²¹ First, M0 secrete the chemokine MIP-I α and MIP- 1β in response to Nef expression. These chemokines promote the chemotaxis of resting T cells, thus increasing the likelihood that CD4⁺ T cells will encounter HIV virions released from the infected M0 before these are cleared by the reticuloendothelial system. Second, M0 that express Nef or are stimulated through the CD40 receptor release soluble CD23 and soluble intercellular adhesion mol­ecules (ICAM) that render T lymphocytes permissive to HIV-1 infection. Thus, Nef expands the cellular reservoir of HIV-1 by permitting the infection of resting T lymphocytes.¹²² This chemotaxis might not be restricted to CD4⁺ T cells but could also target CD8⁺ T cells, thereby increasing M0- mediated CD8⁺ T cell death and the subsequent immune suppression in HIV-infected subjects. Increased survival of productively infected CD4⁺ T cells has been reported to require intercellular contacts between M0 and HIV-infected T cells expressing the Nef protein.¹²³ Furthermore, it has been suggested that Nef might interact with cellular proteins belonging to the TNF-TNFR and Fas-FasL pathways, thereby blocking the apoptotic process.

Nonapoptotic infected cells may serve as viral reservoirs, and it is unlikely that phenotypic and functional abnormalities of infected cells will be reversed by merely inhibiting apoptosis. Also, latently infected CD4⁺ T cells have a markedly prolonged half-life, which limits the probability that viral reservoirs can be eliminated by interference in viral replication alone.¹²⁷ Recent estimates based on the half-life of latently infected cells suggest that 60 years of viral suppression would be required to eliminate viral reservoirs.¹¹⁷ A possible way to achieve viral eradication is to target infected M0 and latently infected CD4⁺ T cells to undergo apoptosis after infection. It was recently proposed that treatment with a procaspase-3 analogue that contains an HIV protease-specific sequence in its prodomain may cause apoptosis of all infected cells.¹²⁸