DISCORDANT RESPONSES TO ANTIRETROVIRAL THERAPY
In many cases, decreased apoptosis correlates with decreased viral load (Table 21.2). However, the response to antiretroviral therapy is often discordant, and either a virological response (as measured by decline in viral load) or immunologic response (as determined by an increase in CD4 T lymphocyte) does not occur.143 Clinical outcomes in those cases having an immunologic, but not a virological, response are not significantly different from those individuals with a complete response (both virological and immunologic) during 18 months of follow-up.143 These cases give an ideal opportunity to dissect whether the reduction of apoptosis during HAART is dissociated from control of viral replication or an increase in CD4 T lymphocyte count.
Discordant responses are often seen in series involving PI-based regimens, which could be explained by PI effects independent of control of viral replication.136 The effects of PI monotherapy in the first 8 days of administration include reduced apoptosis, with increases in CD4 and CD8 T lymphocyte counts, but these effects occur in the absence of significant control of viral replication.144 Conversely, in individuals with a good virological but a poor immunologic response, rates of ex vivo apoptosis correlate with CD4 T lymphocyte counts.145 Under similar circumstances, failure of immunologic response is associated with decreased Bcl-2 expression with enhanced rates of spontaneous apoptosis, compared with individuals demonstrating both immunologic and virological responses to HAART.146 Interleukin-2 (IL-2) therapy in this setting both increases Bcl-2 expression and enhances CD4 T lymphocyte recovery.Another insight into discordance is provided by studies looking at the response of HIV-seropositive individuals to glucocorticoids. These agents inhibit apoptosis but have no effect on viral replication, yet they are associated with sustained increases in CD4 T lymphocyte responses.147,148 However, not all studies analyzing discordant responses identified a relationship between immunologic response and apoptosis induction.126 Lecossier and colleagues found no link between spontaneous apoptosis and the degree of immune response.126 In this study, most individuals were receiving ritonavir or indinavir as the PI, along with two unspecified nucleoside analogues. However, PBMCs were cultured without the removal of monocytes, and apoptosis was measured after 48 hours of incubation, which is longer than in many other studies.
Total cell loss was measured by comparing initial and postincubation numbers, and although cells may have been in a late stage of apoptosis, quantification mainly involved Annexin-V binding. Interestingly, although activation-induced apoptosis and Fas-mediated apoptosis were increased, there was no increase in levels of spontaneous apoptosis in the HIV- seropositive group compared with seronegative controls. No differences were noted between any apoptosis parameter, and no correlation was apparent between levels of apoptosis and CD4 or CD8 T lymphocyte count, when comparing individuals not on treatment to those with a poor immunologic response. However, the authors noted a significant relationship between T cell receptor excision circles (TRECs) in CD4+CD45RA+ (naive) T lymphocytes, a marker of thymic output, and CD4 T lymphocyte recovery, but no relationship between TRECs and viral load. The authors argued that this supports a correlation between thymic output and CD4 T lymphocyte recovery, which they speculated might be influenced by levels of viral resistance affecting thymic replicative capacity.
More on the topic DISCORDANT RESPONSES TO ANTIRETROVIRAL THERAPY:
- IMPACT OF ANTIRETROVIRAL THERAPY ON LEVELS OF LYMPHOCYTE APOPTOSIS
- HIV counselling and combination antiretroviral therapy
- MODULATION OF HIV-MEDIATED IMMUNE ACTIVATION, AICD, AND EFFECT OF ANTIRETROVIRAL THERAPY
- Antiretroviral Therapy Today
- Antiretroviral Therapy and Metabolic Disorders
- Natural History of HIV Infection and Evolution of Antiretroviral Therapy
- 26 HIV-1 Reservoirs and Residual Viral Replication during Highly Active Antiretroviral Therapy
- Twenty years after the first antibody test for the human immunodeficiency virus (HIV), highly active antiretroviral therapy (HAART) became available in Western countries.
- Highly active antiretroviral therapy (ART) with protease inhibitors (PIs) and nucleoside analogue inhibitors of viral reverse transcriptase (NRTI) allowed a major reduction in the severity and morbidity of HIV infection; however, these drugs were associated with the occurrence of secondary effects collectively termed “ART-related lipodystrophy or metabolic syndrome.”
- Antiretroviral drugs